TW202434250A - Lurbinectedin and doxorubicin combination - Google Patents

Abstract

Described are combination therapy for the treatment of cancer, particularly soft-tissue sarcoma, comprising lurbinectedin and doxorubicin at low doses.

Description

Combination of lubitidin and doxorubicin

The present invention relates to therapeutic treatment of cancer, and more particularly to a dosing schedule for treating cancer. Specifically, the present invention relates to a combination therapy using low doses of lurbinectedin and doxorubicin.

Lubitidin, also known as PM01183 and originally called tryptamicidin, is a synthetic alkaloid with antitumor activity and the subject of WO 03/01427. Lubitidin is a selective inhibitor of oncogenic transcription, induces apoptosis by DNA double strand breaks, and modulates the tumor microenvironment. For example, by inhibiting active transcription in tumor-associated macrophages, Lubitidin downregulates IL-6, IL-8, CCL2, and VEGF.

The chemical structure of lubitidin is shown below:

It is a selective inhibitor of oncogenic transcriptional programs that many tumors are particularly dependent on. Along with its effects on cancer cells, lubiteldin inhibits oncogenic transcription in tumor-associated macrophages, thereby downregulating the production of cytokines that are essential for tumor growth. Transcriptional addiction is a recognized target in these diseases, many of which lack other actionable targets.

Lubivent was approved in the United States in 2020 and is sold in the United States for the treatment of adult patients with metastatic small cell lung cancer (SCLC) whose disease has progressed on or after platinum-based chemotherapy. The recommended dose is 3.2 mg/m2 by intravenous infusion every 21 days. In 2021, Lubivent was also approved in the United Arab Emirates, Canada, Australia and Singapore.

Adriamycin is a cytotoxic, anthracycline, and topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius . Chemically, adriamycin hydrochloride is: 5,12-fused tetraphenyldione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxosyl-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride (8S-cis).

The cytotoxic effect of doxorubicin on malignant cells is related to the nucleobase intercalation and cell membrane lipid binding activity of doxorubicin. The interaction between doxorubicin and topoisomerase II to form a DNA-cleavable complex is an important mechanism of the cytocidal activity of HCl doxorubicin.

Doxorubicin is FDA-approved and marketed for the treatment of acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms' tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic skeletal sarcoma, metastatic ovarian cancer, metastatic transitional cell bladder cancer, metastatic thyroid cancer, metastatic gastric cancer, and metastatic bronchogenic carcinoma. As a single agent, the recommended standard starting dose of doxorubicin per cycle in adults is 60-75 mg/m2 of body surface area, with the standard doxorubicin administration cycle limited to 6 cycles.

The combination of lubitidin and doxorubicin has been studied in different clinical trials:

A closed study of PM01183 in combination with fixed doxorubicin (DOX) in selected patients with advanced solid tumors who have not been heavily pretreated. A phase I multicenter, open-label, clinical and pharmacokinetic study (PM1183-A-003-10; NCT01970540) determined the recommended dose (RD) of abiraterone combined with doxorubicin (DOX) as a 1-hour infusion on day 1 every 3 weeks (D1 q3wk) in selected patients with advanced solid tumors. Abiraterone was administered at a dose of 2.0 mg with doxorubicin 50.0 mg/ ^m2 every 3 weeks (q3wk).

On the other hand, the completed Phase III study PM1183-C-003-14 (ATLANTIS) compared albiventin in combination with doxorubicin with CAV or topotecan in patients with small cell lung cancer (SCLC) who had been previously treated with one prior platinum-containing line but no more than one prior platinum-containing line of chemotherapy. Patients received doxorubicin 40 mg/m ² and albiventin 2.0 mg/m ² by intravenous infusion (iv) on D1 q3wk for up to ten cycles, followed by albiventin single agent 3.2 mg/m ² intravenously on D1 q3wk.

Regarding the treatment of sarcomas, Cote et al., Eur, J. Cancer 126 (2020) pp. 21-32 discloses a phase 2 multistratified study using a combination of doxorubicin and lubiventin for the treatment of metastatic and/or resectable sarcomas, such as leiomyosarcoma (LMS). Patients received 50 mg/m2 of doxorubicin on day 1 of a 21-day cycle, followed by 2 mg/m2 of ^lubiventin . After 6 cycles, patients whose disease was controlled continued to use lubiventin alone at 3.2 mg/ ^m2 .

There is a continuing need for more effective cancer treatments that are safe and effective.

The inventors have identified a dosing regimen for the combination of lubitidin and doxorubicin in the treatment of cancer.

In one embodiment, lupiritidin is provided for use in treating cancer in a patient in need thereof, wherein lupiritidin is administered in combination with adriamycin; and wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle.

In another embodiment, alupidin is provided for use in treating cancer in a patient in need thereof, wherein alupidin is administered in combination with adriamycin; and wherein adriamycin is administered at a low dose.

In another embodiment, a method of treating cancer in a patient in need thereof is provided, wherein the treatment comprises: i) administering to the patient one or more cycles of a combination of abiraterone and adriamycin in a first phase, wherein the adriamycin is administered at a low dose, and ii) administering to the patient one or more cycles of abiraterone alone in a second phase.

In another embodiment, apirate is provided for treating cancer in a patient in need thereof, the treatment comprising: i) administering to the patient one or more cycles of a combination of apirate and adriamycin in a first phase, wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle, and ii) administering to the patient one or more cycles of apirate alone in a second phase.

In another embodiment, adriamycin is provided for use in treating cancer in a patient in need thereof, wherein the treatment comprises administering to the patient a combination of lubiventin and adriamycin; and wherein adriamycin is administered at a low dose; or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle.

In another embodiment, alubidin and adriamycin are provided for use in treating cancer in a patient in need thereof, wherein the treatment comprises administering to the patient a combination of alubidin and adriamycin; and wherein adriamycin is administered at a low dose; or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle.

In another embodiment, adriamycin is provided for treating cancer in a patient in need thereof, the treatment comprising: i) administering to the patient one or more cycles of a combination of adriamycin and lupiride in a first phase; wherein: adriamycin is administered at a low dose, or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle; and ii) administering to the patient one or more cycles of lupiride alone in a second phase.

In another embodiment, lubiventin and adriamycin are provided for treating cancer in a patient in need thereof, the treatment comprising: i) administering to the patient one or more cycles of a combination of lubiventin and adriamycin in a first phase; wherein adriamycin is administered at a low dose, or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle; and ii) administering lubiventin to the patient in a second administration cycle.

In another embodiment, a pharmaceutical package is provided, comprising lubiventin and instructions for use in combination with adriamycin, wherein the adriamycin is administered in a low dose.

In another embodiment, a pharmaceutical package is provided, comprising lubiventin and instructions for use in combination with adriamycin, wherein adriamycin is administered at a dose of 30 mg/m ² or less during each administration cycle.

In another embodiment, a pharmaceutical package is provided, comprising adriamycin and instructions for use in combination with lubiventin; wherein adriamycin is administered at a low dose, or wherein adriamycin is administered at a dose of 30 mg/m ² or less during each administration cycle.

In another embodiment, a pharmaceutical package is provided, comprising lubiventin and doxorubicin and instructions for use of the combination, wherein doxorubicin is administered at a low dose, or wherein doxorubicin is administered at a dose of 30 mg/m ² or less during each administration cycle.

In another aspect, a method of treating cancer is provided, the method comprising administering a combination therapy of lubiventin and adriamycin to a patient in need thereof, wherein the adriamycin is administered at a low dose.

In another embodiment, a method of treating cancer is provided, the method comprising administering to a patient in need thereof a combination therapy of lubiventin and adriamycin, wherein adriamycin is administered at a dose of 30 mg/m ² or less during each administration cycle.

