EA046110B1 - METHODS FOR TREATING CHRONIC LYMPHOCYTIC LEUKEMIA USING 2-(2,6-DIOXOPIPERIDIN-3-YL)-4-((2-FLUORINE-4-((3-MORPHOLINOAZETIDIN-1-YL)METHYL)BENZYL)AMINO)ISOINDOLINE-1 ,3-DIONE - Google Patents

Description

This application claims benefit to U.S. Provisional Application No. 62/923,955, filed October 21, 2019, and U.S. Provisional Application No. 63/011,147, filed April 16, 2020, each of which is incorporated herein by reference in its entirety.

Field of technology

The invention relates to methods of using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, alone or in combination with obinutuzumab for the treatment, prevention or management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

State of the art

Cancer is characterized primarily by an increase in the number of abnormal cells originating from a given normal tissue, the invasion of these abnormal cells into adjacent tissues, or the spread of malignant cells through the lymphatic or bloodstream to regional lymph nodes and metastasis. Clinical evidence and molecular biology studies suggest that cancer is a multistage process that begins with minor premalignant changes that, under certain conditions, can progress to neoplasia. A neoplastic lesion may develop clonally and become increasingly capable of invasion, growth, metastasis, and heterogeneity, especially in settings where neoplastic cells escape host immune surveillance. Modern cancer therapy may include surgery, chemotherapy, hormonal therapy and/or radiation therapy to destroy neoplastic cells in the patient. Recent advances in cancer therapy are discussed by Rajkumar et al., in Nature Reviews Clinical Oncology 11, 628-630 (2014).

All modern approaches to cancer therapy have significant disadvantages for the patient. Surgery, for example, may be contraindicated due to the patient's health condition or may be unacceptable to the patient. Additionally, surgery may not completely remove neoplastic tissue. Radiation therapy is effective only when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often cause serious side effects. Hormonal therapy is rarely prescribed as monotherapy. Although hormone therapy can be effective, it is often used to prevent or slow cancer recurrence after other treatments have removed most of the cancer cells.

Despite the availability of a variety of chemotherapeutic agents, chemotherapy has many disadvantages. Almost all chemotherapy agents are toxic, and chemotherapy causes significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. In addition, even when combinations of chemotherapeutic agents are administered, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. In fact, cells that are resistant to certain chemotherapeutic agents used in a treatment protocol are often resistant to other drugs, even if these agents act by a mechanism different from that of the drugs used in the specific treatment. This phenomenon is called pleiotropic drug resistance or multidrug resistance. Due to drug resistance, many cancers are or become resistant to standard chemotherapy treatment protocols. Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy characterized by the progressive accumulation of morphologically mature but functionally incompetent B lymphocytes in the blood, bone marrow, and lymphoid tissues with a unique cluster of differentiation (CD) phenotype CD19'. CD5' and CD23'. It is the most common leukemia in North America and Europe, with an incidence of 4.0 cases per 100,000 people per year, affecting primarily older patients with a mean age at onset of 72 years. The clinical course of CLL ranges from indolent disease with long-term survival of more than 12 years to aggressive disease with a median survival of 2 years and depends on the stage at presentation and certain disease-specific characteristics such as cytogenetic abnormalities. The current clinical course and prognosis reflect the evolving therapeutic landscape, including newer agents becoming available for the treatment of CLL. Despite the recent introduction of several highly effective agents, CLL remains an incurable disease for patients who do not undergo allogeneic stem cell transplantation and therefore requires the development of alternative and complementary treatment options.

The molecular pathogenesis of CLL/SLL is a complex, multifaceted process characterized by specific genetic aberrations and representing a convergence of changes in cellular signaling pathways, including the B-cell receptor and apoptotic pathways, and the influence of the tumor immune microenvironment. The term CLL is used when the disease appears predominantly in the blood, whereas the term small lymphocytic lymphoma (SLL) is used when the lesion is predominantly nodular. Specifically, SLL, as defined by the criteria

- 1 046110 International Workshop on Chronic Lymphocytic Leukemia (iwCLL), is a disease in patients who would otherwise be diagnosed with CLL, but which presents with a relatively normal number of peripheral lymphocytes and requires the presence of lymphadenopathy and/or splenomegaly. Unlike CLL, which is more often found in the blood and bone marrow, as well as in other disease sites such as lymph nodes, spleen, and extranodal sites, patients with SLL have less severe manifestations in the peripheral blood.

As evidenced by recent regulatory approvals of several new targeted agents, such as ibrutinib and venetoclax, the treatment landscape for CLL is an evolving one. However, despite the availability of these newer agents, patients continue to relapse or fail to respond to treatment. Moreover, patients with low-risk cytogenetic characteristics continue to have worse outcomes compared with patients without these characteristics. Improved and new combination treatments for CLL will remain an important medical need. In addition, the widespread use of targeted therapies has generated new mutations that have been shown to confer resistance to therapy. For example, resistance to the BTK inhibitor ibrutinib has been associated with mutations in either the BTK binding site or mutations that result in B cell autonomous receptor activity. Thus, exploring agents with novel mechanisms is important to provide treatment options with unique mechanisms of action (MOA) for patients who may develop resistance to new targeted agents.

The citation or identification of any reference in this section of this application should not be construed as an admission that the reference is prior art to this application.

The essence of the invention

The invention relates to methods of using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, alone or in combination with obinutuzumab for the treatment, prevention or control of CLL/SLL.

In certain embodiments, the invention provides a method of treating CLL/SLL, comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1 of Formula:

or a tautomer, isotopologue or pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a method of treating CLL/SLL, comprising administering to a subject in need thereof a therapeutically effective amount of compound 2 of formula:

or a tautomer, isotopologue or pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a method of treating CLL/SLL, comprising administering to a subject in need thereof a therapeutically effective amount of compound 3 of formula:

- 2 046110 or its enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt.

In certain embodiments, the invention provides a compound for use in a method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), wherein the compound is Compound 3 of formula:

or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound.

In certain embodiments, the invention provides a compound for use in a method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), wherein the compound is Compound 1 of formula:

or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound.

In certain embodiments, the invention provides a compound for use in a method of treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), wherein the compound is Compound 2 of formula:

or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound.

In certain embodiments of the invention, the CLL/SLL is relapsed or refractory CLL/SLL.

In certain embodiments, the methods provided herein further comprise administering to a subject a therapeutically effective amount of obinutuzumab.

The present embodiments of the invention may be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments of the invention.

Brief description of drawings

The figure illustrates a heat map of the normalized percentage of tumor cells after treatment with Compound 1 in combination with obinutuzumab.

Detailed description

Definitions

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. To the extent that there are multiple definitions for a term in this document, those given in this section will prevail unless otherwise noted.

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As used herein and in the specification and appended claims, the singular forms “a” and “a” include both multiple and single references unless the context clearly indicates otherwise.

As used herein, the terms containing and including may be used interchangeably. The terms containing and including should be interpreted as indicating the presence of specified features or components as specified, but not excluding the presence or addition of one or more features or components, or groups thereof. Additionally, the terms containing and including are intended to include examples covered by the term consisting of. Therefore, the term consisting of may be used in place of the terms containing and including to provide more specific embodiments of the invention.

The term consisting of means that an item has at least 90%, 95%, 97%, 98%, or 99% of the stated characteristics or components of which it is composed. In another embodiment of the invention, the term consisting of excludes from the scope of any subsequent listing any other features or components, except those that are not essential to achieve the technical effect.

As used herein, the term or should be interpreted to include or to mean any one or any combination. Therefore, A, B or C means any of the following: A; IN; WITH; A and B; A and C; B and C; A, B, and C. An exception to this definition will occur only when the combination of elements, functions, steps, or activities is somehow inherently mutually exclusive.

As used herein, the term pharmaceutically acceptable salt(s) refers to a salt derived from a pharmaceutically acceptable non-toxic acid or base, including inorganic acid and base and organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compound provided herein include, but are not limited to, metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts derived from lysine, N. N'-dibenzylethylenediamine. chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furanic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic , hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid and p-toluenesulfonic acid. Others are well known in the art, see, for example, Remington's Pharmaceutical Sciences, ^18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, ^19th eds., Mack Publishing, Easton PA (1995).

As used herein and unless otherwise indicated, the term stereoisomer or stereoisomerically pure means one stereoisomer of a compound that contains substantially no other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers contains virtually no other diastereomers of the compound. A typical stereoisomerically pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, more greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. Compounds may have chiral centers and may occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included in the embodiments of the invention presented herein, including mixtures thereof.

The use of stereoisomerically pure forms of such compounds, as well as the use of mixtures of these forms, is covered by the embodiments of the invention presented herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions provided herein. These isomers can be asymmetrically synthesized or separated using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Ap

- 4 046110 proach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may have either the (R) or (S) configuration or may be a mixture thereof. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one skilled in the art will appreciate that administering the compound in its B) form for compounds that undergo epimerization in vivo is equivalent to administering the compound in its (b) form.

Optically active (+) and (-), (R) and (S) or (D) and (L) isomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques such as nachiral stationary phase chromatography.

Tautomers refer to isomeric forms of a compound that are in equilibrium with each other. Concentrations of isomeric forms will depend on the environment in which the compound is found and may vary depending, for example, on whether the compound is a solid or in organic or aqueous solution. For example, in aqueous solution, pyrazoles can have the following isomeric forms, which are called tautomers of each other:

As one skilled in the art will readily appreciate, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of a compound are included within the scope of the compound as presented herein.

It should also be noted that the compound provided herein may contain non-naturally occurring proportions of atomic isotopes at one or more atoms. For example, compounds may be radiolabeled with radioactive isotopes such as, for example, tritium ( ^3H ), iodine-125 ( ^125I ), sulfur-35 ( ^35S ), or carbon-14 ( ^14C ), or may be enriched with isotopes , such as deuterium ( ^2H ), carbon-13 ( ^13C ) or nitrogen-15 ( ^15N ). As used herein, the term isotopologue is an isotopically enriched compound. The term isotopically enriched refers to an atom having an isotopic composition different from that atom's natural isotopic composition. Isotopically enriched may also refer to a compound containing at least one atom having an isotopic composition different from that atom's natural isotopic composition. The term isotopic composition refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents, eg, anticancer therapeutic agents, research reagents, eg, binding assay reagents, and diagnostic agents, eg, in vivo imaging agents. All isotopic variations of a compound, whether radioactive or not, are assumed to be within the scope of the compound presented herein. In some embodiments, isotopologues of compounds are provided herein, for example, the isotopologues are compounds enriched in deuterium, carbon-13 ( ¹³ C) and/or nitrogen-15 ( ¹⁵ N). As used herein, the term deuterated means a compound in which at least one hydrogen (H) is replaced by deuterium (denoted D or ^2H ), that is, the compound is enriched in deuterium at at least one position.

It is understood that, regardless of stereoisomeric or isotopic composition, each compound provided herein may be provided in the form of any of the pharmaceutically acceptable salts provided herein. It is equally understood that the isotopic composition may vary regardless of the stereoisomeric composition of each compound presented herein. In addition, the isotopic composition, limited to those elements present in the corresponding compound or salt thereof, may otherwise vary regardless of the choice of pharmaceutically acceptable salt of the corresponding compound.

It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure should be given greater weight.

As used herein and unless otherwise specified, the term treatment means the alleviation, total or partial, of a disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition, or the slowing or stopping of further progression or worsening of those symptoms, or alleviating or eliminating the cause(s) of the disorder, disease, or condition itself.

As used herein and unless otherwise specified, the term prevention means a method of delaying and/or suppressing the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; protecting the subject from a disorder, disease or condition; or reducing the subject's risk of developing a disorder, disease or condition. As used herein and unless otherwise specified, the term flow control includes

- 5 046110 preventing the relapse of a particular disease or disorder in a patient who has suffered from it, prolonging the period of remission of a patient who has suffered from a disease or disorder, reducing the mortality rates of patients and/or maintaining a reduction in the severity or prevention of a symptom associated with a disease or condition that are being treated. As used herein and unless otherwise specified, the term effective amount in connection with a compound means an amount capable of treating, preventing or controlling a disorder, disease or condition or the symptoms thereof.

As used herein and unless otherwise specified, the term subject or patient includes an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, a rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. As used herein and unless otherwise noted, the term relapse refers to a disorder, disease, or condition that responded to treatment (eg, achieved a complete response) and then progressed. Treatment may include one or more lines of therapy. In one embodiment of the invention, the disorder, disease or condition has previously been treated with one or more lines of therapy. In another embodiment of the invention, the disorder, disease or condition has previously been treated with one, two, three or four lines of therapy. As used herein and unless otherwise noted, the term refractory refers to a disorder, disease or condition that has not responded to prior treatment, which may include one or more lines of therapy. In one embodiment of the invention, the disorder, disease or condition has previously been treated with one, two, three or four lines of therapy. In one embodiment of the invention, the disorder, disease or condition has been previously treated with two or more lines of treatment and has less than a complete response (CR) to the most recent systemic therapy containing the regimen.

In one embodiment, the term relapsed or refractory CLL/SLL may refer to CLL/SLL that has previously been treated with one or more lines of therapy. In one embodiment of the invention, relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with one, two, three or four lines of therapy. In one embodiment of the invention, relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with two or more lines of therapy. In one embodiment, the relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with a B cell receptor signaling inhibitor. In one embodiment of the invention, the relapsed or refractory CLL/SLL is relapsed or refractory to an inhibitor of B cell receptor signaling. In one embodiment, the relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with a Bruton's tyrosine kinase inhibitor (BTK). In one embodiment of the invention, the relapsed or refractory CLL/SLL is relapsed or refractory to a BTK inhibitor. In one embodiment of the invention, the BTK inhibitor is ibrutinib. In one embodiment of the invention, the BTK inhibitor is acalabrutinib. In one embodiment of the invention, the BTK inhibitor is zanubrutinib. In one embodiment of the invention, the BTK inhibitor is tirabrutinib. In one embodiment, the relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with a phosphoinositide 3-kinase (PI3K) inhibitor. In one embodiment of the invention, the relapsed or refractory CLL/SLL is relapsed or refractory to a PI3K inhibitor. In one embodiment of the invention, the PI3K inhibitor is duvelisib. In one embodiment of the invention, the PI3K inhibitor is idelalisib. In one embodiment of the invention, the relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with venetoclax. In one embodiment of the invention, the relapsed or refractory CLL/SLL is relapsed or refractory to venetoclax. In one embodiment, the relapsed or refractory CLL/SLL is CLL/SLL that was previously treated with obinutuzumab. In one embodiment of the invention, the relapsed or refractory CLL/SLL is relapsed or refractory to obinutuzumab.