In another embodiment, a method for treating cancer is provided, comprising administering a combination therapy of lupiltidine and adriamycin to a patient in need thereof according to the following schedule: i) administering one or more cycles of the combination of lupiltidine and adriamycin to the patient in a first phase; wherein adriamycin is administered at a low dose, or at a dose of 30 mg/ ^m2 or less during each administration cycle, and ii) administering one or more cycles of lupiltidine alone to the patient in a second phase.

In another embodiment, a use of lubiventin in the manufacture of a medicament for treating cancer is provided, wherein the treatment comprises administering a combination therapy of lubiventin and adriamycin to a patient in need thereof, wherein adriamycin is administered at a low dose; or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle.

In another embodiment, a method of treating cancer comprising administering a combination of lubiventin and adriamycin to a patient in need thereof, wherein the adriamycin is administered at a low dose; or wherein the adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle.

In another embodiment, a use of lubiventin and adriamycin in the manufacture of a medicament for treating cancer is provided, wherein the treatment comprises administering a combination therapy of lubiventin and adriamycin to a patient in need thereof, wherein adriamycin is administered at a low dose; or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle.

In another embodiment, a use of lupiltidine in the manufacture of a medicament for treating cancer is provided, wherein the treatment comprises: i) administering to the patient one or more cycles of a combination of lupiltidine and adriamycin in a first phase; wherein adriamycin is administered at a low dose, or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle, and ii) administering to the patient one or more cycles of lupiltidine alone in a second phase.

In another embodiment, a use of adriamycin in the manufacture of a medicament for treating cancer is provided, wherein the treatment comprises: i) administering to the patient one or more cycles of a combination of lupiltidine and adriamycin in a first phase; wherein adriamycin is administered at a low dose, or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle, and ii) administering to the patient one or more cycles of lupiltidine alone in a second phase.

In another embodiment, a use of lupiltidine and adriamycin in the manufacture of a medicament for treating cancer is provided, wherein the treatment comprises: i) administering to the patient one or more cycles of a combination of lupiltidine and adriamycin in a first phase; wherein adriamycin is administered at a low dose, or wherein adriamycin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle, and ii) administering to the patient one or more cycles of lupiltidine alone in a second phase.

The following embodiments are applicable to all aspects of the present invention.

In one embodiment of the present invention, adriamycin may be administered at a dose of 30 mg/m ² or less during each administration cycle.

In one embodiment of the present invention, adriamycin may be administered at a dose of less than 30 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of between 15 and 30 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of between 20 and 30 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of between 15 and less than 30 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of between 20 and less than 30 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of between 15 and 25 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of between 20 and 25 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of about 25 mg/m ² during each administration cycle.

In another embodiment, adriamycin may be administered at a dose of 25 mg/m ² during each administration cycle.

In another embodiment, a single dose of adriamycin is administered during each administration cycle.

In another embodiment, a single dose of adriamycin is administered on day 1 of each administration cycle.

In another embodiment, a single dose of about 25 mg/m ² of adriamycin is administered during each administration cycle.

In another embodiment, a single dose of 25 mg/m ² of adriamycin is administered during each administration cycle.

In another embodiment, lupiride may be administered at a dose between 2 mg/m ² and 4 mg/m ² of body surface area during each administration cycle.

In another embodiment, alupidol may be administered at a dose of greater than 2 mg/m ² and less than 4 mg/m ² of body surface area during each administration cycle.

In another embodiment, lupiride can be administered at a dose of between 2.5 and 3.5 mg/m ² of body surface area during each administration cycle.

In another embodiment of the present invention, lubitelidine can be administered on day 1 (D1) of each administration cycle.

In another embodiment, lupiride can be administered at a dose of about 3.2 mg/m ² of body surface area during each administration cycle.

In another embodiment, lupiride can be administered at a dose of 3.2 mg/m ² of body surface area during each administration cycle.

In another embodiment, lubitelidine can be administered on day 1 (D1) of each administration cycle.

In another embodiment, alubitidin can be administered at a dose of about 3.2 mg/ ^m2 of body surface area during each administration cycle; and doxorubicin can be administered as follows: a low dose, at a dose of 30 mg/ ^m2 or less during each administration cycle, at a dose of between 15 and 30 mg/ ^m2 during each administration cycle, at a dose of between 20 and 30 mg/ ^m2 during each administration cycle, at a dose of between 15 and 25 mg/ ^m2 during each administration cycle, at a dose of between 20 and 25 mg/ ^m2 during each administration cycle, at about 25 mg/m2 during each administration cycle. ² or at a dose of 25 mg/m ² during each administration cycle.

In another embodiment, the method further comprises administering granulocyte colony stimulating factor (G-CSF).

In another embodiment, G-CSF can be administered on day 1 of the administration cycle.

In another embodiment, patients can begin primary prophylaxis with G-CSF 24-72 hours after day 1 of the administration cycle. Administration can continue for five days.

In another embodiment, G-CSF may be administered during one or more subsequent administration cycles.

In another embodiment, each administration cycle is between 3 weeks and 4 weeks.

In another embodiment, each administration cycle is 21 consecutive days.

In another embodiment, lubitelidine can be administered on day 1 (D1) of each administration cycle.

In another embodiment, lubitelidine and doxorubicin are administered on day 1 (D1) of each administration cycle.

In another embodiment, alubitidin may be administered on day 1 (D1) of each dosing cycle at a dose of about 3.2 mg/ ^m2 of body surface area; and doxorubicin may be administered on day 1 (D1) of each dosing cycle as follows: a low dose, at a dose of 30 mg/ ^m2 or less, at a dose between 15 and 30 mg/ ^m2 , at a dose between 20 and 30 mg/ ^m2 , at a dose between 15 and 25 mg/ ^m2 , at a dose between 20 and 25 mg/ ^m2 , at a dose of about 25 mg/ ^m2 , or at a dose of 25 mg/ ^m2 .

In another embodiment, alubitidin may be administered on day 1 (D1) of each administration cycle at a dose of about 3.2 mg/ ^m2 of body surface area; and doxorubicin may be administered on day 1 (D1) of each administration cycle as follows: a low dose, at a dose of 30 mg/ ^m2 or less, at a dose between 15 and 30 mg/ ^m2 , at a dose between 20 and 30 mg/ ^m2 , at a dose between 15 and 25 mg/ ^m2 , at a dose between 20 and 25 mg/ ^m2 , at a dose of about 25 mg/ ^m2 , or at a dose of 25 mg/ ^m2 ; wherein each administration cycle is between 3 and 4 weeks.

In another embodiment, alubitidin may be administered on day 1 (D1) of each administration cycle at a dose of about 3.2 mg/ ^m2 of body surface area; and doxorubicin may be administered on day 1 (D1) of each administration cycle as follows: a low dose, at a dose of 30 mg/ ^m2 or less, at a dose between 15 and 30 mg/ ^m2 , at a dose between 20 and 30 mg/ ^m2 , at a dose between 15 and 25 mg/ ^m2 , at a dose between 20 and 25 mg/ ^m2 , at a dose of about 25 mg/ ^m2 , or at a dose of 25 mg/ ^m2 ; wherein each administration cycle is 21 days.

In another embodiment, alubitidin may be administered on day 1 (D1) of each administration cycle at a dose of about 3.2 mg/ ^m2 of body surface area; and doxorubicin may be administered on day 1 (D1) of each administration cycle as follows: a low dose, at a dose of 30 mg/ ^m2 or less, at a dose between 15 and 30 mg/ ^m2 , at a dose between 20 and 30 mg/ ^m2 , at a dose between 15 and 25 mg/ ^m2 , at a dose between 20 and 25 mg/ ^m2 , at a dose of about 25 mg/ ^m2 , or at a dose of 25 mg/m2. ² ; wherein the method further comprises administering granulocyte colony stimulating factor (G-CSF); wherein G-CSF may be administered on day 1 of an administration cycle, or wherein the patient may begin primary prophylaxis with G-CSF 24-72 hours after day 1 of an administration cycle and continue for five days; optionally wherein G-CSF is administered during one or more subsequent administration cycles; optionally wherein each administration cycle is between 3 weeks and 4 weeks or is 21 days.

In another embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 administration cycles are administered.

In another embodiment, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles are administered.

In another embodiment, the patient may have a lifetime adriamycin restriction of 450 mg/m ² .

In another embodiment, 7 or more cycles are administered. In another embodiment, 8 or more cycles are administered. In another embodiment, 9 or more cycles are administered. In another embodiment, 10 or more cycles are administered. In another embodiment, 11 or more cycles are administered. In another embodiment, 12 or more cycles are administered. In another embodiment, 13 or more cycles are administered. In another embodiment, 14 or more cycles are administered. In another embodiment, 15 or more cycles are administered. In another embodiment, 16 or more cycles are administered. In another embodiment, 17 or more cycles are administered.

In another embodiment, 7 to 18 cycles are administered. In another embodiment, 8 to 18 cycles are administered. In another embodiment, 9 to 18 cycles are administered. In another embodiment, 10 to 18 cycles are administered. In another embodiment, 11 to 18 cycles are administered. In another embodiment, 12 to 18 cycles are administered. In another embodiment, 13 to 18 cycles are administered. In another embodiment, 14 to 18 cycles are administered. In another embodiment, 15 to 18 cycles are administered. In another embodiment, 16 to 18 cycles are administered. In another embodiment, 17 to 18 cycles are administered. In another embodiment, 18 cycles are administered.

In another embodiment, lubiventin and doxorubicin may be administered as a 1-hour intravenous infusion during each administration cycle.

In another embodiment, adriamycin is administered first, followed by lubitelidine.

In another embodiment, after the combination of lubiventin and doxorubicin is administered for one or more cycles during the first phase; lubiventin is administered alone for one or more cycles during the second phase.

In this application, a number of general terms and phrases are used which should be interpreted as follows.

As used herein, unless otherwise indicated, the term "treating" means reversing, reducing, alleviating, or inhibiting the progression of the disease or condition to which such term applies, or one or more symptoms of such disease or condition. As "treating" is defined just above, as used herein, unless otherwise indicated, the term "treatment" refers to the act of treating.

“Patient” includes humans, non-human mammals (e.g., dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer and the like) and non-mammalian animals (e.g., birds and the like), preferably humans.

To provide a more concise description, some quantitative expressions given herein are not limited by the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each quantity given herein is intended to refer to the actual given value, and it is also intended to refer to the approximate value of the given value reasonably inferred based on the general skilled in the art, including equivalent values and approximate values obtained due to the experimental and/or measurement conditions of the given value.

The expression "administration cycle" refers to a treatment period in which a single cancer drug or a combination of drugs is administered and is usually followed by a rest period. In the present invention, a treatment cycle is a period of four weeks, preferably three weeks, and more preferably 21 consecutive days.

In the present invention, the expression "phase" refers to a treatment period including various administration cycles.

"Albiventin" or PM01183 is a novel synthetic alkaloid that binds to DNA minor grooves, causing spatial distortion of DNA and protein complexes and leading to the formation of DNA double-strand breaks (DSBs), thereby inducing cell apoptosis and delaying progression into the S/G2 phase of the cell cycle. Albiventin has the following structure:

The COMPARE analysis of lubiventin was negative when compared to 98 other standard anticancer agents in the standard National Cancer Institute (NCI) 36 cell line panel. Therefore, its mechanism of action may be significantly different from other drugs. It only showed a positive correlation with trabectedin (S rank > 0.8).

In vitro, lubitidin exhibited cytotoxic effects against a broad selection of tumor-derived cell lines with half-maximal inhibitory concentration (IC ₅₀ ) values in the low to very low nanomolar range (median IC ₅₀ approximately 1E-10 M).

Additional information about the clinical development of PM01183 (lubiventin) can be found in: - Elez, ME. et al., Clin. Cancer Res. 2014, 20(8), 2205-2214; - 50 ^th ASCO Annual Meeting, May 30–June 3, 2014, Chicago, IL, Abstract 5505; - 26 ^th EORTC - 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 18-21, 2014, Barcelona, Spain, published in Eur. J. Cancer 2014, 50 (Suppl 6), pp. 13-14, Abstract 23. - 51 ^th ASCO Annual Meeting, May 29-June 2, 2015, Chicago, IL, Abstracts TPS2604 and 7509, published in J. Clin. Oncol. 33, 2015 (Suppl.); - 54 ^th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract 11519, published in J. Clin. Oncol. 36, 2018 (Suppl.); - Cruz, C. et al., J. Clin. Oncol. 2018, 36(31), 3134-3143; - 54 ^th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract 8570, published in J. Clin. Oncol. 36, 2018 (Suppl.).

Additional information can be found in Xie et al., Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity, Oncoimmunology, 2019, Vol. 8, No. 11, e1656502 (page 9).

In addition, any drug mentioned herein may be in crystalline or amorphous form as a free compound or a solvate (e.g., a hydrate), and all forms are intended to be within the scope of the present invention. Solvation methods are generally known in the art.

Preferred routes of administration are parenteral administration, including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal, or transdermal. The preferred mode of administration is determined by the physician and may depend in part on the site of the medical condition. In a more preferred embodiment, lupiride and doxorubicin according to the present invention are administered intravenously.

In certain embodiments, it may be desirable to administer lubiventin and/or adriamycin locally to the area in need of treatment. In one embodiment, administration may be by direct injection at the site (or former site) of a cancer, tumor, or metastatic or pre-metastatic tissue.

In certain embodiments, lubiventin and/or adriamycin for the treatment of cancer may be administered by infusion and with an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours, and optimally 1 hour. In embodiments, dosing may be from -5 minutes to +20 minutes of the infusion time.

Lubitel may be administered every three weeks or every four weeks, preferably every three weeks.

By "low dose" doxorubicin, it is meant a dose that is less than the dose in which doxorubicin is typically used. Low dose may mean a dose that is less than the dose currently included in the product information for doxorubicin for the relevant indication.

References to doses in mg/ ^m2 refer to doses based on body surface area (BSA).

In a preferred embodiment, the treatment of the present invention comprises: i) administering to the patient one or more cycles of abiraterone at a dose of 3.2 mg/m ² on D1 of each administration cycle in the first phase and adriamycin at a dose of about 25 mg/m ² on D1 of each administration cycle, wherein each administration cycle is 21 days, and ii) administering to the patient one or more cycles of abiraterone alone at a dose of 3.2 mg/m ² on D1 of each administration cycle in the second phase.

In another embodiment, the patient may also receive an antiemetic prophylaxis prior to each infusion, preferably 1 minute before, more preferably 45 minutes before, more preferably 30 minutes before. The antiemetic prophylaxis comprises a corticosteroid and a 5HT3 antagonist. Preferably, the corticosteroid is dexamethasone and the 5HT3 antagonist is ondansetron.

Patients may also receive preventive medications, as described herein, prior to receiving treatment by infusion. Preventive medications include corticosteroids and 5-HT3 receptor antagonists. Specific corticosteroids include dexamethasone. Specific 5-HT3 receptor antagonists include ondansetron. Specific doses include dexamethasone 8 mg intravenous (or an equivalent dose of another intravenous corticosteroid) and ondansetron 8 mg intravenous (or an equivalent dose of another intravenous 5-HT3 receptor antagonist). Preventive medications may be administered on Day 1 of each cycle. In addition, other preventive medications may be administered as needed. Examples include metoclopramide or an equivalent, which may be administered every eight hours in embodiments. After Day 1 and Day 8 of each cycle, extended oral corticosteroids (e.g., dexamethasone up to 20 mg/day) and/or 5-HT3 receptor antagonists (e.g., ondansetron 4-8 mg (or equivalent) orally (or intravenously)) may be administered.