In the context of cancer, inhibition can be assessed by inhibiting disease progression, inhibiting tumor growth, shrinking the primary tumor, alleviating tumor-associated symptoms, inhibiting tumor-secreted factors, delaying the occurrence of primary or secondary tumors, delaying the development of primary or secondary tumors, reducing the occurrence of primary or secondary tumors. secondary tumors, slowing or reducing the severity of secondary effects of the disease, stopping tumor growth and regression of tumors, increasing time to progression (TTP), increasing Progression Free Survival (PFS), increasing Overall Survival (OS), among others. OS, as used herein, refers to the time from the start of treatment to death from any cause. As used herein, TTP refers to the time from initiation of treatment to tumor progression; TTP does not include deaths. In one embodiment of the invention

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PFS refers to the time from the start of treatment to tumor progression or death. In one embodiment of the invention, PFS means the time from the first dose of a compound to the first occurrence of disease progression or death from any cause. In one embodiment of the invention, PFS scores are calculated using Kaplan-Meier estimates. Event-free survival (EFS) refers to the time from the start of treatment to any treatment failure, including disease progression, discontinuation of treatment for any reason, or death. In one embodiment of the invention, the overall response rate (ORR) means the percentage of patients who achieve a response. In one embodiment of the invention, ORR means the sum of the percentage of patients achieving complete and partial responses. In one embodiment of the invention, ORR means the percentage of patients whose best response > partial response (PR). In one embodiment of the invention, duration of response (DoR) is the time from achievement of response to relapse or disease progression. In one embodiment of the invention, DoR is the time from achieving response > partial response (PR) to disease relapse or progression. In one embodiment of the invention, DoR is the time from the first detection of response to the first recording of disease progression or death. In one embodiment of the invention, DoR is the time from the first detection of response > partial response (PR) to the first detection of progressive disease or death. In one embodiment of the invention, time to response (TTR) means the time from the first dose of a compound to the first confirmation of a response. In one embodiment of the invention, TTR means the time from the first dose of a compound to the first confirmation of response > partial response (PR). As a last resort, complete inhibition is referred to herein as prevention or chemoprevention. In this context, the term prevention includes either preventing the occurrence of clinically obvious cancer in general or preventing the occurrence of a preclinically obvious stage of cancer. This definition is also intended to include preventing transformation into malignant cells or stopping or reversing the progression of precancerous cells to malignant cells. This includes preventive treatment for individuals at risk of developing cancer.

In one embodiment, response to treatment for CLL/SLL can be assessed using the International Workshop on Chronic Lymphocytic Leukemia criteria (see Hallek, M, et al., iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL Blood, 131(25), 2745-2760 (2018)) (Table 1). In one embodiment of the invention, response to treatment for CLL/SLL can be assessed using the International Lymphoma Workshop Response Criteria (see Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al., Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068) (Table 1a).

Table 1

Determining response after treatment in patients with chronic lymphocytic leukemia

Group Parameter CR PR P.D. SD A The lymph nodes No > 1.5 cm Reduction > 50% (from baseline) ³ Increase >50% from baseline or response Change from -49% to +49% Liver and/or spleen size ¹³ Spleen size, < 13 cm; liver size is normal Reduction > 50% (from baseline) Increase >50% from baseline or response Change from -49% to +49% Constitutional symptoms No Any Any Any

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The number of circulating lymphocytes in Normal Reduction >50% from baseline Increase > 50% above base lines Change from -49% to +49% IN Number of platelets in > 100 X 10 ⁹ /l > 100 X 10 ⁹ /l or increase > 50% above baseline Reduction >50% from baseline secondary to CLL Change from -49% to +49% Hemoglobin > 11.0 g/dL (without transfusion and without erythropoiesis on) > 11.0 g/dl or increase > 50% above base lines Decrease > 2 g/dL from baseline, secondary to CLL Increase .11.0 g/dL or <50% above the basic lines or decrease < 2 g/dl Bone brain Normocellular, without CLL cells, without B- lymph nodes Presence of CLL or B- cells lymph nodes or failure >50% increase in CLL cell counts on consecutive biopsies No change in bone marrow infiltrate

CR=complete remission (all criteria must be achieved); PD=progressive disease (at least 1 criterion of group A or group B must be met); PR=partial remission (for PR, at least 2 parameters of group A and 1 parameter of group B must be improved if there were previous abnormalities; if only 1 parameter of both groups A and B is abnormal before therapy, only 1 parameter needs to be improved) ; SD=stable disease (all criteria must be met; constitutional symptoms alone do not define PD).

a Sum of products of 6 or fewer lymph nodes (as assessed by computed tomography and physical examination in clinical trials or physical examination in general practice).

^b Spleen size is considered normal if <13 cm. There is no well-established international consensus on normal liver size; Therefore, liver size should be assessed by imaging and manual palpation in clinical studies and recorded according to the definition used in the study protocol.

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Table 1a

Summary indicators of the revised criteria for assessing the response

Categories I Answer Based on RET-ST Answer ST Based Answer CR Complete Metabolic Response 5PS Score of 1, 2, or 3 with or without residual mass Complete metabolic response, even with a persistent mass, is considered complete remission Target nodules/nodular masses should regress to <1.5 cm in greatest diameter. Absence of extralymphatic foci of disease PR Partial metabolic response Score 4 or 5 with reduced absorption compared to baseline and residual masses of any size All of the following: >50% reduction in SPD up to 6 targeted measurable lymph nodes and extranodal sites The length of the spleen should regress by more than 50% compared to normal SD No metabolic response Score 4 or 5 without significant change in FDG uptake by compared to baseline <50% reduction from SPD baseline up to 6 treatable dominants measuring lymph nodes and extranodal sites PD criteria not met P.D. Progressive metabolic disease Score 4 or 5 with increasing intensity of uptake compared to baseline and/or New lesions sensitive to FDG correspond to lymphoma Bone marrow: New or recurrent lesions, sensitive to FDG. At least 1 of the following: Single node/lesion must be abnormal with: Greatest diameter > 1.5 cm and > 50% increase from nadir and Increase in greatest diameter or smallest diameter from nadir In the setting of splenomegaly, the length of the spleen should increase by more than 50% of the extent of its previous increase compared to the baseline New or recurrent splenomegaly New or clear progression earlier existing unmeasured lesions Re-growth earlier allowed lesions Bone marrow: New or recurrent lesion

Abbreviations: 5PS: 5-point scale; CR=complete response; CT=computed tomography;

FDG=fluorodeoxyglucose; 1ΨΤ positron emission tomography; PR=partial response;

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PD=progressive disease; SD=stable disease; SPD=cyMMa of perpendicular product diameters for multiple lesions.

In one embodiment of the invention, response to treatment for CLL/SLL can be assessed by Eastern Cooperative Oncology Group (ECOG) performance status (Table 2).

table 2

ECOG General Condition Score

Degree ECOG 0 Fully active, able to perform all activities as before the disease without limitation. 1 Limited in physical activity, but ambulatory and able to perform light or sedentary work, eg light housework, office work. 2 Ambulatory and capable of self-care, but unable to perform any work. Up to and beyond about 50% of waking hours. 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 Completely disabled. Can't study self-service. Completely confined to a bed or chair. 5 Death.

ECOG=Eastern Cooperative Oncology Group, Robert Komis, MD, Group Chairman.

Source: Oken M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655 (1982).

In certain embodiments of the invention, stable disease or the absence thereof can be determined by methods known in the art, such as assessment of the patient's symptoms, physical examination, imaging of the tumor, which has been imaged, for example, using FDG-PET (fluorodeoxyglucose positron emission tomography). ), PET/CT (positron emission tomography/computed tomography), MRI (magnetic resonance imaging) of the brain and spine, CSF (cerebrospinal fluid), ophthalmological examination, vitreal fluid sampling, retinal photography, bone marrow assessment and other conventional assessment methods.

As used herein and unless otherwise specified, the terms co-administration and in combination with include the administration of one or more therapeutic agents (eg, a compound provided herein and another anti-CLL/SLL agent or maintenance therapy agent) or together, simultaneously or sequentially without any specific time restrictions. In one embodiment of the invention, the agents are present in the cell or body of the patient at the same time or exhibit their biological or therapeutic effect at the same time. In one embodiment of the invention, the therapeutic agents are in the same composition or unit dosage form. In another embodiment of the invention, the therapeutic agents are in separate compositions or unit dosage forms.

The term maintenance agent refers to any substance that treats, prevents, or controls an adverse effect from treatment with another therapeutic agent.

As used herein and unless otherwise indicated, the terms about and approximately, when used in connection with doses, amounts, or weight percentages of the ingredients of a composition or dosage form, mean the dose, amount, or weight percent that is recognized by one skilled in the art to provide a pharmacological effect equivalent to that obtained from a specified dose, amount or percentage by weight. In one embodiment of the invention, the terms about and about when used in this context suggest a dose, amount, or percentage by weight within 30%, within 20%, within 15%, within 10%, or within 5% of the stated dose, amount or mass percent.

Connections

For use in the methods presented herein, a connection is provided

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^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoin dolin-1,3- dione, designated as compound 1:

or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. The invention relates to compound 1 for use in the methods of treatment presented herein.

Also provided for use in the methods presented herein is the compound ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl) methyl)benzyl)ami no)isoindoline-1,3-dione, designated as compound 2:

or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. The invention relates to compound 2 for use in the methods of treatment presented herein.

For use in the methods presented herein, the compound 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl) is provided. amino)isoindo lin-1,3-dione, designated as compound 3:

or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. The invention relates to compound 3 for use in the methods of treatment presented in this document.

In one embodiment of the invention, Compound 1 is used in the methods presented herein. In one embodiment of the invention, the tautomer of compound 1 is used in the methods presented herein. In one embodiment of the invention, the isotopologue of compound 1 is used in the methods presented herein. In one embodiment of the invention, a pharmaceutically acceptable salt of Compound 1 is used in the methods presented herein.

In one embodiment of the invention, compound 2 is used in the methods presented herein. In one embodiment of the invention, the tautomer of compound 2 is used in the methods presented herein. In one embodiment of the invention, the isotopologue of compound 2 is used in the methods presented herein. In one embodiment of the invention, a pharmaceutically acceptable salt of Compound 2 is used in the methods presented herein.

In one embodiment of the invention, compound 3 is used in the methods presented herein. In one embodiment of the invention, the enantiomer of compound 3 is used in the methods presented herein. In one embodiment of the invention, a mixture of enantiomers of compound 3 is used in the methods presented herein. In one embodiment of the invention, the tautomer of compound 3 is used in the methods presented herein. In one embodiment of the invention, the isotopologue of compound 3 is used in the methods presented herein. In one embodiment of the invention, a pharmaceutically acceptable salt of compound 3 is used in the methods presented herein.

- 11 046110

Methods of treatment and prevention

In one embodiment, the invention relates to methods of using 2-(2,6dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1 ,3dione or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, alone or in combination with obinutuzumab for the treatment, prevention or management of CLL/SLL.

As used herein and unless otherwise indicated, CLL/SLL or CLL and/or SLL means CLL or SLL or CLL and SLL. In one embodiment of the invention, the methods presented herein are intended to treat, prevent, or manage CLL. In one embodiment of the invention, the methods presented herein are intended to treat, prevent, or manage SLL. In one embodiment of the invention, the methods presented herein are intended to treat, prevent, or manage CLL and CLL.

In one embodiment, the invention provides a method of treating CLL/SLL, comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1 of Formula:

or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a method of treating CLL/SLL, comprising administering to a subject in need thereof a therapeutically effective amount of compound 2 of formula:

2, or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a method of treating CLL/SLL, comprising administering to a subject in need thereof a therapeutically effective amount of compound 3 of formula:

or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method for preventing CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 1 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method for preventing CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of preventing CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method of managing CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of Compound 1 or a tautomer, isotopologue, or pharmaceutically acceptable compound thereof.

- 12 046110 salt. In one embodiment, provided herein is a method of managing CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of managing CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof.

In one embodiment of the invention, a subject with CLL/SLL has failed one or more lines of therapy. In one embodiment of the invention, the subject has failed to complete at least one previous therapy. In one embodiment of the invention, the subject has failed to complete at least two prior therapies. In one embodiment of the invention, the subject has previously been treated with an inhibitor of B cell receptor signaling. In one embodiment, the subject has relapsed or is refractory to a B cell receptor signaling inhibitor. In one embodiment of the invention, the subject has previously been treated with a Bruton's tyrosine kinase inhibitor (BTK). In one embodiment of the invention, the subject has relapsed or is refractory to a BTK inhibitor. In one embodiment of the invention, the BTK inhibitor is ibrutinib. In one embodiment of the invention, the BTK inhibitor is acalabrutinib. In one embodiment of the invention, the BTK inhibitor is zanubrutinib. In one embodiment of the invention, the BTK inhibitor is tirabrutinib. In one embodiment of the invention, the subject has previously been treated with a phosphoinositide 3 kinase (PI3K) inhibitor. In one embodiment of the invention, the subject has relapsed or is refractory to a PI3K inhibitor. In one embodiment of the invention, the PI3K inhibitor is duvelisib. In one embodiment of the invention, the PI3K inhibitor is idelalisib. In one embodiment of the invention, the subject has previously been treated with venetoclax. In one embodiment of the invention, the subject has relapsed or is refractory to venetoclax. In one embodiment of the invention, the subject has previously been treated with obinutuzumab. In one embodiment of the invention, the subject has relapsed or is refractory to obinutuzumab.

In one embodiment of the invention, the CLL/SLL is newly diagnosed CLL/SLL. In one embodiment of the invention, the CLL/SLL is relapsed or refractory CLL/SLL (R/R CLL/SLL).