Patients may also receive granulocyte colony stimulating factor G-CSF. An example of G-CSF is nonpegylated filgrastim. For example, patients may receive primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 and over a five-day period. In embodiments, primary G-CSF prophylaxis may also be administered using the same regimen for additional cycles. G-CSF prophylaxis may also be administered at the discretion of the physician.

The present invention has identified a dosing regimen suitable for treating cancer.

In one embodiment, the cancer is a sarcoma.

In one embodiment, the cancer is soft tissue sarcoma.

Sarcomas are rare cancers that develop in muscles, bones, nerves, cartilage, tendons, blood vessels, and fat and fibrous tissue. They can affect almost any part of the body, inside or outside. Sarcomas usually affect the arms, legs, and trunk. They also develop in the stomach and intestines and in the back of the abdomen (retroperitoneal sarcomas) and in the female reproductive system (gynecological sarcomas).

"Soft tissue sarcomas" can affect any part of the body. They arise in supporting or connective tissues such as muscle, nerves, fatty tissue, and blood vessels. Soft tissue sarcomas include: GIST, which is a common type of sarcoma that arises in the gastrointestinal tract (Gl); gynecological sarcomas, which arise in the female reproductive system: uterus (womb), ovaries, vagina, vulva, and fallopian tubes; and retroperitoneal sarcomas, which arise in the retroperitoneal cavity.

There are more than 50 different types of soft tissue sarcoma, including:

Leiomyosarcoma is a type of cancer that starts in the smooth muscle tissue. These tumors usually start in the abdomen, but they can also start in other parts of the body (such as the arms or legs) or in the uterus.

Liposarcoma is a malignant tumor of fatty tissue. It can start anywhere in the body, but it most often starts in the thighs, behind the knees, and inside the back of the abdomen. It mostly appears in adults between the ages of 50 and 65.

Synovial sarcoma is a malignant tumor of the tissue around joints. The most common locations are the hip, knee, ankle, and shoulder. This tumor is more common in children and adolescents, but it can occur in older people.

In a preferred embodiment, the soft tissue sarcoma is selected from leiomyosarcoma (LMS), gastrointestinal stromal tumor (GIST), liposarcoma (LPS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), malignant peripheral nerve sheath tumor (MPNST), angiosarcoma, hemangioendothelioma (EHE), solitary fibroma (SFT), Fibrosarcoma, dermatofibrosarcoma protuberans (DFSP), low-grade fibromyxoid sarcoma (LGFMS), endometrial stromal sarcoma (ESS), myxofibrosarcoma (myxFS), fibromatosis, follicular dendritic cell sarcoma (FDCS), connective tissue proliferative small round cell tumor (DSRC), pleomorphic liposarcoma (PLS), and synovial sarcoma.

In a more preferred embodiment, the cancer may be advanced or metastatic leiomyosarcoma.

Leiomyosarcoma can be autologous soft tissue leiomyosarcoma, cutaneous or subcutaneous leiomyosarcoma, vascular leiomyosarcoma, and uterine (uLMS) or non-uterine leiomyosarcoma.

In a specific embodiment, at D1 of each dosing cycle, a single dose of about 25 mg/m ² of doxorubicin is administered in combination with a dose of about 3.2 mg/m ² of lubiventin for the treatment of leiomyosarcoma.

Pharmaceutical compositions can be prepared using methods well known in the pharmaceutical art. For example, compositions intended for administration by injection can be prepared by combining leuprolide with water or other physiologically suitable diluents (such as phosphate buffered saline) to form a solution. Surfactants may be added to facilitate the formation of a uniform solution or suspension.

Preferred compositions containing albitidin in the present invention may include: ●   A pharmaceutical composition containing albitidin and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosucrose, isotrehalose, turanose, melibiose, gentianbiose and mixtures thereof. ●   A freeze-dried pharmaceutical composition containing albitidin and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosucrose, isotrehalose, turanose, melibiose, gentianbiose and mixtures thereof.

In embodiments of the present invention, the ratio of reuptake to disaccharide is determined based on the solubility of the disaccharide and, when freeze drying the formulation, the freeze drying properties of the disaccharide. It is contemplated that in some embodiments, this reuptake: disaccharide ratio (w/w) may be about 1:10, in other embodiments about 1:20, and in still other embodiments about 1:50. It is contemplated that other embodiments have such ratios ranging from about 1:5 to about 1:500, and still other embodiments have such ratios ranging from about 1:10 to about 1:500.

Compositions comprising alupididine may be lyophilized. Compositions comprising alupididine are typically present in vials containing a specified amount of such compound.

Albivent is available as a lyophilized powder for solution concentrate for infusion, 4 mg/vial. Prior to use, the 4-mg vial can be reconstituted with 8 mL of Sterile Water for Injection to yield a solution containing 0.5 mg/mL albivent. For administration to patients as an intravenous infusion, the reconstituted vial can be diluted with dextrose 50 mg/mL (5%) or sodium chloride 9 mg/mL (0.9%) solution for infusion.

The complete composition of the PM01183 4 mg vial and reconstitution solution/mL can be as follows Components Concentration/vial Concentration after reconstitution/vial PM01183 4.0 mg 0.5 mg/mL sucrose 800 mg 100 mg/mL Lactic acid 22.08 mg 2.76 mg/mL Sodium hydroxide 5.12 mg 0.64 mg/mL

In one embodiment of the present invention, the pharmaceutical package contains lubiventin and, if appropriate, instructions for use in combination with adriamycin, wherein lubiventin is administered in a dose of more than 2 mg/m ² and less than 4 mg/m ² on D1 of each administration cycle in combination with adriamycin at a dose of 30 mg/m ² or less administered on D1 of each administration cycle.

In another embodiment of the present invention, the pharmaceutical package contains lubiventin and doxorubicin, as appropriate, and instructions for their combined use, wherein lubiventin is administered in a dose of more than 2 mg/m ² and less than 4 mg/m ² on D1 of each administration cycle in combination with doxorubicin administered in a dose of 30 mg/m ² or less on D1 of each administration cycle.

In a preferred embodiment of the present invention, the pharmaceutical package contains lubiventin and, if appropriate, instructions for its use in combination with doxorubicin, wherein lubiventin is administered at a dose of 3.2 mg/m ² on D1 of each administration cycle in combination with doxorubicin at a dose of about 25 mg/m ² administered on D1 of each administration cycle.

The present invention will now be further described with reference to the following examples:

Phase 1b Lead-In to Randomized Phase 2 Trial of Abiraterone Plus Adriamycin in Patients with Leiomyosarcoma Study Objectives The objectives of the Phase 1b study are to investigate the safety and efficacy of abiraterone plus adriamycin. After determining the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), a randomized Phase 2 trial in participants with advanced leiomyosarcoma (LMS) will be initiated.

Phase Ib primary objectives: ● To determine the MTD and RDP2 of rubitidin plus doxorubicin in patients with advanced soft tissue sarcoma. Secondary objectives: ● To assess the initial anti-tumor activity of the combination, including disease control rate (DCR) at 6 and 12 months, and PFS, overall survival (OS) and objective response (OR) rates assessed by RECIST version 1.1 criteria. ● To assess the safety and tolerability of the combination of rubitidin plus doxorubicin. Phase II primary objectives: ● To determine the progression-free survival (PFS) rate of rubitidin plus doxorubicin compared with doxorubicin alone in patients with advanced leiomyosarcoma. Secondary objectives: ● To evaluate the anti-tumor activity of the combination, including disease control rate (DCR) at 6 and 12 months, and the ratio of OS and OR, assessed by RECIST version 1.1 criteria. ● To evaluate the safety and tolerability of the combination of lubiventin and doxorubicin. Exploratory objectives of both phases: ● Archival tumor, germline DNA and ctDNA will be collected for related studies that explore genomic markers of sensitivity/resistance.