In one embodiment of the invention, CLL is characterized by an IGHV (Immunoglobulin Heavy Chain Gene) mutation. In one embodiment of the invention, CLL is characterized by unmutated IGHV.

In one embodiment of the invention, CLL is characterized by one or more mutations in TP53 (Tumor Protein 53). In one embodiment of the invention, CLL is characterized by wild-type TP53.

In one embodiment, CLL is characterized by one or more cytogenetic abnormalities, e.g. del(13q), del(11q), del(17p), tri12, t(6;17), del(11q22.3), t(11 ;14), del(18q) and t(14;19). In one embodiment of the invention, CLL is characterized by del(17p).

In one embodiment of the invention, CLL is characterized by Richter Transformation (also known as Richter Syndrome).

In one embodiment, the methods provided herein further comprise administering to a subject a therapeutically effective amount of obinutuzumab.

In one embodiment of the invention, the first therapy (e.g., an agent such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) provided herein is administered before (e.g. , in 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) administration of a second therapy (eg, obinutuzumab) to the subject.

In one embodiment of the invention, the first therapy (e.g., an agent such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) provided herein is administered concurrently with the administration of the second therapy (eg, obinutuzumab) to the subject.

In one embodiment of the invention, the first therapy (e.g., an agent such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt) provided herein is administered following (via , e.g. 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) by administering a second therapy (eg, obinutuzumab) to the subject.

In one embodiment of the invention, a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered at a dose of about 0.1 mg to about 1 mg. .6 mg per day. IN

- 13 046110 In one embodiment of the invention, the compound is administered at a dose of about 0.1 mg to about 1.2 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.1 mg to about 0.8 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.1 mg to about 0.6 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.1 mg to about 0.4 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.1 mg to about 0.2 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.2 mg to about 1.6 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.2 mg to about 1.2 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.2 mg to about 0.8 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.2 mg to about 0.6 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.2 mg to about 0.4 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.4 mg to about 1.6 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.4 mg to about 1.2 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.4 mg to about 0.8 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.4 mg to about 0.6 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.6 mg to about 1.6 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.6 mg to about 1.2 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.6 mg to about 0.8 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.8 mg to about 1.6 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 0.8 mg to about 1.2 mg per day. In one embodiment of the invention, the compound is administered at a dose of about 1.2 mg to about 1.6 mg per day.

In certain embodiments of the invention, a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered at a dose of about 0.1 mg, about 0. 2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg or about 1.6 mg per day. In certain embodiments of the invention, the compound is administered at a dose of about 0.1 mg per day. In certain embodiments of the invention, the compound is administered at a dose of about 0.2 mg per day. In certain embodiments of the invention, the compound is administered at a dose of about 0.4 mg per day. In certain embodiments of the invention, the compound is administered at a dose of about 0.6 mg per day. In certain embodiments of the invention, the compound is administered at a dose of about 0.8 mg per day. In certain embodiments of the invention, the compound is administered at a dose of about 1.2 mg per day. In certain embodiments of the invention, the compound is administered at a dose of about 1.6 mg per day.

In one embodiment, obinutuzumab is administered in accordance with a locally approved label or pharmaceutical guide containing information regarding preparation, administration and storage. In one embodiment of the invention, obinutuzumab is administered intravenously. In one embodiment of the invention, obinutuzumab is administered subcutaneously. In one embodiment of the invention, obinutuzumab is administered by intravenous (IV) injection or IV infusion. In one embodiment of the invention, obinutuzumab is administered by intravenous injection. In one embodiment of the invention, obinutuzumab is administered by intravenous infusion.

In one embodiment of the invention, obinutuzumab is administered in an amount determined by the physician. In one embodiment of the invention, obinutuzumab is administered daily. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 1100 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 125 mg per day, about 800 mg to about 1000 mg per day, or about 900 mg to about 1100 mg per day. In one embodiment of the invention, obinutuzumab is administered at a dose of about 100 mg per day. In one embodiment of the invention, obinutuzumab is administered at a dose of about 900 mg per day. In one embodiment of the invention, obinutuzumab is administered at a dose of about 1000 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 100 mg on day 1 of the first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg on each of days 8 and 15 of the first 28-day cycle and on day 1 from the second to the sixth 28-day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg combined on days 1 and 2 of the first 28-day cycle, and about 1000 mg on each of days 8 and 15 of the first 28-day cycle and on day 1 of the second to sixth 28 -day cycle. Obinutuzumab can be administered for longer than six cycles. In one embodiment, obinutuzumab is administered in the first 28-day cycle, as described herein, and is administered at a dose of about 1000 mg on day 1 from the second to 12th 28-day cycle. In one embodiment, obinutuzumab is administered in the first 28-day cycle as described herein, and is administered at a dose of about 1000 mg on day 1 from the second to the 24th of the 28-day cycle. In one embodiment, obinutuzumab is administered during the first 28-day cycle as described herein, and is administered at a dose of about 1000 mg on day 1 of subsequent 28-day cycles until disease progression. In one embodiment, provided herein is a method of treating newly diagnosed CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 1 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one

- 14 046110 In this embodiment, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, provided herein is a method of treating newly diagnosed CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, provided herein is a method of treating newly diagnosed CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, provided herein is a method of preventing newly diagnosed CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer thereof , a mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In another embodiment, provided herein is a method of managing newly diagnosed CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, provided herein is a method of treating relapsed or refractory CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 1 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab. In one embodiment, provided herein is a method of treating relapsed or refractory CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab. In one embodiment, provided herein is a method of treating relapsed or refractory CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, provided herein is a method for preventing relapsed or refractory CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In another embodiment, provided herein is a method of managing relapsed or refractory CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., Compound 1, Compound 2, or Compound 3, or its enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt. In one embodiment of the invention, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

In another embodiment, provided herein are methods of achieving a complete response, partial response, or stable disease, as defined by the criteria of the International Workshop on Chronic Lymphocytic Leukemia, in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g., Compound 1 , compound 2 or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, to a patient with CLL/SLL. In one embodiment

- 15046110 of the invention, detection of minimal residual disease (MRD) can be performed in subjects undergoing bone marrow assessment to confirm a complete response (CR). In one embodiment, provided herein are methods of achieving minimal residual disease (MRD) negativity in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture of enantiomers , tautomer, isotopologue, or pharmaceutically acceptable salt, to a patient with CLL/SLL. In one embodiment of the invention, MRD negativity is measured in peripheral blood and/or bone marrow. In one embodiment of the invention, MRD negativity persists for a minimum of 3 months. In another embodiment of the invention, methods are provided herein for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression or disease-free survival in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g. compound 1, compound 2 or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, to a patient with CLL/SLL. In another embodiment, provided herein are methods of achieving increased overall survival in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue thereof or a pharmaceutically acceptable salt, to a patient with CLL/SLL. In another embodiment, provided herein are methods of achieving increased progression-free survival in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer , isotopologue or pharmaceutically acceptable salt, to a patient with CLL/SLL. In another embodiment, provided herein are methods of achieving increased event-free survival in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, isotopologue or pharmaceutically acceptable salt to a patient with CLL/SLL. In another embodiment, provided herein are methods of achieving an increase in time to progression in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, isotopologue or pharmaceutically acceptable salt to a patient with CLL/SLL. In another embodiment, provided herein are methods of achieving increased disease-free survival in a patient, comprising administering a therapeutically effective amount of a compound described herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, isotopologue or pharmaceutically acceptable salt to a patient with CLL/SLL. In one embodiment of the invention, the methods further comprise administering to the subject a therapeutically effective amount of obinutuzumab.

The methods presented herein cover treatment of a patient regardless of the age of the patient. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments of the invention, the subject is under 65 years of age. In other embodiments of the invention, the subject is over 65 years of age.

Pharmaceutical compositions and routes of administration

The compound provided herein can be administered to a subject orally, topically or parenterally in conventional formulation forms such as capsules, microcapsules, tablets, granules, powder, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments , gels, sprays, solutions and emulsions. Suitable formulations can be prepared by methods commonly used using conventional organic or inorganic additives such as a diluent (eg sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binder (eg ., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), raising agent (e.g. starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricant (e.g. ., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavor (e.g. citric acid, menthol, glycine or orange powder), preservative (e.g. sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizer ( e.g. citric acid, sodium citrate or acetic acid), suspending agent (e.g. methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersing agent (e.g. hydroxypropyl methylcellulose), water and base wax (e.g. cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compounds in the pharmaceutical composition may be at a level that provides the desired effect when administered either orally or parenterally.

- 16 046110

The compound provided herein can be administered orally. In one embodiment of the invention, when administered orally, a compound of the present invention is administered with food and water. In another embodiment of the invention, a compound provided herein is dispersed in water or juice (eg, apple juice or orange juice) and administered orally as a solution or suspension.

The compound of the invention can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, transmucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The route of administration is at the discretion of the practitioner and may depend in part on the location of the medical condition.

In one embodiment, the invention provides capsules containing a compound provided herein without additional excipient. In another embodiment, the invention provides compositions containing an effective amount of a compound provided herein and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient may include a diluent, binder, disintegrant, glidant, lubricant, or a mixture thereof. In one embodiment of the invention, the composition is a pharmaceutical composition.

The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions and the like. The compositions may be formulated to contain a daily dose or a convenient portion of a daily dose in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment of the invention, solutions are prepared from water-soluble salts. Typically, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules can be prepared by mixing the compound provided herein with a suitable excipient and filling the capsules with the appropriate amount of the mixture. Common excipients include, but are not limited to, inert powders such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flour and similar food powders. Capsule filling can also be prepared by wet granulation or dry granulation.

The capsules may require a lubricant to prevent the powder from sticking to the post. The lubricant may be selected from such lubricant solids as talc, magnesium calcium stearate, sodium stearyl fumarate, stearic acid and hydrogenated vegetable oils. Disintegrants are substances that swell when wet, thereby breaking the capsule's shape and releasing the compound. These include starches, clays, celluloses, crospovidone, croscarmellose sodium, sodium starch glycolate, algins and gums. In particular, you can use, for example, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, as well as sodium lauryl sulfate. Glidants may also be used, including silica, talc and calcium silicate.

Tablets can be prepared by direct compression, wet granulation or dry granulation. Their formulations typically include diluents, binders, lubricants and disintegrants, as well as a compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also suitable. Typical tablet binders are starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also suitable, including gum acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant may be necessary in the tablet formulation to prevent the tablet and punches from sticking to the die. The lubricant may be selected from such lubricant solids as talc, magnesium calcium stearate, sodium stearyl fumarate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, breaking the tablet and releasing a compound. These include starches, clays, celluloses, crospovidone, croscarmellose sodium, sodium starch glycolate, algins and gums. In particular, you can use, for example, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, as well as sodium lauryl sulfate. Glidants may also be used, including silica, talc and calcium silicate. Tablets may be coated with sugar as a flavoring and sealant or with film-forming protective agents to modify the dissolution properties of the tablet. Songs can also

- 17 046110 be prepared in the form of chewable tablets, for example, using substances such as mannitol.

When it is desired to administer a compound provided herein in the form of a suppository, conventional bases can be used. Cocoa butter is a traditional suppository base that can be modified by adding waxes to slightly increase its melting point. Water-miscible suppository bases are widely used, including, in particular, polyethylene glycols of various molecular weights.

The effect of the compound presented herein can be delayed or prolonged through proper formulation. For example, a slowly dissolving pellet of a compound of the present invention may be prepared and included in a tablet or capsule or as a sustained release implantable device. This technique also involves making pellets with several different dissolution rates and filling capsules with a mixture of pellets. Tablets or capsules may be coated with a film to prevent dissolution for a predictable period of time. Even preparations for parenteral administration can be made prolonged by dissolving or suspending the compound presented herein in oily or emulsified vehicles that allow it to be slowly dispersed in serum.

Depending on the stage of the disease being treated and the condition of the subject, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, can be administered orally, parenterally (eg, intramuscularly). , intraperitoneal, intravenous, IV, intracystic injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual or topical (eg, transdermal or topical) routes of administration. Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, may be formulated alone or together in a suitable dosage form with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, suitable for each route of administration.

In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered orally. In another embodiment, Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered parenterally. In yet another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered intravenously.

Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, may be delivered in unit dosage form, such as, for example, a single bolus injection or oral capsules, tablets or pills; or over time, eg by continuous infusion over time or divided bolus doses over time. The compounds described herein can be re-administered as needed, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease progression or unacceptable toxicity.

Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, can be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times a day (TID) and four times a day (QID). In addition, administration may be continuous (ie, daily for consecutive days or every day), intermittent, eg, in cycles (ie, including days, weeks or months of rest without drug). As used herein, the term daily means that a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered one or more times per day, for example, for a certain period of time. The term continuous means that a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered daily for a continuous period of at least 7 days up to 52 weeks. The term intermittent or intermittent as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is one to six days per week, administered in cycles (e.g., daily administration for two to eight consecutive weeks, followed by a rest period without administration

- 18 046110 nia for up to one week) or administration every other day. The term cycling as used herein means that a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered daily or continuously, but with a rest period.

In some embodiments, the frequency of administration ranges from about a daily dose to about a monthly dose. In one embodiment of the invention, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once a week, once every two weeks, once every three weeks or once every four weeks. In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered once daily. In another embodiment, Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered twice daily. In yet another embodiment of the invention, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered three times daily. In yet another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered four times daily.

In one embodiment, the methods provided herein include administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 in one or more 7-day treatment cycles. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 5 in a 7-day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 3 in a 7-day cycle.

In one embodiment, the methods provided herein include administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 in one or more 14-day treatment cycles. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 7 in a 14-day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 10 in a 14-day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 5 in a 14-day cycle.

In one embodiment, the methods provided herein include administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 in one or more 28-day treatment cycles. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 21 in a 28-day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 5, Days 8 to 12, Days 15 to 19, and Days 22 to 26 on 28 day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 10 and days 15 to 24 in a 28-day cycle. In another embodiment, the methods provided herein include administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 7 and days 15 to 21 in a 28-day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 14 in a 28-day cycle.

In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 is administered once daily for 5 days followed by 2 days of rest. In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 is administered once daily for 3 days followed by 4 days of rest. In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 is administered once daily for 5 days followed by 9 days of rest. In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 is administered once daily for 7 days followed by 7 days of rest. In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 is administered once daily for 10 days followed by 4 days of rest. In one embodiment of the invention, compound 1, compound 2 or compound 3 is administered

- 19 046110 once a day for 21 days followed by 7 days of rest. In one embodiment of the invention, Compound 1, Compound 2, or Compound 3 is administered once daily for 14 days followed by 14 days of rest.

In one embodiment, treatment comprises administering a therapeutically effective amount of obinutuzumab in one or more treatment cycles. In one embodiment of the invention, obinutuzumab is administered twice every 7 days. In one embodiment of the invention, obinutuzumab is administered once a week. In one embodiment of the invention, obinutuzumab is administered once every 4 weeks. In one embodiment, obinutuzumab is administered on days 1, 2, 8, and 15 of the first 28-day cycle and is administered on day 1 of the second to sixth 28-day cycles. In one embodiment, obinutuzumab is administered on day 1 of the second to 12th 28-day cycle. In one embodiment, obinutuzumab is administered on day 1 of the second to 24th 28-day cycle. In one embodiment, obinutuzumab is administered on day 1 of subsequent 28-day cycles until disease progression.

In one embodiment, obinutuzumab is administered at a dose of about 100 mg on day 1 of the first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg on each of days 8 and 15 of the first 28-day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg combined on days 1 and 2 of the first 28-day cycle, and about 1000 mg on each of days 8 and 15 of the first 28-day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1 from the second to sixth 28-day cycles. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1 from the second to 12th 28-day cycles. In one embodiment of the invention, obinutuzumab is administered at a dose of about 1000 mg on day 1 from the second to the 24th 28-day cycles. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1 of subsequent 28-day cycles until disease progression. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg in a first 28-day cycle at least one week before starting administration of a compound provided herein, e.g., Compound 1.

In one embodiment of the invention, the subject receives an initial dose of obinutuzumab at least one week before receiving the initial dose of Compound 1. In one embodiment of the invention, the subject receives an initial dose of obinutuzumab one week before receiving the initial dose of Compound 1. In one embodiment of the invention, the subject receives an initial dose of obinutuzumab 13 days before receiving an initial dose of Compound 1. In one embodiment, the subject receives an initial dose of obinutuzumab 14 days before receiving an initial dose of Compound 1. In one embodiment, the subject receives an initial dose of obinutuzumab 14 days before receiving an initial dose compound 1 and receives subsequent doses of obinutuzumab 13 days and 7 days before receiving the initial dose of compound 1. In one embodiment of the invention, the initial dose of obinutuzumab is at least 1000 mg. In one embodiment of the invention, the starting dose of obinutuzumab is about 1000 mg. The initial dose of obinutuzumab can be a single dose administered over one day or combination doses administered over more than one day. In one embodiment, the subject receives obinutuzumab at a dose of about 100 mg on day 1 of the first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg before receiving the initial dose of Compound 1 on day 15 of the first 28-day cycle. cycle. In one embodiment, the subject receives obinutuzumab at a combined dose of about 1000 mg in combination on days 1 and 2 of the first 28-day cycle and about 1000 mg on day 8 of the first 28-day cycle before receiving an initial dose of Compound 1 on day 15 of the first 28-day cycle. daily cycle. In one embodiment of the invention, the method presented herein includes administering an initial dose of obinutuzumab at least one week before the administration of the initial dose of compound 1. In one embodiment of the invention, the method presented herein includes administering an initial dose of obinutuzumab one week before before administration of the initial dose of Compound 1. In one embodiment of the invention, the method presented herein includes administering an initial dose of obinutuzumab 13 days before administration of the initial dose of Compound 1. In one embodiment of the invention, the method presented herein includes administering the initial dose obinutuzumab 14 days before the initial dose of Compound 1. In one embodiment of the invention, the method provided herein includes administering an initial dose of obinutuzumab 14 days before the initial dose of Compound 1 and administering subsequent doses of obinutuzumab 13 days and 7 days before the administration starting dose of compound 1. In one embodiment of the invention, the starting dose of obinutuzumab is at least 1000 mg. In one embodiment of the invention, the starting dose of obinutuzumab is about 1000 mg. The initial dose of obinutuzumab can be a single dose administered over one day or combination doses administered over more than one day. In one embodiment of the invention, the method presented in this document includes the administration of obinutuzumab at a dose of about 100 mg on day 1 of the first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg before the initial dose of compound 1 on day 15 of the first 28-day cycle. In one embodiment it is done

- 20 046110 of the invention, the method presented in this document includes the administration of obinutuzumab at a combined dose of about 1000 mg on days 1 and 2 of the first 28-day cycle and about 1000 mg on day 8 of the first 28-day cycle before administration of the initial dose of compound 1 in day 15 of the first 28-day cycle. In one embodiment, the method provided herein comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the first 28-day cycle ( “cycle 1) and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s) (“cycle 2 and so on); and (ii) administering compound 1 in cycles of once daily for 7 days followed by 7 days of rest, starting on day 15 of cycle 1.

In one embodiment, the method provided herein comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the first 28-day cycle ( “cycle 1) and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s) (“cycle 2 and so on); and (ii) administering compound 1 in cycles of once daily for 5 days followed by 9 days of rest, starting on day 15 of cycle 1.

In one embodiment, the method provided herein comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the first 28-day cycle ( “cycle 1) and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s) (“cycle 2 and so on); and (ii) administering Compound 1 in cycles of once daily for 14 days followed by 14 days of rest starting on day 15 of cycle 1.

In one embodiment, the method provided herein comprises (i) administering obinutuzumab at a dose of about 100 mg on day 1, about 900 mg on day 2, about 1000 mg on each of days 8 and 15 of the first 28-day cycle ( cycle 1) and at a dose of about 1000 mg on day 1 of the subsequent 28-day cycle(s) (cycle 2 and so on); and (ii) administration of compound 1 in cycles of once daily for 21 days followed by 7 days of rest, starting on day 15 of cycle 1.

Any treatment cycle described herein may be repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more cycles. In certain cases, the treatment cycle described herein includes from 1 to about 24 cycles, from about 2 to about 16 cycles, or from about 2 to about 4 cycles. In certain cases, the treatment cycle described herein includes from 1 to about 4 cycles. In some embodiments, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3, and/or obinutuzumab is administered over 1 to 13 cycles of 28 days (eg, about 1 year). In some embodiments, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3, and/or obinutuzumab is administered over 1 to 24 cycles of 28 days (eg, about 2 years). In certain cases, cycle therapy is not limited to the number of cycles, but therapy is continued until the disease progresses. Cycles may, in certain cases, include varying the length of the administration periods and/or rest periods described herein.

Examples

The following Examples are provided by way of illustration and not limitation. Compounds are named using the automatic naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to obtain the desired products.

Abbreviations used:_____________________________________________

DCM Dichloromethane DIEA Ν,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide ESI Electrospray ionization EtOAc Ethyl acetate LCMS Liquid chromatography mass spectrometry MeOH Methanol MS Mass spectrometry NMP N-Methylpyrrolidone NMR Nuclear magnetic resonance THF Tetrahydrofuran

Example 1: Synthesis of ^)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)me

- 21 046110 til)benzyl)amino)isoindoline-1,3-dione (compound 1)

ABOUT

(b)-2-(2.6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3dione: Suspension of (b)-4-amino-2- (2.6-dioxopiperidin-3-yl)isoindolin-1,3-dione (5.00 g, 18.3 mmol) and 2-fluoro-4-(hydroxymethyl)benzaldehyde (2.82 g, 18.30 mmol) in 2:1 dioxane-MeOH (75 ml) was cooled to 0°C and BiqHi ₄ (4.92 g, 40.3 mmol) was added in small portions over 5 min. The reaction flask was equipped with a septum and a needle valve (pressure) and stirred vigorously for 10 min. The mixture was allowed to reach ambient temperature and stirred for 3 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel (0-10% MeOH-DCM) to give ^)-2-(2,6-dioxopiperidin-3-yl)- 4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3dione as a yellow solid (4.23 g, 56%). LCMS (ESI) m/z 411.8 [M+H]+.

^)-4-((4-(Chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione: Solution of ^)-2-(2, 6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3dione (0.727 g, 1.77 mmol) in dry NMP (6 ml) was cooled to 0 °C and methanesulfonyl chloride (0.275 ml, 3.35 mmol) and DIEA (0.617 ml, 3.53 mmol) were added sequentially. The reaction mixture was allowed to reach ambient temperature and stirred for 18 hours. The reaction mixture was slowly added to H ₂ O (60 ml), cooled to 0° C., with vigorous stirring. The resulting suspension was filtered and the collected solid was washed with H2O and Et ₂ O. The solid was dissolved in EtOAc and the solution was dried over MgSO4, filtered and concentrated to give (S)-4-((4(chloromethyl)-2-fluorobenzyl)amino) -2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione as a yellow solid (0.600 g, 79%). LCMS (ESI) m/z 430.0 [M+H]+.

^)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione : To a solution of ^)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3yl)isoindoline-1,3-dione (300 mg, 0.698 mmol) in dry DMSO (1.0 ml), 4(azetidin-3-yl)morpholine hydrochloride (125 mg, 0.698 mmol) and DIEA (0.122 ml, 0.698 mmol) were added. The reaction mixture was stirred at ambient temperature for 18 hours and diluted with DMSO (1 ml). The solution was purified by chiral reverse phase chromatography to give ^)-2-(2,6-dioxopiperidin-3yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino) isoindoline-1,3-dione (89 mg, 24%, 97% ee). LCMS (ESI) m/z 536.2 [M+H]+.

Example 2: Synthesis of ^)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindolin- 1,3-diones (compound 2)

ABOUT

The chiral reverse phase chromatography described in Example 1 further provided ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl) methyl)benzyl)amino) isoindoline-1,3-dione (16 mg, 97% ee). LCMS (ESI) m/z 535.6 [M+H]+.

Example 3: Synthesis of 2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3- dione (compound 3)

ABOUT

(4-Bromo-3-fluorophenyl)methanol: A solution of 4-bromo-3-fluorobenzoic acid (15.0 g, 68.5 mmol) in THF (150 ml) was cooled to 0°C and the complex was added dropwise under nitrogen atmosphere borane with dimethyl sulfide (13.7 ml, 137 mmol, 10 M in THF). The cooling bath was removed and the mixture was stirred at ambient temperature for 12 hours. The mixture was cooled to 0°C, quenched with MeOH (50 ml) and poured into water (30 ml). The mixture was concentrated in vacuo and the remaining aqueous mixture was diluted with ethyl acetate (150 ml) and water (150 ml) and stirred for 15 minutes. The organic phase was removed and the aqueous phase was extracted with ethyl acetate (150 mlx2). The organic fractions were combined, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column

- 22 046110 chromatography on silica gel (2-10% ethyl acetate in petroleum ether) to obtain (4-bromo-3fluorophenyl)methanol (13.1 g, 93.3% yield) as a colorless liquid. LCMS (ESI) m/z 187.0 [MH 18 ⁺ ]. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 - 7.45 (m, 1H), 7.14 (d, J=9.2 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 4.64 (d, J=4.6 Hz, 2H), 2.20 (br s, 1H).

(4-Bromo-3-fluorophenyl)methoxy-tert-butyldimethylsilane: A solution of (4-bromo-3-fluorophenyl)methanol (13.1 g, 63.9 mmol) and imidazole (12.2 g, 179 mmol) in DMF (150 ml) was cooled to 0°C and t-butylchlorodimethylsilane (14.4 g, 95.8 mmol) was added. The cooling bath was removed and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into cooled water (30 ml), diluted with ethyl acetate (100 ml) and water (100 ml) and stirred for 15 minutes. The organic phase was removed and the aqueous phase was extracted with ethyl acetate (150 mlx2). The organic fractions were combined, washed with saturated NaCl solution (50 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give (4-bromo-3-fluorophenyl)methoxy-tert-butyldimethylsilane (18.6 g, 91.2% yield) as a colorless liquid. ^1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.49 (dd, J=7.1, 8.1 Hz, 1H), 7.18 - 7.08 (m, 1H), 7.01 - 6.92 (m, 1H), 4.69 (s, 2H) , 0.96 (s, 9H), 0.12 (s, 6H).

4-[[tert-Butyl(dimethyl)silyl]oxymethyl]-2-fluorobenzaldehyde: Under nitrogen, a solution of (4-bromo3-fluorophenyl)methoxy-tert-butyldimethylsilane (18.6 g, 58.3 mmol) in THF (150 ml) was cooled to -78°C and n-BuLi (25.6 ml, 64.0 mmol, 2.5 M in hexane) was added dropwise. The mixture was stirred at -78°C for 5 minutes and DMF (5.83 ml, 75.7 mmol) was added. The mixture was stirred at -78°C for 2 hours and allowed to warm to ambient temperature. The reaction mixture was cooled to 0°C and quenched with saturated ammonium chloride solution (60 ml) and water (30 ml). The mixture was extracted with ethyl acetate (2x150 ml), the combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-2% ethyl acetate in petroleum ether) to give 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluorobenzaldehyde (11.5 g, 73.5% yield) as yellow liquid. MS (ESI) m/z: 269.1 [M+l] ⁺ .

3-((4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid: Solution of 4[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluorobenzaldehyde (7.50 g , 27.9 mmol) and 3-aminophthalic acid (5.06 g, 27.9 mmol) in a 1:10 acetic acid-MeOH mixture (110 ml) was stirred at 25°C for 30 min and cooled to 0°C . Borane 2-methylpyridine complex (4.48 g, 41.9 mmol) was added and the mixture was allowed to reach ambient temperature. The mixture was stirred at ambient temperature for 16 hours and the mixture was concentrated under reduced pressure. The residue was diluted with water (25 ml) and ethyl acetate (25 ml) and stirred for 15 minutes. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (30 mlx2). The organic fractions were combined, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (2-5% ethyl acetate in petroleum ether) to give 3-((4(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid (9.90 g, yield 81.8%) as a white solid. LCMS (ESI) m/z: 434.1 [M+1] ⁺ .