Study Design The study will be divided into two parts: Phase 1b is ongoing to determine the maximum tolerated dose (MTD) of lubiventin plus doxorubicin in patients with soft tissue sarcoma and to determine the recommended Phase II dose. Phase II is a randomized (1:1) study of lubiventin + doxorubicin versus doxorubicin alone in anthracycline-naïve leiomyosarcoma.

Phase Ib Phase 1b lead-in follows a standard 3+3 design. Patients will receive two dose levels of doxorubicin (the first dose level is 25 mg/ ^m2 of doxorubicin on day 1 only and the second dose level is 25 mg/ ^m2 of doxorubicin on days 1 and 8) intravenously (iv) every three weeks (q3wk) on day 1 as a 60-minute infusion, followed by a fixed dose of 3.2 mg/ ^m2 of PM01183 intravenously as a 1-hour infusion. Cycles are defined as three-week intervals. Phase 1b lead-in follows a standard 3+3 design, where dose escalation will be performed if 0 of 3 patients or 1 of 6 patients experience dose-limiting toxicity (DLT).

In Phase II , 50 patients with leiomyosarcoma will be randomized 1:1 to one of two treatment arms: Arm 1: lubiventin + adriamycin, vs. adriamycin monotherapy. Randomization will be stratified by uterine-derived vs. non-uterine-derived leiomyosarcoma. Participants in Arm 1 will receive lubiventin and adriamycin at the RP2D defined during Phase 1b. Participants in Arm 2 will receive single-agent adriamycin at a dose of 75 mg/m ² on Day 1 of each cycle, up to a lifetime maximum dose of 450 mg/m ² .

●Patients who progress radiation sickness after receiving treatment in the second group will be allowed to switch to lubiventin monotherapy at 3.2 mg/ ^m2 on day 1 of each 21-day cycle. Study Population Inclusion Criteria Phase Ib 1) Patients with locally advanced or metastatic soft tissue sarcoma and no available curative multimodality treatment options 2) Voluntarily signed and dated written informed consent before any specific study procedure. 3) Age > 18 years. 4) Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 2. (Karnofsky ≥ 60%) 7) Measurable disease according to RECIST v.1.1. Note: Irradiated lesions may be targeted if progression has been documented. 9) Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤7 days prior to study entry): a) Platelet count ≥100×109/L, hemoglobin ≥9.0 g/dL, and absolute neutrophil count (ANC) ≥1.5×109/L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×upper limit of normal (ULN), independent of the presence of liver metastases. c) Alkaline phosphatase (AP) ≤2.5×ULN. d) Total bilirubin ≤1.5×ULN or direct bilirubin ≤ULN. e) International normalized ratio (INR) <1.5 (unless the patient is on oral anticoagulation). f) Calculated creatinine clearance (CrCL) ≥ 30 mL/min (using the Cockcroft and Gault formula). g) Creatine phosphokinase (CPK) ≤ 2.5×ULN. h) Albumin ≥ 3.0 g/dL. Albumin infusions to achieve inclusion criteria are contraindicated. i) Thyrotropin (TSH) within institutional normal limits. If TSH is above ULN, free T4 within institutional normal limits is acceptable. 10) Women of childbearing potential (WOCBP) No evidence of reproductive status. Women and men must agree to use highly effective contraception prior to study entry and for at least 6 months during the trial and after completion of study drug administration. Fertile male patients with WOCBP spouses must agree to refrain from fathering children or donating sperm during the trial and for up to five months after cessation of treatment. Acceptable methods of contraception include abstinence, intrauterine device (IUD), oral contraceptive pill, subcutaneous implant, and/or double barrier. 11) For participants with known chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if indicated. 12) Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with known HCV infection who are currently on treatment are eligible if they have undetectable HCV viral load. 13) Left ventricular ejection fraction (LVEF) ≥ 50% on screening echocardiogram (ECHO) or multigated acquisition (MUGA) scan. 14) Participants must have archival tissue available for analysis in the form of formalin-fixed paraffin-embedded (FFPE) blocks or unstained slides. Participants without available archival tissue may be enrolled with the approval of the Sponsor-Investigator. NOTE: Confirmation of the availability of archival tissue is the only eligibility requirement and archival tissue does not need to be received by the study team or site prior to enrollment. 15) Patients with prior or concurrent malignancies whose natural history or treatment does not have the potential to interfere with safety or efficacy assessments of the investigational regimen as assessed by the treating Investigator may be included with the approval of the Sponsor-Investigator.

Phase II participants must have histologically confirmed advanced or metastatic leiomyosarcoma (LMS) with no available curative multimodality treatment options. Exclusion Criteria 1) Participants who have received prior anthracycline or trabectedin (Yondelis, ET-743) (including prior exposure to doxorubicin or liposomal doxorubicin). 2) Participants who have received more than 2 prior lines of cytotoxic chemotherapy for the Phase 1b study and no more than 1 prior line of cytotoxic chemotherapy for the Phase 2 study. There is no restriction on the number of prior lines of non-cytotoxic chemotherapy (e.g., pazopanib, immunotherapy). 3) Prior exposure to lubitidin (PM01183). 4) Participants who have received prior radiation therapy >45 Gy to the pelvis. 5) Participants who have received or undergone prior chemotherapy within 14 days of Cycle 1 Day 1, received or undergone curative radiation therapy within 21 days of Cycle 1 Day 1, or received or undergone major surgery within 21 days of Cycle 1 Day 1. 6) Participants who have received prior palliative radiation therapy within 7 days of Cycle 1 Day 1. 7) Participants who have received prior antibody-based therapy (e.g., nivolumab) within 4 weeks or 3 half-lives (whichever is shorter) of Cycle 1 Day 1. 8) Participants who have received prior oral small molecule or tyrosine kinase inhibitor (TKI) therapy within 2 weeks or 3 half-lives (whichever is shorter) of Cycle 1 Day 1. 9) Participants whose adverse events attributed to any prior anticancer therapy have not recovered to ≤ Grade 1 or baseline, with exceptions for alopecia, controlled endocrine toxicity (e.g., hypothyroidism), and skin toxicity being allowed at Grade 2. 10) Participants who have received any other study medication. 11) Participants with known CNS disease involvement, except for patients with previously treated brain metastases who have remained stable on MRI for ≥ 28 days prior to Cycle 1 Day 1 without the use of steroids or anti-epileptic drugs. 12) History of allergic reactions attributed to compounds with similar chemical or biological composition to lubitidin or doxorubicin. 13) Participants receiving any medication or substance that is a strong or moderate inhibitor or inducer of CYP3A, CYP2D6, or P-gp are not eligible. Because the list of these medications is constantly changing, it is important to regularly consult the frequently updated medical reference literature. As part of the enrollment/informed consent process, participants must be informed of the risk of interactions with other medications and how to proceed if a new medication needs to be prescribed or if the participant is considering a new over-the-counter medication or herbal product. 14) Uncontrolled intermittent illnesses include (but are not limited to): persistent or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, chronic indwelling drains, or psychiatric illness/social conditions that would limit compliance with study requirements. 15) History of interstitial pneumonia or pulmonary fibrosis. 16) Known cardiomyopathy. 17) Pregnant women were excluded from this study because lubiventin and doxorubicin are anticancer agents that may cause teratogenic or abortifacient effects. Because of the unknown but potential risk of adverse events in nursing infants from maternal treatment with ruxolitin or doxorubicin, breastfeeding should be discontinued if the mother is treated with ruxolitin or doxorubicin. Females of childbearing potential should have a negative pregnancy test prior to the first dose of study drug. 18) Immunocompromised patients, including those known to be serologically positive for human immunodeficiency virus (HIV), due to the increased risk of fatal infection when treated with myelosuppressive therapy. HIV testing is not required as part of screening.

Expected Number of Patients in Study Population Phase Ib follows a standard 3+3 design. A minimum of 2 patients and a maximum of 12 patients will participate in Phase 1b. The starting dose is dose level 1. Three participants can be recruited at starting dose level 1. A minimum of 6 patients must be treated at the recommended Phase II dose (R2PD). Of the 50 patients in Phase II, for the overall maximum sample size of 62 participants, there will be 1:1 randomization into one of two treatment groups: Group 1: lubiventin + doxorubicin, and Group 2: doxorubicin monotherapy. Participants participating in Phase 2 will be stratified by uterine leiomyosarcoma vs. non-uterine leiomyosarcoma.

Study Drug Formulation PM01183 PM01183 drug product is supplied as a lyophilized powder for solution concentrate for infusion in 4-mg vials.

Prior to use, the 4-mg vial should be reconstituted with 8 mL of Sterile Water for Injection to yield a solution containing 0.5 mg/mL PM01183. For administration to patients as an intravenous infusion, the reconstituted vial should be diluted with Dextrose 50 mg/mL (5%) Solution or Sodium Chloride 9 mg/mL (0.9%) Solution for Infusion.

The complete composition of the PM01183 4-mg vial and reconstitution solution/mL is shown in Table 1. Table 1. Composition of PM01183 vials. Components PM01183 4 mg Concentration after reconstitution/vial PM01183 4.0 mg 0.05 mg/mL sucrose 800 mg 100 mg/mL Lactic acid 22.08 mg 2.76 mg/mL Sodium hydroxide 5.12 mg 0.64 mg/mL

Aldrin hydrochloride Aldrin hydrochloride drug product is supplied as a lyophilized powder for solution concentrate for infusion in 10 mg, 20 mg, 50 mg, or 150 mg vials.

Prior to use, doxorubicin HCl should be reconstituted with 0.9% Sodium Chloride Injection USP to obtain the following final concentration pf 2 mg/mL: ●   5 mL 0.9% Sodium Chloride Injection USP to reconstitute a 10 mg HCl doxorubicin vial ●   10 mL 0.9% Sodium Chloride Injection USP to reconstitute a 20 mg HCl doxorubicin vial ●   25 mL 0.9% Sodium Chloride Injection USP to reconstitute a 50 mg HCl doxorubicin vial ●   75 mL 0.9% Sodium Chloride Injection USP to reconstitute a 150 mg HCl doxorubicin vial

In the treatment schedule 1b , PM01183 was administered as a fixed dose of 3.2 mg/ ^m2 as an intravenous infusion over 1 hour (± 5 minutes) on day 1 of each dosing cycle.

Adriamycin is administered by intravenous infusion in accordance with institutional standards of practice and/or FDA product labeling. Adriamycin administration continues up to a lifetime maximum dose of 450 mg/ ^m2 or until the participant meets other treatment discontinuation criteria. After discontinuation of adriamycin, participants will continue to receive lubiventin as monotherapy at a dose of 3.2 mg/ ^m2 on Day 1 of each dosing cycle until treatment discontinuation criteria are met.

The dosing cycle is defined as 21 consecutive days.

Route of Administration and Dosage In Phase Ib , on days when both leuprolide and doxorubicin are administered, doxorubicin is administered first, followed by leuprolide. The leuprolide infusion is started within 1 hour of the completion of the doxorubicin infusion.

The starting dose level is dose level 1.

At dose level 1 (starting dose level): Adriamycin was administered at a dose of 25 mg/ ^m2 as a 1-hour intravenous infusion on day 1 only, followed by lubiventin at a fixed dose of 3.2 mg/ ^m2 as a 1-hour (± 5 minutes) intravenous infusion.

At dose level 2: Adriamycin was administered at a dose of 25 mg/ ^m2 as a 1-hour intravenous infusion on days 1 and 8, followed by lubiventin at a fixed dose of 3.2 mg/ ^m2 as a 1-hour (± 5 minutes) intravenous infusion.

Dose escalation regimen (Phase Ib) Dose escalation will be conducted in a standard 3+3 design according to the following guidelines: Number of participants with DLT at a given dose level Incremental decision rules 0 out of 3 Three participants were entered at the next dose level. ≥2 Dose escalation will be discontinued. This dose level will be declared the maximally administered dose (highest dose ever administered). If only 3 participants were previously treated at that dose, three (3) additional participants will be entered at the next lowest dose level. 1 out of 3 Enter at least 3 additional participants at this dose level. ● If 0 of these 3 participants experience a DLT, proceed to the next dose level. ● If 1 or more in this group experience a DLT, stop dose escalation and declare this dose as the maximum dose administered. If only 3 participants were previously treated at that dose, enter three (3) additional participants at the next lowest dose level. ≤ 1 out of 6 at the highest dose level below the maximum administered dose This is usually the maximum tolerated dose (MTD). At least 6 participants must enter at the MTD.

During Phase Ib, body surface area (BSA) will be calculated each cycle according to the DuBois formula. PM01183 doses will be recalculated before the start of a new cycle. Doses will be rounded to the first decimal point.

Prophylactic Medication On Day 1 of each cycle (before administration of lubitidin), all patients will receive the following prophylactic medications: • Dexamethasone 8 mg IV or equivalent, maximum 20 mg/day. If feasible, medications and doses administered in Cycle 1 should be maintained in Cycle 2. • 5-HT3 antagonist, i.e. ondansetron 8 mg IV not to exceed 16 mg.

Other Potential Prophylactics: • Treatment with a 5-HT3 antagonist and/or dexamethasone may be extended orally for three to five consecutive days after the drug infusion (i.e., at 4 to 8 mg/day). • Additional antiemetics may be used as necessary. PERMITTED MEDICATIONS / THERAS • Granulometabolism Stimulating Factor (G-GSF): Pegylated G-GSF is required for patients receiving combination therapy with abiraterone and doxorubicin. Pegylated G-GSF should be administered at dose level 1 on day 2 and at dose level 2 on day 9. • Therapy for preexisting and treatment-induced medical conditions, including pain management and topical management of mucositis/stomatitis. • Blood products and transfusions as clinically indicated. • Bisphosphonates. • In case of nausea or vomiting, secondary prophylaxis and/or symptomatic treatment for emesis according to American Society of Clinical Oncology (ASCO) guidelines (considering the aforementioned limitation of daily corticosteroids). • Erythropoietin use according to ASCO guidelines. • Low molecular weight heparin (LMWH) and/or any other anticoagulant as clinically indicated. Oral anticoagulants must be carefully monitored. • Palliative limited-field bone RT (e.g., for pain control external to the chest wall). • Megestrol acetate for appetite stimulation. • Contraceptives. Contraindicated Drugs / Therapies • Concomitant administration of any other antineoplastic therapy. • Other investigational agents. • Immunosuppressive therapies other than corticosteroids for antiemetic prevention or pain control, or low-dose alternatives in patients who need them. • Aprepitant or fosaprepitant or any other NK-1 antagonist or related substance P-antagonist (except rolapitant). • CYP3A4 inhibitors such as ketoconazole, fluconazole, voriconazole, telithromycin, clarithromycin, erythromycin, nafcillin, aprepitant, fosaprepritant, verapamil, modafinil, nefazodone, or grapefruit juice. • CYP3A enzyme inducers and/or inhibitors (unless strictly necessary and when no therapeutic alternatives exist). • Use of any prescription or over-the-counter herbal and/or dietary supplements within 14 days prior to the first dose of medication and until 31 days after the last dose of lubiventin, unless the Investigator, with the Sponsor's consent, determines that it will not interfere with the study procedures for patient safety. Drug - Drug Interactions ● Lubiventin

In vitro studies using human microsomes demonstrated that CYP3A4 is the major CYP isoform involved in PM01183 metabolism, followed by CYP2E1, CYP2D6, and CYP2C9. The estimated contribution of other CYP isoenzymes to PM01183 metabolism is considered negligible. For participants enrolled in the dose escalation portion of the trial, coadministration of lubiventin with strong or moderate CYP3A inhibitors during Cycle 1 was strictly prohibited. For all other participants, coadministration of lubiventin with strong or moderate CYP3A inhibitors should be avoided when clinically feasible.