4-((4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione: Solution of 3-( (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid (11.8 g, 27.2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (6.72 g, 40.8 mmol) in pyridine (150 ml) was stirred at 120°C for 12 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (2-5% ethyl acetate in petroleum ether) to give 4-((4-((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2 -(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (9.90 g, 69.2% yield) as a yellow solid. LCMS (ESI) m/z: 526.2 [M+1] ⁺ .

2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione: To a solution of 4-((4-((( tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3yl)isoindoline-1,3-dione (9.90 g, 18.8 mmol) in THF (100 ml ) concentrated sulfuric acid (20.0 ml, 368 mmol) was added and the mixture was stirred at ambient temperature for 12 hours. The mixture was concentrated in vacuo and the residue was treated with 1:5 ethyl acetate-petroleum ether (20 ml). The resulting suspension was stirred for 30 minutes and filtered. The collected solid was washed with 1:5 ethyl acetate-petroleum ether and dried in vacuo to give 2-(2,6dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1 ,3-dione (6.58 g, 85.2% yield) as a yellow solid. MS (ESI) m/z: 412.0 [M+1] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.12 (s, 1H), 7.54 (dd, J=7.3, 8.4 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.16 - 7.07 ( m, 3H), 7.05 (d, J=7.0 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 5.33 - 5.25 (m, 1H), 5.07 (dd, J=5.3, 12.9 Hz, 1H ), 4.59 (d, J=6.3 Hz, 2H), 4.47 (d, J=5.8 Hz, 2H), 2.95 - 2.84 (m, 1H), 2.65 - 2.52 (m, 2H), 2.09-2.01 (m, 1H).

4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: Solution of 2-(2,6-dioxopiperidin-3- yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (6.58 g, 16.0 mmol) in dichloromethane (200 ml) was cooled to 0°C and thionyl chloride (20.0 mL, 276 mmol) was added dropwise. After addition was complete, the cooling bath was removed and the reaction mixture

- 23 046110 was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (1.00-1.25% MeOH in dichloromethane) to give 4-((4-(chloromethyl)-2 -fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (3.80 g, 55.4% yield) as a yellow solid. LCMS (ESI) m/z: 430.0 [M+1]+. ^1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (s, 1H), 7.54 (dd, J=7.3, 8.4 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.32 (dd, J=1.5, 11.0 Hz, 1H), 7.24 (dd, J=1.6, 7.8 Hz, 1H), 7.16 (t, J=6.3 Hz, 1H), 7.06 (d, J=6.9 Hz, 1H), 6.98 ( d, J=8.5 Hz, 1H), 5.08 (dd, J=5.3, 12.9 Hz, 1H), 4.74 (s, 2H), 4.63 (d, J=6.3 Hz, 2H), 2.95 - 2.85 (m, 1H ), 2.66 - 2.53 (m, 2H), 2.09 2.02 (m, 1H).

2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione: K 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione solution (215 mg, 0.500 mmol) (prepared as described herein) and 4-(azetidin-3-yl)morpholine hydrochloride (107 mg, 0.600 mmol) in dry DMSO (1.7 mL), DIEA (262 μL, 1.50 mmol) was added and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was diluted with 20% formic acid in DMSO (2.5 ml) and filtered through a membrane syringe filter (nylon 0.45 μm). The solution was purified by standard methods to obtain 2-(2,6dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3dione ( 173 mg, yield 64.6%). LCMS (ESI) m/z 536.2 [M+H]+.

Example 4: Cell proliferation and viability assay using CLL cell lines

The following are examples of cellular assays that can be used to determine the antiproliferative activity and apoptotic effect of the compounds described herein, using exemplary CLL cell lines (Table 3). The in vitro growth inhibitory activity of compound 1 described herein was assessed using a 384-well flow cytometry assay.

Table 3 CLL cell lines

Cellular Line Type tumors Subtype tumors Salesman Cultural conditions ENEV CLL indefined DSMZ RPMI + 10% FBS, IX NEAA, 2 mM L-glutamine WA-C3-CD5+ CLL indefined DSMZ WA-OSEL CLL indefined DSMZ PGA1 CLL indefined DSMZ HG3 CLL indefined DSMZ I83-E95 CLL indefined DSMZ RPMI + 20% FBS, IX NEAA, 2 mM L-glutamine JV CLL indefined DSMZ C.I. CLL indefined DSMZ Month2 CLL indefined DSMZ IMDM+ 10% FBS Mecl CLL indefined DSMZ

RPMI=RPMI1640;

FBS=fetal bovine serum;

NEAA=nonessential amino acid;

IMDM=Dulbecco's medium as modified by Iskov.

Cell lines were seeded under the conditions shown in table. 3 into 384-well flat-bottom plates and incubated with increasing concentrations of compound ranging from 0.00015 to 10 μM or dimethyl sulfoxide (DMSO) as a control. The final DMSO concentration was 0.1% v/v. After addition of compound 1 or DMSO and incubation for 120 h, cell number and cell death were analyzed by flow cytometry (Attune®, Thermo Fisher) using Annexin V and a cell-impermeable DNA dye, DRAQ7. Phosphatidylserine moves from the inner layer to the outer layer of the cell membrane during the early stage of apoptosis, and Annexin V binds to exposed phosphatidylserine found on the surface of the apoptotic cell. The vital dye DRAQ7 is excluded by intact living cells and stains only cells that have died as a result of apoptosis or necrosis.

Flow cytometry data were then analyzed using software

- 24 046110 Flow Jo_v10 to determine the number of viable cells (double negative Annexin V and DRAQ7 stained cells) and the percentage of apoptotic cells (Annexin V positive cells) for each condition. The number of viable cells for each concentration was normalized to the DMSO control (considered as 100% viable cells) to calculate the percentage of viable cells remaining after treatment and plotted using GraphPad Prism 7.03. IC50 (50% inhibitory concentration) and _Emax (maximum efficacy achieved) values were then calculated by fitting a nonlinear regression curve using ^(inhibitor) vs. normalized response - variable slope analysis on GraphPad Prism 7.03. Area under the curve (AUC) was calculated by analyzing the area under the curve on GraphPad Prism 7.03. Similarly, for the apoptosis assay, the percentage of apoptosis combining both early (Annexin V positive and DRAQ7 negative) and late apoptosis (Annexin V and DRAQ7 positive) cell gates relative to DMSO was plotted using GraphPad Prism 7.03. The AUC, EC50 (concentration of compound 1 that produces a half-maximal apoptotic response), and _Ymax (maximum percentage of apoptosis achieved) values from the apoptosis curves were calculated by performing area under the curve analysis and fitting a nonlinear regression curve using log(agonist) vs. normalized response - Variable Slope analysis on GraphPad Prism 7.03.

As shown in table. 4, dose-response proliferation curves for compound 1 for a panel of CLL cell lines and non-linear curve fitting regression were used to determine _IC50 , AUC and _Emax for % viable cells ( _Emax for viability varies between 100 at low doses and 0 at high doses , corresponding to inhibition of all viable cells), and apoptosis dose curves for compound 1 were used to determine the EC ₅₀ , AUC and Y _max for % apoptosis (Y _max for apoptosis varies between 0 at low doses and 100 at higher doses, corresponding to death all cells).

Compound 1 was found to have antiproliferative activity and/or apoptotic effects in CLL cell lines (Table 4).

Table 4

Antiproliferative activity and apoptotic effect of compound 1 in CLL cell lines

Cellular Line % Viable Cells Apoptosis AUC IC50 Emax AUC ECso Ymax ENEV 319.3 0.0303 28.68 65.03 0.5062 8.42 WA-C3-CD5+ 474.8 0.53 44.2 162.9 0.05244 17.47 WA-OSEL 616.1 10 54.42 69.39 0.112 7.38 PGA1 736.7 10 69.21 48.94 0.1219 5.075 HG3 676.2 10 59.58 131.5 0.1107 14.28 I83-E95 259.2 0.01728 21.6 358.4 0.06111 40.69 JV 926.1 10 78.23 238.1 0.145 26.11 C.I. 603.9 9,701 53.58 123.2 0.02294 13.01 Month2 312.5 0.07552 25.55 339.8 0.01331 35.28 Mecl 866.5 10 83.45 302.4 0.2097 36.61

AUC=area under the curve;

IC5 ₀ =50% inhibitory concentration (µM);

E _max = achieved maximum efficiency of tumor cell elimination, expressed as a percentage of the remaining tumor cells;

EC ₅₀ =concentration of compound causing half-maximal response to apoptosis (µM);

Y _mαx = calculated percentage of control at the highest concentration of compound 1.

Example 5: Cell Proliferation and Viability Assay for B Cells from CLL Patients

The following are examples of cellular assays that can be used to determine the antiproliferative activity and apoptotic effect of the compounds described herein, using exemplary cells from CLL patients. The effect of compound 1 on the viability and apoptosis of CLL B cells was assessed using an ex vivo model.

CLL is characterized by the accumulation of clonal CD5+CD19+ lymphocytes that are resistant to apoptosis. The effect of Compound 1 on the viability and apoptosis of CLL B cells was assessed using an ex vivo model in which primary CLL cells from patient blood were stimulated with 10% fetal bovine serum (FBS), 5 ng/ml recombinant human interleukin-4 (rh IL-4 ), 10 ng/ml recombinant

- 25 046 110 human interleukin-10 (rh IL-10) and co-cultured with fibroblasts expressing surface CD154 (CD40L). Percentage of cells stained

Annexin V and/or DRAQ-7 were measured by flow cytometry analysis after 3, 6 or 10 days of incubation with vehicle control or with increasing concentrations of Compound 1 ranging from 0.001 to 1 μM. Peripheral blood mononuclear cells (PBMCs) from patients with CLL (Table 5), containing 70-95% CD5+CD19+ tumor cells, were cultured on a monolayer of CD154-expressing fibroblasts in 24-well plates at a patient cell density of 0.8x106 cells/well in medium RPMI 1640 supplemented with 10% FBS, 5 ng/ml rh IL-4 and 10 ng/ml rh IL-10 and treated with vehicle control (0.1% DMSO) or increasing concentrations of compound 1 ranging from 0.001 to 1 μM. After treatment, flow cytometry analysis was used to determine the number of viable or apoptotic cells.

Table 5

Characteristics of the CLL samples used

CLL Pt Burden Tumors Mutation Status IGHV Cytogenetics Previous Therapy 1 89% Mutated del(13q); tri 12 Η 2 94% Not Mutated del(13q) Η 3 94% Not Mutated del(13q) Η 4 78% Mutated del(13q) Η 5 80% Mutated del(13q) Η 6 95% Not Mutated del(13q) + t(6;17) Η 7 62% Not Mutated tril2; del(llq22.3) Η 8 91% Mutated del(13q) Η 9 83% Mutated tri 12; del(13q) Η 10 72% But Richter syndrome Η

IGHV status refers to a somatic mutation in the IGHV gene of CLL cells compared to the germline gene sequence.

Nd=^ done/unknown;

tri trisomy; del=deletion; t=translocation.

After 3, 6, or 10 days of treatment with the compound, cells were incubated with Annexin V to detect the externalization of phosphatidylserine as a result of lipid asymmetry disruption in the plasma membrane of cells, a well-characterized phenomenon in apoptosis, with the vital far-red fluorescent DNA dye DRAQ-7, which stains only the nuclei. dead and permeabilized cells and analyzed by flow cytometry (Attune®, Thermo Fisher). An analysis was then performed to determine the percentage of viable living cells (double negative stained Annexin V and DRAQ-7 cells) using FlowJoV10 and plotted using GraphPad Prism 7.03 software. The number of viable cells for each condition was normalized to the DMSO control (considered as 100% viable cells) to calculate the percentage of viable cells remaining after treatment. _IC50 (50% inhibitory concentration) and _Emax (maximum tumor cell elimination efficiency achieved) values were then calculated by fitting a nonlinear regression curve using log(inhibitor) vs. normalized response - variable slope analysis on GraphPad Prism 7.03. The area under the curve (AUC) value of the number of viable cells over time was calculated by performing an area under the curve analysis on GraphPad Prism 7.03 (Table 6).

Potent dose-dependent inhibition of CLL cell proliferation was observed for Compound 1 in all CLL patient samples evaluated (Table 6), with concentrations of Compound 1 resulting in 50% growth inhibition (IC ₅₀ ) ranging from 0.0001 to 0.003 μM. Susceptibility to compound 1 was independent of IGHV mutation status and other chromosomal characteristics.

- 26 046110

Table 6

Antiproliferative effect of compound 1 ex vivo on cell cultures of patients with CLL

Patient number IC 50 Emax AUC Ptl l,63E-08 4.621 32.79 Pt2 0.001048 30.58 181.6 Pt3 0.000723 12.98 106.1 Pt4 l,63E-08 6,501 44.01 Pt5 0.000305 22.77 139.6 Pt6 0.002748 27.42 154.9 Pt7 3.6E-05 5.873 44.86 Pt8 0.000209 4.82 75.03 Pt9 6.52E-05 4,141 48.14 PtlO 0.000129 10.21 57.87

АiС=area under the curve;

IC50=50% inhibitory concentration (µM);

Em _ax =% of the maximum achieved efficiency in eliminating tumor cells, expressed as a percentage of remaining tumor cells;

Pt=patients

Example 6. Antiproliferative effect of compound 1 in combination with obinutuzumab in B cells of patients with CLL.

Obinutuzumab (GA101) is a humanized glycoengineered type 2 antibody directed against CD20. Obinutuzumab demonstrated superior efficacy to rituximab, causing direct cell death and increased antibody-dependent cellular cytotoxicity. The effect of treatment with Compound 1 in combination with obinutuzumab on the proliferation and survival of CLL B cells was assessed using an ex vivo model in which primary CLL cells from patient blood were stimulated to proliferate with 10% fetal bovine serum (FBS), 5 ng/ml recombinant human interleukin-4 (rh IL-4), 10 ng/ml recombinant human interleukin-10 (rh IL-10) and co-cultured with fibroblasts expressing surface CD154 (CD40L) in a 96-well plate format.