Do not co-administer lubiventin with aprepitant or any other NK-1 antagonist or related substance P-antagonist (except rolapitant). ●   Adriamycin

Doxorubicin is a major substrate for cytochrome P450 CYP3A4 and CYP2D6, as well as P-glycoprotein (P-gp). Clinically significant interactions have been reported with CYP3A4, CYP2D6, and/or P-gp inhibitors (e.g., verapamil), resulting in increased doxorubicin concentrations and clinical effects. CYP3A4 inducers (e.g., phenobarbital, phenytoin, St. John's Wort) and P-gp inducers can reduce doxorubicin concentrations. Therefore, coadministration of doxorubicin HCl with CYP3A4, CYP2D6, or P-gp inhibitors and inducers must be avoided.

Patient evaluability Phase Ib Patients evaluable for the primary objective of this Phase Ib (i.e., determination of MTD and RP2D) should have received at least one complete infusion of doxorubicin and PM01183 and have been followed for at least one complete cycle (i.e., three weeks = 21 days). Patients who discontinue early or missed/delayed doses and/or clinically relevant assessments (i.e., hematology) will be evaluable if these events are the result of treatment-related toxicity (excluding allergic reactions and/or extravasation).

Evaluation Criteria Primary Endpoints Phase Ib Determination of MTD and MAD : The maximum administered dose (MAD) of study drug will be defined as the dose level at which at least two participants experience toxicity that meets the definition of DLT.

The dose level immediately below the MAD will be defined as the MTD.

In the event that none of the dose levels have ≥ 2 DLTs, the MTD will be the highest dose administered (ie, dose level 2).

The Phase 1b trial will be stopped if dose level 1 is found to be intolerable (where 2 of 3 patients or ≥ 2 of 6 patients experience a DLT).

Alternative doses and/or schedules may be considered with protocol modifications (eg, lubiventin 2 mg/m ² and doxorubicin 50 mg/m ² , a dose schedule known to be tolerated).

The MTD will be determined in a minimum of 6 participants. After the MTD is announced, a review of available safety and efficacy data generated during Phase 1b will be conducted to confirm the RP2D of the combination.

Secondary Endpoints • Safety : Patients will be evaluable for safety if they have received at least one infusion of doxorubicin and PM01183. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. • Efficacy : The antitumor activity of the combination will be assessed as follows: ○ Progression-free survival is defined as the time from the date of enrollment to the date of progression or death (regardless of cause of death) recorded according to RECIST v.1.1. If a patient receives further antitumor therapy or is lost to PD, PFS will be censored at the date of the last tumor assessment before the date of subsequent antitumor therapy. ○ Duration of response (DoR) will be calculated from the date of the first documented response per RECIST v.1.1 (complete or partial response, whichever comes first) to the date of documented PD or death. The deletion rules defined above for PFS will apply to DoR. ○ Clinical benefit is defined as the percentage of evaluable patients with a complete response, partial response, or stable disease lasting ≥3 months as defined by RECIST v1.1. ○ Overall survival (OS): calculated from the date of enrollment to the date of death (mortality event) or last contact (in which case survival data will be deleted on that date). ○ Interim and long-term survival (12, 18, and 24 months OS) will be Kaplan-Meier estimates of the probability of being alive at these time points. • Pharmacokinetics : PK parameters will be assessed in plasma by standard non-compartmental methods (with compartmental modeling where appropriate). • Pharmacogenetics : Factors that may help explain individual variability in key PK parameters, the presence or absence of germline mutations or polymorphisms that may be involved in the metabolism and/or transport of PM01183 will be analyzed in extracted leukocyte DNA. • Pharmacogenomics : Tumor samples available at baseline will be assessed in all patients in order to determine predictive/prognostic markers of response and/or resistance to PM01183 and doxorubicin. In addition, blood samples (Day 1 of each cycle) and on-treatment tumor samples from biopsy (Weeks 4 to 6 after initiation of treatment) will be obtained and assessed for patients who consent to the PGx sub-study.

Results A total of 10 patients were treated in Phase 1b, including 3 male patients (30%) and 7 female patients (70%), with a median age of 59 years. The median ECOG PS (range) was 0. The median value of the previous line was 0.5.

From ten enrolled patients: 5 affected by leiomyosarcoma (1 patient with LMS and 4 patients with uterine leiomyosarcoma (uLMS)), 1 affected by dedifferentiated liposarcoma (DDLPS), 1 affected by undifferentiated pleomorphic sarcoma (UPS), 1 affected by solitary fibroma (SFT), 1 affected by endometrial stromal sarcoma (ESS), and 1 affected by myxofibrosarcoma (myxFS).

Three patients were enrolled at dose level 1 (lubiventin 3.2 mg/m ² + doxorubicin 25 mg/m ² on day 1 only) with no DLTs.

At dose level 2 (3.2 mg/m ² + doxorubicin 25 mg/m ² on days 1 and 8), 1 patient (1 of 3 patients) experienced a DLT (neutropenia grade 3 on day 8, leading to discontinuation of doxorubicin). This DLT resolved to grade 1 within 7 days.

The fourth patient was enrolled at dose level 2 and experienced a DLT (grade 2 elevated alanine transaminase (ALT)/aspartate transaminase (AST)). This DLT occurred on day 8, led to discontinuation of doxorubicin, and resolved to grade 1 within 7 days.

Three additional slots have been opened for dose level 1 confirmation. One of the three patients experienced grade 3 ALT elevation, which resolved to grade 1 within 4 days.

No other grade 3 or 4 adverse events occurred. Most treatment-related adverse events were grade 1 or 2 nausea, fatigue, reversible cytopenia, alopecia, anemia, and dehydration, which are typical adverse events of doxorubicin and lubitidin.

Treatment-emergent adverse events are shown in Table 2. Adverse Events Level 2 Level 3 Fatigue 5 0 Anemia 3 1 Nausea 5 0 Decreased neutrophil count 4 1 Alopecia 3 0 Vomiting 3 0 Anorexia 2 0 ALT elevation 1 1 Dehydration 2 0 Table 2 Treatment-emergent adverse events

Updated Results Updated treatment-emergent adverse events are shown in Table 3. Adverse Events Level 2 Level 3 Level 4 Fatigue 7 0 0 High blood pressure 6 0 0 Infect 6 0 0 Nausea 5 0 0 White blood cell count 3 1 0 Decreased neutrophil count 3 1 0 Anemia 2 1 0 Vomiting 3 0 0 Alopecia 3 0 0 Anorexia 2 0 0 Difficulty breathing 2 0 0 Elevated alanine transaminase 1 1 0 Dehydration 2 0 0 Decreased lymphocyte count 0 1 1 Duodenal obstruction 0 1 0 Gastric outlet obstruction 0 1 0 *Includes G2 events with n ≥ 2 Table 3 Updated Treatment Emergent Adverse Events DLT: 1. Failure to meet treatment criteria on Day 8 (G2 ALT/AST) 2. Failure to meet treatment criteria on Day 8 (G3 Neutropenia) 3. G3 ALT Dose Delays: 1. Neutropenia 2. SBO/Surgery 3. Viral respiratory tract infection (covid excluded) Dose Reductions: 1. DL2 → DL1 n = 2 (G2 LFT; G3 neutropenia; other items same as above DTL) 2. DL1 n = 2 (neutropenia; fatigue)

The median duration of treatment without progression was 330 days (range, 42-617), with three patients continuing on study at the time of data cutoff.