Peripheral blood mononuclear cells (PBMCs) from patients with CLL (Table 7), containing 5286% CD5+CD19+ tumor cells, were cultured at a density of 0.06-0.1x106 cells/well on a monolayer of CD154-expressing fibroblasts at a density of 0.09x106 cells/well. well in 96-well plates in RPMI 1640 medium supplemented with 10% FBS, 5 ng/ml rh IL-4 and 10 ng/ml rh IL-10. Cells were treated with vehicle control (0.1% DMSO) or increasing concentrations of Compound 1 ranging from 0.0001 to 1 μM and GA101 ranging from 8 ng/mL to 5 μg/mL for all different concentrations of Compound 1. After 144 h treatment with both agents, flow cytometry analysis was used to determine the number of tumor cells that were viable or apoptotic.

Tumor cell counts were assessed by staining patient PBMCs in each condition with tumor cell surface markers CD5 and CD19 along with Live/Dead fixative dye to exclude dead cells, followed by intracellular staining with Caspase 3 antibody to identify apoptotic cells and measured by flow cytometry (Attune NxT , Thermo Fisher). The number of live tumor cells for each condition was calculated by normalizing to the exact number of beads added to each sample.

Table 7

Characteristics of the CLL samples used

CLL Pt Burden Tumors IGHV Mutation Status Cytogenetics Previous Therapy eleven 85% Not Mutated del(13q) N 12 75% Not Mutated del(13q) (35%) N 13 thirty% Mutated del(13q); tri 12 n 14 86% Mutated del(13q); abnormality in cell interphase (86%) Mitomycin

- 27 046110

The number of viable tumor cells was then normalized to the DMSO control (considered as 100% viable) to calculate the percentage of viable cells remaining after treatment. The normalized percentage of tumor cells was then plotted as a heat map using Graph Pad Prism 8.0.0 to indicate the degree of tumor toxicity for each of the combinations (Figure). Based on the data shown in the figure, synergy/additivity calculations were performed using the HSA and Bliss Independence Model. Either a synergistic or additive effect was observed in three (pt11, 12 and 13) of the four patient samples tested.

For the apoptosis assay, the percentage of apoptosis combining both early (Caspase 3 positive and Live-Dead fixative dye negative) and late apoptosis (Caspase 3 positive and Live-Dead fixative dye positive) cell gates minus the DMSO baseline value was plotted to the graph using GraphPad Prism 8.0.0.0. Y _max (maximum percentage of apoptosis achieved) values from apoptosis curves were calculated by fitting a nonlinear regression curve using log(agonist) vs. normalized response - analysis with Variable slope and determination of the maximum value on GraphPad Prism 8.0.0 (Table 8). Obinutuzumab alone induced apoptosis and moderately increased the ability of Compound 1 to induce apoptosis.

Table 8

Maximum apoptosis effect of compound 1 in combination with obinutuzumab

Obinutuzumab concentrations Ymax Pt and (%) Ymax Pt 12 (%) Ymax Pt 13 (%) Ymax Pt 14 (%) DMSO + Cpdl DRC 18.81 19.11 29.40 24.11 8 ng/ml + Cpdl DRC 16.73 17.82 36.37 17.58 40 ng/ml + Cpdl DRC 24.43 20.94 38.57 17.00 200 ng/ml + Cpdl DRC 32.17 21.44 38.25 19.14 1 µg/ml + Cpdl DRC 30.93 24.91 38.96 25.82 5 µg/ml + Cpdl DRC 29.96 23.65 41.95 25.23 Obinutuzumab only 27.98 24.91 35.87 25.82

Example 7: Phase I Clinical Study

A Phase 1b, multicenter, open-label study is being conducted to determine the safety, pharmacokinetics, and preliminary efficacy of Compound 1 in combination with obinutuzumab in subjects with relapsed or refractory chronic lymphocytic leukemia/small cell lymphocytic lymphoma (R/R CLL/SLL).

Objectives: The primary objectives of the study are to determine the safety and tolerability of compound 1 in combination with obinutuzumab in subjects with R/R CLL/SLL. Another primary objective is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of compound 1 in combination with obinutuzumab in subjects with R/R CLL/SLL.

Secondary objectives are to evaluate the preliminary efficacy of Compound 1 in combination with obinutuzumab in subjects with R/R CLL/SLL and to determine the pharmacokinetics (PK) of Compound 1 when used in combination with obinutuzumab in subjects with R/R CLL/SLL.

Study Design: This is an open-label, phase 1b study to evaluate the safety, PK, and preliminary efficacy of compound 1 administered orally in combination with obinutuzumab in subjects with R/R CLL/SLL. All eligible subjects must have relapsed or been refractory to at least 2 prior lines of therapy for CLL/SLL, including a Bruton's tyrosine kinase inhibitor (BTK). All subjects must have an indication for treatment at study entry. The study is conducted in two parts: Part A (dose escalation) and Part B (dose cohort expansion). Dose Escalation (Part A) evaluates the safety, tolerability, and RC of increasing doses of Compound 1 administered in combination with intravenous obinutuzumab to determine the MTD and RP2D of Compound 1 when administered in combination with obinutuzumab. Compound 1 is administered orally once daily (QD) on scheduled dosing days. If the initial dose/regimen is not tolerated, a lower dose or less intense regimen may be studied. All treatments are continued until disease progression, unacceptable toxicity, death, or subject/physician decision to discontinue treatment, for up to 24 total treatment cycles.

Following completion of dose escalation (Part A), a selected expansion cohort (Part B) of approximately 20 evaluable subjects receives Compound 1 in combination with obinutuzumab.

The total daily dose to be administered to the next dose cohort is determined based on calculations taking into account available safety, collected PK and PD data.

In Part B, cohort expansion can occur with the MTD set in the expansion phase to

- 28 046110 zy, or with an alternative permissible dosage regimen, based on safety data, RK and PD from part A.

The best overall response is determined by the criteria outlined in the iwCLL (Table 1). The answer is assessed by the Researcher. To expand the cohort, one or more dosing regimens may be selected.

Study Population: Study subjects will include men and women aged 18 years or older with R/R CLL/SLL who have failed previous therapy as specified in the inclusion/exclusion criteria.

Inclusion Criteria: To be included in the study, subjects must meet the following criteria:

1. Subject is >18 years of age at the time of signing the Informed Consent Form (ICF).

2. The subject must understand and voluntarily sign the ICF prior to any study-related assessments/procedures.

3. The subject is willing and able to comply with the study visit schedule and other protocol requirements.

4. The subject must have a documented diagnosis of CLL/SLL requiring treatment (iwCLL Guide to the Diagnosis and Treatment of CLL (Tables 1 and 2).

Additionally:

A. The presence of a clinically measurable disease, defined by at least one of the following factors:

nodular lesion measuring >1.5 cm in the longest dimension (LD) and >1.0 cm in the longest perpendicular dimension (LPD), or spleen measuring >14 cm in the longest vertical dimension (LVD) with a minimum of 2 cm enlargement , or liver size >20 cm in LVD with at least 2 cm increase, or peripheral blood B-lymphocyte count >5000/µl.

5. The subject must meet criteria for relapsed and/or refractory disease according to iwCLL guidelines for at least two prior lines of therapy.

6. All eligible subjects must have relapsed or be refractory to at least two prior lines of therapy, one of which must include an approved BTK inhibitor.

7. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Table 2).

8. Subjects who meet the following laboratory parameters:

a. Absolute neutrophil count (ANC) >1500 cells/mm ³ or >1000 cells/mm ³ if the disease is secondary to bone marrow involvement.

b. Platelet count >100,000 cells/mm ³ (100x10 ⁹ /L) or >50,000 cells/mm ³ (50x 10 ⁹ /L) if the disease is secondary to bone marrow damage.

c. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) <3.0 x upper limit of normal (ULN).

d. Serum bilirubin <1.5xULN unless associated with Gilbert's syndrome.

e. Estimated creatinine clearance >60 ml/min.

9. Agrees with scheduled pregnancy testing and the Pregnancy Risk Management Plan during the study and after completion of study treatment. This applies even if the subject practices complete abstinence from heterosexual intercourse. A woman of childbearing age (FCBP) is a woman who: 1) has reached menarche at some point, 2) has not had a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea after cancer treatment does not preclude reproductive function) for at least 24 consecutive months (i.e. she had menstruation at any time during the previous 24 consecutive months) and must:

A. Has two negative pregnancy tests confirmed by the investigator prior to initiation of study therapy. She must agree to ongoing pregnancy testing during the study and after the end of study therapy. This applies even if the subject practices complete abstinence from heterosexual intercourse.

b. Either agrees to completely abstain from heterosexual intercourse (which must be reviewed monthly and documented), or agrees to use and be able to comply with two reliable forms of contraception without interruption, as defined in the RRR and provided to the subject at the time of obtaining informed consent, 28 days before administration of Compound 1, during study therapy (including dosage breaks) and for 28 days after discontinuation of study therapy or 18 months after the last dose of obinutuzumab, as appropriate.

- 29 046110 from what comes last.

Male subjects must practice total abstinence (to be reviewed monthly) or consent to the use of a condom during sexual intercourse with a pregnant woman or woman of childbearing potential while participating in the study, during dosing intervals, and for at least 3 months after discontinuation of the study product or longer if required for each compound and/or local regulations, even if he has undergone a successful vasectomy. (Total abstinence is acceptable if consistent with the subject's preferred and usual lifestyle. Intermittent abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and abstinence are not acceptable methods of contraception.)

Exclusion Criteria: The presence of any of the following excludes a subject from inclusion:

1. The subject has any serious medical condition, laboratory abnormality, or mental illness that prevents the subject from participating in the study.

2. The subject has any condition, including the presence of laboratory abnormalities, that would place the subject at an unacceptable risk if he/she were to participate in the study.

3. The subject has a condition that interferes with the ability to interpret test data.

4. Previous allogeneic stem cell transplant (ICT)/bone marrow transplantation within 12 months after signing the ICF. Subjects who received allogeneic SCT >12 months before signing the ICF may be eligible for participation provided there is no ongoing graft-versus-host disease (GVHD) and ongoing immunosuppressive therapy.

5. Current or active infection requiring parenteral antibiotics.

6. Uncontrolled intercurrent illness, including but not limited to:

a. Uncontrolled diabetes mellitus. Glycemic targets for subjects with diabetes should take into account the age, comorbidities, life expectancy and functional status of the subjects and be consistent with established guidelines (eg, International Diabetes Federation, European Diabetes Working Group and American Diabetes Association recommendations). For those younger (<70 years) or those with a life expectancy >10 years, the target glycosylated hemoglobin type A1C (HbA1c) level should be <7.0%. The target HbA1c for older adults (>70 years) or those with a life expectancy <10 years should be <8.0%. When deciding on optimal diabetes control, consultation with an endocrinologist is recommended. Subjects with stable HbA1c levels above the estimated target may be included in the study after discussion with a medical supervisor.

b. Chronic symptomatic congestive heart failure (Class III or IV according to the New York Heart Association Classification of Cardiovascular Diseases).

c. Active central nervous system disease confirmed by cytology or cerebrospinal fluid imaging.

d. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.

e. Other underlying severe and/or uncontrolled underlying medical conditions that may pose an unacceptable safety risk or compromise protocol compliance.

7. Subject has previously received systemic anticancer treatment (approved or investigational) >5 half-lives or 4 weeks prior to initiation of Compound 1, whichever is shorter.

8. Subject has previously received CAR-T or other T cell-targeted therapy (approved or investigational) <4 weeks prior to initiation of Compound 1.

9. Subject has previously received therapy with a CRBN modulating drug (eg, lenalidomide, avadomide/CC-122, pomalidomide) <4 weeks prior to initiation of Compound 1.

10. A history of second malignancies with a life expectancy of <2 years or the need for therapy that could distort the study results. This does not include the following:

a. Basal cell carcinoma of the skin.

b. Squamous cell carcinoma of the skin.

c. Carcinoma in situ of the cervix.

d. Carcinoma in situ of the breast.

e. Carcinoma in situ of the bladder.

f. Incidental histological detection of prostate cancer (tumor, node, metastasis [TNM] stage TNM T1a or T1b).

11. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV) or hepatitis B or C virus (HBV, HCV). Screening for hepatitis B is mandatory for all patients (HBsAg and anti-HBc). Patients with active hepatitis B should not be treated

- 30 046110 obinutuzumab. Patients should be referred to a specialist if they are carriers before starting treatment (see PI or SmPC). Subjects who are positive for anti-HBc and/or antiHBs but negative for HBsAg and HBV DNA can be treated after consultation with a hepatologist.

12. Peripheral neuropathy >2 degrees.

13. Use of systemic corticosteroids in doses exceeding the dose of prednisolone equivalent to 20 mg/day.

14. Drugs are likely to cause QT prolongation or torsade de pointes (TdP). Subjects chronically taking medications in this category may be included after discussion with a medical supervisor if a change in these medications is not in the patient's medical best interests.

15. History of hypersensitivity to immunomodulatory imide drugs (IMiDs®) (lenalidomide, pomalidomide, thalidomide).

16. Cardiac dysfunction or clinically significant heart disease, including any of the following:

a. LVEF<45% according to MUGA scan or ECHO.

b. Complete left bundle branch block or bifascicular block.

With. Congenital long QT syndrome.

d. Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation.

e. QTcF>470 ms on screening ECG (average of three recordings).

f. Unstable angina or myocardial infarction <6 months before starting Compound 1.

g. Uncontrolled congestive heart failure or uncontrolled hypertension.

17. Persistent diarrhea or malabsorption >NCI CTCAE grade 2 despite drug treatment.

18. Transformation of active disease (i.e. Richter syndrome); subjects with Richter syndrome that resolved >2 years after signing the ICF are eligible to participate.

19. Known acute or chronic pancreatitis.

20. Pregnant or breastfeeding women.

21. Hypersensitivity to obinutuzumab or any of the excipients.

Duration of Study: The entire study is expected to last approximately 4 years. The study consists of three phases: screening, treatment and follow-up. During the screening phase, which lasts up to 28 days from signing the informed consent to the first dose, subjects are assessed to determine their eligibility.

Subjects eligible for study inclusion will enter the treatment phase, during which subjects receive investigational product(s) [IP] at a predetermined dose and schedule until the underlying CLL/SLL progresses or the subject discontinues treatment of IP due to unacceptable toxicity or other reasons.

The follow-up phase begins when study treatment is discontinued. Subjects are visited at the end of treatment as soon as possible after discontinuation of IP and 28 days after the last dose of IP. All subjects who discontinue participation for any reason other than progressive disease, withdrawal of consent, or death are contacted every 90 days after the date of the 28-day follow-up visit to obtain information about their disease status and the type and start date for any subsequent antineoplastic therapy. . Efficacy assessments (including clinical, laboratory tests, and CT scans) continue until Parkinson's disease is confirmed or subsequent anti-CLL therapy is initiated.

The end of the trial is defined as either the date of the last visit of the last subject to complete post-treatment follow-up, or the date of the last data point from the last subject that is required for primary, secondary and/or exploratory analyzes as specified in the protocol, as appropriate. what date will be later?

Study Treatment: Subjects begin treatment once eligibility is confirmed.

Obinutuzumab is administered as an intravenous infusion. Obinutuzumab is administered on days 1, 2, 8, and 15 of cycle 1. Obinutuzumab is administered at a dose of 100 mg on day 1 of cycle 1, 900 mg on day 2 of cycle 1, and 1000 mg on each of days 8 of cycle 1 and day 15 of cycle 1. The dose of obinutuzumab on days 1 and 2 of cycle 1 may be adjusted according to institutional practice if the combination dose is 1000 mg. Obinutuzumab is administered at a dose of 1000 mg per day 1 of cycles 2 to 6.

All active subjects who, in the judgment of the treating investigator, are receiving clinical benefit may continue to receive investigational treatment for up to a maximum of 24 cycles of Compound 1 or until disease progression (PD), unacceptable toxicity, or discontinuation of treatment for any other reason, whichever occurs. earlier. If Compound 1 is discontinued prior to obinutuzumab, obinutuzumab will also be discontinued. In case of graduation

- 31 046110 for permanent discontinuation of obinutuzumab, administration of compound 1 can be continued. Subjects who achieve minimal residual disease (MRD) negativity (in both peripheral blood and bone marrow) for at least 3 months have the option to discontinue study treatment; study treatment in these subjects may be restarted at the time of positive MRD.

Overview of Key Effectiveness Evaluations: Efficacy evaluations include 1) overall response rate (ORR) [complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodal partial response (nPR), partial response (PR), partial response with lymphocytosis (PRL)] as assessed by iwCLL 2018 guidelines (Tables 1 and 2); 2) clinical laboratory tests; 3) tumor imaging assessment (CT scan), 4) one bone marrow aspiration/biopsy; 5) general ECOG status; 6) assessment of Vsymptom.

Summary of Key Safety Assessments: Safety assessments include 1) adverse events using NCI CTCAE v 5 unless otherwise noted for individual AEs; 2) vital signs; 3) medical examination; 4) concomitant medications and procedures; 5) electrocardiogram (ECG); 6) clinical and laboratory studies (including hematology and clinical chemistry with assessment of renal and liver function); 7) pregnancy testing; 8) left ventricular ejection fraction (LVEF).

Overview of pharmacokinetic evaluations: Blood samples were collected according to intensive and selective sampling strategies to characterize the PK of compound 1 when administered in combination with obinutuzumab. Obinutuzumab serum concentrations are measured at specific time points. Exposure-response relationship trends for Compound 1 and markers of efficacy, safety, and biological response are also examined.

Example 8: Phase I Clinical Study

A Phase 1b, multicenter, open-label study is being conducted to determine the safety, pharmacokinetics, and preliminary efficacy of Compound 1 in combination with obinutuzumab in subjects with relapsed or refractory chronic lymphocytic leukemia/small cell lymphocytic lymphoma (R/R CLL/SLL).

Objectives: The primary objectives of the study are to determine the safety and tolerability of Compound 1 in combination with obinutuzumab in subjects with R/R CLL/SLL. Another primary objective is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of Compound 1 in combination with obinutuzumab in subjects with R/R CLL/SLL.

Secondary objectives are to evaluate the preliminary efficacy of Compound 1 in combination with obinutuzumab in subjects with R/R CLL/SLL and to determine the pharmacokinetics (PK) of Compound 1 when used in combination with obinutuzumab in subjects with R/R CLL/SLL.

Study Design: This is an open-label, phase 1b study to evaluate the safety, PK, and preliminary efficacy of compound 1 administered orally in combination with obinutuzumab in subjects with R/R CLL/SLL. All eligible subjects must have relapsed or been refractory to at least 2 prior lines of therapy for CLL/SLL, including a B cell receptor signaling inhibitor (approved Bruton's tyrosine kinase inhibitor [BTKi] or phosphoinositide 3-kinase inhibitor [PDKi] ]) or venetoclax. Prior therapy with a regimen containing obinutuzumab is allowed.

All subjects must have an indication for treatment at study entry. The study is conducted in two parts: Part A (dose escalation) and Part B (dose cohort expansion). Dose Escalation (Part A) evaluates the safety, tolerability, and RC of increasing doses of Compound 1 administered in combination with intravenous obinutuzumab to determine the MTD and RP2D of Compound 1 when administered in combination with obinutuzumab. Part A may include approximately 25-30 subjects. The actual amount depends on the number of regimens/dose levels required to determine the MTD or RP2D. Compound 1 is administered orally once daily (QD) on scheduled dosing days. The starting dose/schedule of compound 1 is 0.2 mg/day for 7 consecutive days (starting on day 15 of cycle 1), followed by 7 days off study drug every 14 days (7/14 day regimen) at every 28 day cycle. If the initial dose/regimen is not tolerated, a lower dose or less intense regimen may be studied. All treatments are continued until disease progression, unacceptable toxicity, death, or subject/physician decision to discontinue treatment, up to 24 cycles or 2 years of total treatment.

Following completion of dose escalation (Part A), a selected expansion cohort (Part B) of approximately 20 evaluable subjects receives Compound 1 in combination with obinutuzumab. Safety/tolerability, PK, and preliminary efficacy evaluations of additional expansion cohorts of combinations of Compound 1 with other CLL/SLL agents of interest (eg, rituximab, ibrutinib, venetoclax, or other agent) may be initiated in parallel in Part B. Study enrollment occurs worldwide , including in the United States (US), Europe and/or Canada. Additional countries and locations may be added for Part B and/or Part A.

A Bayesian logistic regression model (BLRM) is used to assist in making decisions about increasing/decreasing the dose of compound 1 (Neuenschwander B, et al., Statistics in medicine 2008,

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27:2420-39) with overdose control (EWOC) (Babb J, et al., Statistics in Medicine 1998, 17:1103-20).

A subject to be assessed for dose-limiting toxicity (DLT) is defined as a subject who: 1) received at least 75% of the planned dose of compound 1 and obinutuzumab from day 15 of cycle 1 to day 14 of cycle 2 without experiencing a DLT, or 2 ) experienced DLT after receiving at least 1 dose or fraction thereof of compound 1 from day 15 of cycle 1 to day 14 of cycle 2.

An alternative dosing schedule for Compound 1 (eg, 5/14 days, 14/28 days, or 21/28 days) may be explored based on a review of available clinical safety, PQ, and PD data. If a new regimen is being studied, the total planned dose intensity for the cycle will not exceed the intensity of the previously tolerated regimen or its currently permitted increase, and the maximum daily dose will not exceed a 100% increase in the previously tolerated daily dose in any regimen. The BLRM will be adjusted with each regimen as a covariate while another regimen may be examined.

The first cohort is treated on a 7/14 day dosing schedule with a daily dose of 0.2 mg.

If toxicity is observed at the initial dose, a dose level of -1 (DL-1)0.1 mg/day can be studied.

The total daily dose to be administered to the next cohort is determined based on the calculation or dose recommended by the BLRM (Neuenschwander B, et al., Statistics in medicine 2008, 27:2420-39) with overdose control (EWOC) (Babb J, et al ., Statistics in Medicine 1998, 17:1103-20), taking into account the available safety, collected RK and PD data. Planned dose levels are 0.1 mg, 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.2 mg, and 1.6 mg. However, it is possible that the actual dose levels selected for the study may differ from the preliminary dose levels based on the analysis of safety, PK, PD, and efficacy data.

The MTD of Compound 1 in combination with obinutuzumab had a MTD of 25%; the minimum sample size per dose cohort will be 3 subjects. The total number of subjects required to determine the MTD of compound 1 in combination with obinutuzumab is estimated to be approximately 25-30 subjects.

In Part B, cohort expansion may occur at the MTD established in the dose escalation phase or at an alternative valid dosing schedule based on the safety, PQ, and PD data from Part A.

Best overall response is determined by the criteria outlined at the international workshop on chronic lymphocytic leukemia (iwCLL) (Table 1). The answer is assessed by the researcher. To expand the cohort, one or more dosing regimens may be selected.

Study Population: Study subjects will include men and women aged 18 years or older with R/R CLL/SLL who have failed previous therapy as specified in the inclusion/exclusion criteria.

Inclusion Criteria: To be included in the study, subjects must meet the following criteria:

1. Subject's age >18 years at the time of signing the informed consent form (ICF).

2. The subject must understand and voluntarily sign the ICF prior to any study-related assessments/procedures.

3. The subject is willing and able to comply with the study visit schedule and other protocol requirements.

4. The subject must have a documented diagnosis of CLL/SLL requiring treatment (iwCLL Guidelines for the Diagnosis and Treatment of CLL (Tables 1 and 2).

Additionally:

A. The presence of a clinically measurable disease determined by at least one of the following factors:

nodular lesion measuring >1.5 cm in the longest dimension (LD) and >1.0 cm in the longest perpendicular dimension (LPD), or spleen measuring >14 cm in the longest vertical dimension (LVD) with a minimum of 2 cm enlargement , or liver size >20 cm in LVD with at least 2 cm increase, or peripheral blood B-lymphocyte count >5000/μL.

5. The subject must meet criteria for relapsed and/or refractory disease according to iwCLL guidelines for at least two prior lines of therapy.

6. All eligible subjects must have relapsed or be refractory to at least two prior lines of therapy, one of which must include a B-cell receptor signaling inhibitor (BTKi or PDKi approved) or venetoclax. Prior therapy with a regimen containing obinutuzumab is allowed.

7. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Table 2).

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8. Subjects who meet the following laboratory parameters:

A. Absolute neutrophil count (ANC) >1500 cells/mm ³ or >1000 cells/mm ³ if the disease is secondary to bone marrow involvement.

b. Platelet count >100,000 cells/mm ³ (100x10 ⁹ /L) or >50,000 cells/mm ³ (50x 10 ⁹ /L) if the disease is secondary to bone marrow damage.

c. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) <3.0 x upper limit of normal (ULN).

d. Serum bilirubin <1.5xULN unless associated with Gilbert's syndrome.

e. Estimated serum creatinine clearance >60 mL/min using the Cockcroft-Gault equation or directly from the 24-hour urine collection method.

9. Consent to scheduled pregnancy testing and pregnancy risk management plan during the study and 28 days after the end of study treatment. This applies even if the subject practices complete abstinence from heterosexual intercourse. A woman of childbearing age (FCBP) is a woman who: 1) has reached menarche at some point, 2) has not had a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea after cancer treatment does not preclude reproductive function) for at least 24 consecutive months (i.e. she had menstruation at any time during the previous 24 consecutive months) and must:

a. Have two negative pregnancy tests confirmed by the investigator before starting study therapy. A pregnancy screening test (urine or serum) is performed on day -14, day -1, day 1 before cycle 1, and a second confirmatory test (serum) is performed within 24 hours of day 1 of cycle 1. In addition, a pregnancy test must be performed 24 hours before day 15 of cycle 1 before administration of compound 1. She must agree to ongoing pregnancy testing during the study and after completion of study therapy. This applies even if the subject practices complete abstinence from heterosexual intercourse.

b. Either agrees to completely abstain from heterosexual intercourse (which must be reviewed monthly and documented), or agrees to use and be able to comply with two reliable forms of contraception without interruption, as defined in the RRR and provided to the subject at the time of obtaining informed consent, 28 days before administration of Compound 1, during study therapy (including dosing breaks) and for 28 days after discontinuation of study therapy or 18 months after the last dose of obinutuzumab, whichever occurs last.

c. Avoid conception for 28 days after the last dose of Compound 1.

d. Agrees to refrain from breastfeeding while taking Compound 1 and for 28 days after stopping it.

e. Agree to refrain from donating eggs while taking Compound 1 and for 30 days after stopping it.

Male subjects must practice total abstinence (which should be reviewed monthly) or consent to the use of a condom (latex condom recommended) during sexual intercourse with a pregnant or childbearing-age woman while participating in the study, during dosage breaks, and during at least 3 months after discontinuation of the study product, or longer if required for each compound and/or local regulations, even if he has had a successful vasectomy. Men must agree to refrain from donating semen or sperm while taking Compound 1 and for 90 days after stopping it. (True abstinence is acceptable if consistent with the subject's preferred and usual lifestyle. Intermittent abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and abstinence are not acceptable methods of contraception.)

Exclusion Criteria: The presence of any of the following excludes a subject from inclusion:

1. The subject has any serious medical condition, laboratory abnormality, or mental illness that prevents the subject from participating in the study.

2. The subject has any condition, including the presence of laboratory abnormalities, that would place the subject at an unacceptable risk if he/she were to participate in the study.

3. The subject has a condition that interferes with the ability to interpret test data.

4. Previous allogeneic stem cell transplant (SCT)/bone marrow transplant within 12 months of signing the ICF. Subjects who received allogeneic SCT >12 months before signing the ICF may be eligible for participation provided there is no ongoing graft-versus-host disease (GVHD) and ongoing immunosuppressive therapy.