The median time to response was 81 days (range 43-207) and the median duration of response was 169 days (range 126-364)

Eight of the 10 patients were treated for 6 months; four of the 10 were treated for 12 months, and three were treated for 500 days.

The median time to partial response was 81 days (range 46-207).

Response Assessment (Fig. 1): ■   Six patients have shown partial response to RECIST 1.1 for the following: - Undifferentiated pleomorphic sarcoma, - Leiomyosarcoma, including uterine leiomyosarcoma. - Dedifferentiated liposarcoma, - Myxofibrosarcoma. ■   Three patients have shown stable disease according to RECIST 1.1 for the following: - Leiomyosarcoma (uterine leiomyosarcoma), - Endometrial stromal sarcoma, - Solitary fibroma.

The recommended dose was determined to be lubiventin 3.2 mg/m ² and doxorubicin 25 mg/m ² on day 1, for a 21-day cycle.

Conclusions Full-dose rubitidin and low-dose doxorubicin are a feasible, well-tolerated, and active combination. It resulted in six partial responses and two prolonged disease stabilizations (>430 days) in ten patients.

In summary, the present invention has identified exciting activity of lubitidin plus adriamycin in the treatment of cancer. The present invention has identified dosing regimens that are particularly well tolerated. Among other advantages, these regimens may allow for more cycles to be administered to patients, thereby extending the time of disease control. In addition, these regimens may increase response/disease control rates. Additionally, these regimens may reduce the high levels of toxicity typically produced by adriamycin.

without

[Figure 1] shows the best response according to RECIST 1.1, including progressive disease, stable disease, and partial response in 10 patients with the following different sarcomas: leiomyosarcoma (LMS including uterine leiomyosarcoma (uLMS)), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), solitary fibroma (SFT), endometrial stromal sarcoma (ESS), and myxofibrosarcoma (myxFS).

[Figure 2] shows the time in the study for each patient. PR means partial response; PD means progressive disease and the arrow indicates that the treatment is still being administered.

Claims (22)

A method for treating cancer in a patient in need thereof, wherein lurbinectedin is administered in combination with doxorubicin; and wherein doxorubicin is administered at a dose of 30 mg/ ^m2 or less during each administration cycle or at a dose of less than 30 mg/ ^m2 during each administration cycle. Lubiventin as used in claim 1, wherein Lubiventin is administered in combination with adriamycin; and wherein adriamycin is administered at a dose of between 15 and 30 mg/ ^m2 , or between 20 and 30 mg/ ^m2 , or between 15 and less than 30 mg/ ^m2 , or between 20 and less than 30 mg/ ^m2 during each administration cycle. Lubiventin for use in any of the preceding claims, wherein Lubiventin is administered in combination with adriamycin; and wherein adriamycin is administered at a dose of between 15 and 25 mg/ ^m2 , or between 20 and 25 mg/ ^m2 , preferably about 25 mg/ ^m2 , preferably 25 mg/ ^m2 during each administration cycle. Lupiride for use in any of the preceding claims, wherein adriamycin is administered in an amount of about 25 mg/ ^m2 . Apiridin for use as claimed in any of the preceding claims, wherein a single dose of adriamycin is administered during each administration cycle. Alupirdine for use as claimed in any of the preceding claims, wherein alupirdine is administered during each administration cycle in a dose of between 2 mg/ ^m2 and 4 mg/ ^m2 , above 2 mg/ ^m2 and below 4 mg/ ^m2 , between 2.5 and 3.5 mg/ ^m2 , preferably about 3.2 mg/ ^m2 , preferably 3.2 mg/ ^m2 of body surface area. Lupiride for use as claimed in any of the preceding claims, wherein Lupiride is administered in an amount of about 3.2 mg/ ^m2 . The method for use of Lubitel as claimed in any of the preceding claims, wherein the administration cycle is every three weeks to every four weeks, preferably every 21 days. Lupidin for use in any of the preceding claims, wherein Lupidin is administered on day 1 (D1) of each cycle; or wherein doxorubicin is administered on day 1 (D1) of each cycle; or wherein Lupidin and doxorubicin are administered on day 1 (D1) of each cycle. Lubiventin as used in any of the preceding claims, wherein the combination with adriamycin is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles; preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles, preferably 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles. Lubiventin for use as claimed in any of the preceding claims, wherein adriamycin is administered first, followed by lubiventin. Lupiride for use in any of the preceding claims, wherein Lupiride is administered as a 1-hour intravenous infusion during each administration cycle; or wherein Adriamycin is administered as a 1-hour intravenous infusion during each administration cycle; wherein Lupiride and Adriamycin are administered as a 1-hour intravenous infusion during each administration cycle. Lubiventin for use in any of the preceding claims, wherein Lubiventin is administered in combination with adriamycin, wherein Lubiventin is administered at a dose of about 3.2 mg/m ² on D1 of each administration cycle; and wherein adriamycin is administered at a dose of about 25 mg/m ² on D1 of each administration cycle; and wherein each administration cycle is 21 days. Abiraterone for use as in any of the preceding claims, wherein the method further comprises administering granulocyte colony stimulating factor (G-CSF). Lubitel for use as claimed in claim 14, wherein G-CSF is administered on day 1 of the administration cycle; or wherein the patient begins primary prophylaxis with G-CSF 24-72 hours after day 1 of the administration cycle and continues for five days. Abiraterone as used in claim 14 or claim 15, wherein G-CSF is administered during a first administration cycle; optionally wherein G-CSF is administered during one or more subsequent administration cycles. Lubiventin for use as in any of the preceding claims, wherein after lubiventin and adriamycin are administered in combination during the first phase; lubiventin is administered alone for one or more cycles during the second phase; wherein lubiventin can be administered as in one or more of claims 6 to 9, 12 or 14 to 16. Lubiteldin for use as claimed in any of the preceding claims, wherein the cancer is a sarcoma, preferably a soft tissue sarcoma. As used in claim 18, the leuprosarcoma is selected from leiomyosarcoma, gastrointestinal stromal tumor, liposarcoma, dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumor, angiosarcoma, hemangioendothelioma, solitary fibroma, fibrosarcoma, cutaneous fibrosarcoma protuberans, low-grade fibromyxoid sarcoma, endometrial stromal sarcoma, myxofibrosarcoma, fibromatosis, follicular dendritic cell sarcoma, connective tissue proliferative small round cell tumor, pleomorphic liposarcoma and synovial sarcoma. Lubiteldin as used in claim 19, wherein the soft tissue sarcoma is advanced or metastatic leiomyosarcoma, which is selected from autologous soft tissue leiomyosarcoma, cutaneous or subcutaneous leiomyosarcoma, vascular leiomyosarcoma, and uterine or non-uterine leiomyosarcoma. A method for treating cancer in a patient in need thereof, the treatment comprising: i) administering to the patient one or more cycles of a combination of abiraterone and adriamycin as described in any of claims 1 to 20 in a first phase, and ii) administering to the patient one or more cycles of abiraterone alone in a second phase; wherein abiraterone may be administered as described in one or more of claims 6 to 9, 12, or 14 to 16. A pharmaceutical package comprising lubitidin and instructions for use in combination with adriamycin as described in any one of claims 1 to 21.