5. Current or active infection requiring parenteral antibiotics.

6. Uncontrolled intercurrent illness, including but not limited to:

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A. Chronic symptomatic congestive heart failure (class III or IV according to the New York Heart Association classification of cardiovascular diseases).

b. Active central nervous system disease confirmed by cytology or cerebrospinal fluid imaging.

c. Uncontrolled/active autoimmune hemolytic anemia or thrombocytopenia.

d. Other underlying severe and/or uncontrolled underlying medical conditions that may pose an unacceptable safety risk or compromise protocol compliance.

7. Subject has previously received systemic anticancer treatment (approved or investigational) <5 half-lives or 4 weeks prior to initiation of Compound 1, whichever is shorter.

8. Subject has previously received CAR-T or other T cell-targeting therapy (approved or investigational) <4 weeks prior to initiation of Compound 1.

9. Subject has previously received therapy with a CRBN modulating drug (eg, lenalidomide, avadomide/CC-122, pomalidomide) <4 weeks prior to initiation of Compound 1.

10. A history of second malignancies with a life expectancy of <2 years or the need for therapy that could distort the study results. Such cases should be discussed with a medical supervisor. This does not include the following:

a. Basal cell carcinoma of the skin.

b. Squamous cell carcinoma of the skin.

c. Carcinoma in situ of the cervix.

d. Carcinoma in situ of the breast.

e. Carcinoma in situ of the bladder.

f. Incidental histological detection of prostate cancer (tumor, node, metastasis [TNM] stage TNM T1a or T1b).

11. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV) or hepatitis B or C virus (HBV, HCV). Screening for hepatitis B is mandatory for all patients (HBsAg and anti-HBc). Patients with active hepatitis B should not be treated with obinutuzumab. Patients should be referred to a specialist if they are carriers before starting treatment (see Gazyva PI or Gazyvaro SmPC). Subjects who are positive for antiHBc and/or anti-HBs but negative for HBsAg and HBV DNA can be treated after consultation with a hepatologist. This does not include false-positive results for patients receiving intravenous immunoglobulin (IVIG).

12. Peripheral neuropathy >2 degrees.

13. Subject is on chronic systemic immunosuppressive therapy or corticosteroids (eg, prednisolone or equivalent not to exceed 10 mg per day for the last 14 days) or subjects with clinically significant GVHD.

a. Stable use of inhaled corticosteroids is acceptable.

b. The use of topical steroids for ongoing cutaneous or ocular GVHD is permitted.

14. History of hypersensitivity to lenalidomide, pomalidomide, thalidomide.

15. Cardiac dysfunction or clinically significant heart disease, including any of the following:

A. LVEF <45% by MUGA or ECHO scan.

b. Complete left bundle branch block or bifascicular block.

With. Congenital long QT syndrome.

d. Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation.

e. QTcF >470 ms on screening ECG (average of three recordings).

f. Unstable angina or myocardial infarction <6 months before starting Compound 1.

16. Persistent diarrhea or malabsorption >NCI CTCAE grade 2 despite drug treatment.

17. Transformation of active disease (i.e. Richter syndrome); subjects with Richter syndrome that resolved >2 years after signing the ICF are eligible to participate.

18. Known acute or chronic pancreatitis.

19. Pregnant or breastfeeding women.

20. Hypersensitivity to obinutuzumab or any of the excipients.

21. Concomitant use of strong CYP3A4/5 modulators.

Duration of Study: The entire study is expected to last approximately 4 years. The study consists of three phases/periods: screening, treatment and follow-up. During the screening phase, which lasts up to 28 days from signing the informed consent to the first dose, subjects are assessed to determine their eligibility.

Subjects eligible for inclusion in the study will enter the treatment phase.

- 35 046110 study during which subjects receive investigational product(s) [IP] at a predetermined dose and schedule in combination with obinutuzumab until the underlying CLL/SLL progresses or the subject discontinues IP treatment due to unacceptable toxicity or for other reasons.

The follow-up phase begins when study treatment is discontinued. Subjects are visited at the end of treatment as soon as possible after discontinuation of IP and 28 days after the last dose of IP. All subjects who discontinue participation for any reason other than progressive disease, withdrawal of consent, or death are contacted every 90 days after the date of the 28-day follow-up visit to obtain information about their disease status and the type and start date for any subsequent antineoplastic therapy. . Efficacy assessments (including clinical, laboratory tests, and CT scans) continue until Parkinson's disease is confirmed or subsequent anti-CLL therapy is initiated.

The end of the study is defined as either the date of the last visit of the last subject to complete post-treatment follow-up, or the date of the last data point from the last subject that is required for the primary, secondary and/or exploratory analysis as specified in the protocol, as appropriate. what date will be later?

Study Treatment: Subjects begin treatment once eligibility is confirmed.

Compound 1 is supplied as oral capsules in appropriate dosages. Compound 1 is started on day 15 of cycle 1 at a dose of 0.2 mg daily and is administered orally for 7 consecutive days, followed by a 7-day break in study drug every 14 days (7/14 day regimen) in each 28-day period. cycle.

Obinutuzumab is administered as an intravenous infusion. Obinutuzumab is administered on days 1, 2, 8, and 15 of cycle 1. Obinutuzumab is administered at a dose of 100 mg on day 1 of cycle 1, 900 mg on day 2 of cycle 1, and 1000 mg on each of days 8 of cycle 1 and day 15 of cycle 1. The dose of obinutuzumab on days 1 and 2 of cycle 1 may be adjusted according to institutional practice if the combination dose is 1000 mg. Subjects should receive the full initial dose of obinutuzumab 1000 mg in cycle 1 at least one week before starting Compound 1. Obinutuzumab is administered at a dose of 1000 mg on day 1 of cycles 2 to 6.

All active and/or ongoing subjects who, in the judgment of the treating investigator, are receiving clinical benefit may continue to receive investigational treatment for up to a maximum of 24 cycles, or 2 years of Compound 1, or until disease progression (PD), unacceptable toxicity, or discontinuation by any other reason, whichever comes first. If Compound 1 is discontinued prior to obinutuzumab, obinutuzumab will also be discontinued. If obinutuzumab is permanently discontinued, Compound 1 may be continued. Subjects who achieve minimal residual disease (MRD) negativity (in both peripheral blood and bone marrow) for at least 3 months have the option to discontinue study treatment; study treatment in these subjects may be restarted at the time of positive MRD. Overview of Key Effectiveness Evaluations: Efficacy evaluations include 1) overall response rate (ORR) [complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodal partial response (nPR), partial response (PR), partial response with lymphocytosis (PRL)] as assessed by iwCLL 2018 guidelines (Tables 1 and 2); 2) clinical laboratory tests; 3) tumor imaging assessment (CT scan), 4) one bone marrow aspiration/biopsy; 5) General ECOG condition; 6) Assessment of B-symptom.

Summary of Key Safety Assessments: Safety assessments include 1) adverse events (AEs) using NCI CTCAE v 5 unless otherwise noted for selected AEs; 2) vital signs; 3) medical examination; 4) concomitant medications and procedures; 5) electrocardiogram (ECG); 6) clinical and laboratory studies (including hematology and clinical chemistry with assessment of renal and liver function); 7) pregnancy testing; 8) left ventricular ejection fraction (LVEF).

Overview of pharmacokinetic evaluations: Blood samples were collected according to intensive and selective sampling strategies to characterize the PK of compound 1 when administered in combination with obinutuzumab. Obinutuzumab serum concentrations are measured at specific time points. Exposure-response relationship trends for Compound 1 and markers of efficacy, safety, and biological response are also examined. Exposure-response relationships can be studied for clinical response rates (efficacy and toxicity) and biomarkers.

A number of references have been cited, the description of which is incorporated herein by reference in their entirety.

The embodiments of the invention described above are intended to be exemplary only, and those skilled in the art will understand or be able to ascertain, using no more than routine experimentation, numerous equivalents to specific compounds, materials, and procedures. All such equivalents are deemed to be within the scope of the invention and are covered by the appended claims.

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Claims (41)

CLAIM 1. A method of treating chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), comprising administering to a subject with CLL/SLL a therapeutically effective amount of a compound of formula 3: or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. 2. A method of treating chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), comprising administering to a subject with CLL/SLL a therapeutically effective amount of compound 1 of formula: or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. 3. A method of treating chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), comprising administering to a subject with CLL/SLL a therapeutically effective amount of compound 2 of formula: or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. 4. The method according to claim 2, including the introduction of compound 1 of the formula: 5. The method according to claim 2, including the administration of a pharmaceutically acceptable salt of compound 1 of the formula: 6. The method according to any one of claims 1 to 5, wherein the CLL/SLL is relapsed or refractory CLL/SLL. 7. The method of claim 6, wherein the CLL/SLL is relapsed or refractory to at least two prior therapies. 8. The method according to claim 7, wherein at least one of the preceding therapies is with - 37 046110 bout Bruton's tyrosine kinase inhibitor (BTK), phosphoinositide 3-kinase inhibitor or venetoclax. 9. The method of claim 8, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib. 10. The method according to any one of claims 1 to 5, in which CLL has been diagnosed for the first time. 11. Method according to any one of claims 1 to 10, wherein the compound is administered orally. 12. The method according to any one of claims 1 to 11, in which the compound is administered once a day for 5 days, followed by a 2-day break. 13. The method according to any one of claims 1 to 11, in which the compound is administered once a day for 7 days, followed by a 7-day break. 14. The method according to any one of claims 1 to 11, in which the compound is administered once a day for 5 days, followed by a 9-day break. 15. The method according to any one of claims 1 to 11, in which the compound is administered once a day for 14 days, followed by a 14-day break. 16. The method according to any one of claims 1 to 11, in which the compound is administered once a day for 21 days, followed by a 7-day break. 17. The method according to any one of claims 1 to 11, in which the compound is administered from days 1 to 5 of a 7-day cycle, from days 1 to 3 of a 7-day cycle, from days 1 to 5 of a 14-day cycle, from 1 to 7 days of a 14-day cycle, days 1 to 10 of a 14-day cycle, days 1 to 7 and days 15 to 21 of a 28-day cycle, days 1 to 21 of a 28-day cycle or days 1 to 14 of a 28-day cycle cycle. 18. The method according to any one of claims 1 to 17, in which the compound is administered in an amount of 0.1 mg, 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.2 mg or 1, 6 mg per day. 19. The method of any one of claims 1 to 18, further comprising administering to the subject a therapeutically effective amount of obinutuzumab. 20. The method of claim 19, wherein obinutuzumab is administered intravenously. 21. The method according to claim 20, in which obinutuzumab is administered at a dose of 100 mg on day 1 of the first 28-day cycle, 900 mg on day 2 of the first 28-day cycle and 1000 mg on each of days 8 and 15 of the first 28-day cycle and 1 day from the second to sixth 28-day cycles. 22. The method according to claim 19, including (i) administering obinutuzumab at a dose of 100 mg on day 1, 900 mg on day 2, 1000 mg on each of days 8 and 15 of the first 28-day cycle (cycle 1) and at a dose of 1000 mg on day 1 of subsequent 28-day cycle(s); and (ii) administering Compound 1 or a pharmaceutically acceptable salt thereof in cycles of once daily for 7 days followed by a 7-day rest period, beginning on day 15 of Cycle 1. 23. The method according to claim 19, including (i) administering obinutuzumab at a dose of 100 mg on day 1, 900 mg on day 2, 1000 mg on each of days 8 and 15 of the first 28-day cycle (cycle 1) and at a dose of 1000 mg on day 1 of subsequent 28-day cycle(s); and (ii) administering Compound 1 or a pharmaceutically acceptable salt thereof in cycles of once daily for 5 days followed by a 9-day rest period, beginning on day 15 of Cycle 1. 24. The method according to claim 19, including (i) administering obinutuzumab at a dose of 100 mg on day 1, 900 mg on day 2, 1000 mg on each of days 8 and 15 of the first 28-day cycle (cycle 1) and at a dose of 1000 mg on day 1 of subsequent 28-day cycle(s); and (ii) administering Compound 1 or a pharmaceutically acceptable salt thereof in cycles of once daily for 14 days followed by a 14-day rest period, beginning on day 15 of Cycle 1. 25. The method according to claim 19, comprising (i) administering obinutuzumab at a dose of 100 mg on day 1, 900 mg on day 2, 1000 mg on each of days 8 and 15 of the first 28-day cycle (cycle 1) and at a dose of 1000 mg on day 1 of subsequent 28-day cycle(s); and (ii) administering Compound 1 or a pharmaceutically acceptable salt thereof in cycles of once daily for 21 days followed by a 7-day rest period beginning on day 15 of Cycle 1. 26. Application of compound 3 of the formula: ABOUT 3, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof, for the treatment of chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL). 27. Application of compound 1 of the formula: - 38 046110 or a tautomer, isotopologue or pharmaceutically acceptable salt thereof, for the treatment of chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL). 28. Application of compound 2 of the formula: or a tautomer, isotopologue or pharmaceutically acceptable salt thereof, for the treatment of chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL). 29. Use according to claim 27, where the compound is compound 1 of the formula: 30. Use according to claim 27, where the compound is a pharmaceutically acceptable salt of compound 1 of the formula: 31. Use according to any one of claims 26 to 30, wherein the CLL/SLL is relapsed or refractory CLL/SLL. 32. Use according to claim 31, wherein the CLL/SLL is relapsed or refractory to at least two previous therapies. 33. The use of claim 32, wherein at least one of the preceding therapies is a Bruton's tyrosine kinase (BTK) inhibitor, a phosphoinositide 3-kinase inhibitor, or venetoclax. 34. Use according to claim 33, wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib. 35. Use according to any one of claims 26-30, wherein CLL is newly diagnosed. 36. Use according to any one of claims 26 to 35, wherein the compound is administered orally. 37. Use according to any one of claims 26-36, where the compound is administered once a day for 5 days, followed by a 2-day break. 38. Use according to any one of claims 26-36, where the compound is administered once a day for 7 days, followed by a 7-day break. 39. Use according to any one of claims 26-36, where the compound is administered once a day for 5 days, followed by a 9-day break. 40. Use according to any one of claims 26-36, where the compound is administered once a day for 14 days, followed by a 14-day break. 41. Use according to any one of claims 26-36, where the compound is administered once a day for 21 days from -