TW201716065A - Treatment of pancreatic cancer with liposomal IRINOTECAN - Google Patents

Abstract

A liposome-encapsulated formulation of irinotecan can be used for the treatment of pancreatic cancer in combination with 5-fluorouracil and leucovorin, including treatment of patients diagnosed with metastatic adenocarcinoma of pancreas who have been previously treated with gemcitabine.

Description

Treatment of pancreatic cancer with liplipid irinotecan (IRINOTECAN)

The present disclosure relates to the treatment of pancreatic cancer and intravenous infusion using a topoisomerase 1 inhibitor irinotecan liposome injection, including the use of irinotecan liposome injection with fluorouracil and The combination of leucovorin is used to treat metastatic adenocarcinoma of the pancreas of patients previously treated with gemcitabine.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and Europe. Although cancer treatment has been improved, particularly in the case of advanced cancers (such as pancreatic cancer) that are generally resistant or resistant to current treatment modalities, there is still a great need for further improved therapies to maintain quality of life. At the same time extend the lives of patients. The incidence of pancreatic cancer has increased significantly over the past few decades. It is now rated as the fourth leading cause of cancer death in the United States. The high mortality rate of pancreatic cancer is due to the lack of effective therapies and the complete lack of reliable and durable therapies. Because of the location of the pancreas, pancreatic cancer is often not diagnosed until the tumor becomes large enough to produce systemic symptoms. This combination does not have good screening tools and limited understanding of risk factors, resulting in patients often having advanced disease at the time of diagnosis, usually a late metastatic disease. Metastatic pancreatic cancer has a poor prognosis and is almost fatal, with an overall survival rate of less than 4% at 5 years.

Chemotherapy using one or more of 5-fluorouracil (5-FU) and gemcitabine has been shown to prolong the survival of pancreatic cancer. Also use a combination of the following to treat some pancreas Cancer: aldehyde folic acid (formaldehyde tetrahydrofolate or levaformin tetrahydrofolate), 5-fluorouracil and irinotecan (FOLFIRI); aldehyde folic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX); A combination of aldehyde folic acid, 5-fluorouracil and oxaliplatin (FOLFOX) is less common. Irinotecan 7-ethyl-10-[4-(1-piperidinyl)-1-piperidinyl]carbonyloxycamptothecin, IUPAC name (S)-[1,4'-bi-piperidine] -1'-formic acid-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-di- oxy 1H-pyrano[3',4':6 , 7]-pyridazino[1,2-b]quinolin-9-yl ester. Irinotecan is a member of the topoisomerase I inhibitor drug and is a semi-synthetic water-soluble analog of the natural alkaloid camptothecin. Irinotecan, also known as CPT-11, is currently marketed as CAMPTOSAR® (Irinotecan Hydrochloride Injection) as irinotecan hydrochloride trihydrate salt. CAMPTOSAR® is approved as a component for the combination of 5-fluorouracil (5-FU) and formazantetrahydrofolate (LV) for patients with colon or rectal metastases. However, CAMPTOSAR® has not been approved for the treatment of other cancer types, such as pancreatic cancer. Topoisomerase I inhibitors such as irinotecan are used to prevent uncontrolled cell growth by inhibiting DNA unwinding and thereby preventing DNA replication.

The pharmacology of irinotecan is complex, and a wide range of metabolic transformations are involved in the activation, inactivation and elimination of drugs. Irinotecan is converted to a 100-1000 fold stronger active metabolite SN-38 prodrug by a non-specific carboxylesterase. SN-38 is not recognized by P-glycoprotein, a drug transport protein that plays an important role in acquired drug resistance by pumping certain drugs out of cells, so irinotecan may be in other Standard chemotherapy is active in resistant tumors. In vivo, SN-38 is cleared by glucuronidation (which has been described as its major pharmacogenetic polymorphism) and by bile excretion. These drug properties contribute to the significant heterogeneity of efficacy and toxicity observed when irinotecan is used clinically. Irinotecan hydrochloride injection is approved in the United States for the treatment of metastatic colon or kidney cancer and is also used to treat colorectal cancer, gastric cancer, lung cancer, cervical cancer and ovarian cancer.

There are few approved treatment options for advanced or metastatic pancreatic cancer (especially those of exocrine sources), and there is no pancreatic cancer after disease progression after first-line chemotherapy. FDA approved treatment. Gemcitabine has been approved as a single agent for the treatment of pancreatic cancer and is used in combination with paclitaxel for the treatment of metastatic breast cancer after failure of previous anthracycline-assisted chemotherapy, unless the anthracycline is contraindicated clinically. Clinically, FDA-approved therapies are still needed to safely and effectively treat patients with pancreatic cancer, including metastatic adenocarcinoma of the pancreas, when the disease evolves after one-line therapy based on gemcitabine.

The invention provides a method of treating pancreatic cancer in a patient (ie, a human patient) comprising administering to the patient, either alone or with 5-fluorouracil (5-FU) and formazan tetrahydrofolate, according to a particular clinical dosage regimen (together 5-FU/LV) combination of liplipid irinotecan (for example, irinotecan sucrose octasulfate microlipid injection, also known as MM-398). Compositions suitable for use in such methods are also provided.

In one aspect, a method of treating pancreatic cancer in a patient is provided, the method comprising administering to the patient a respective effective amount of aliline irinotecan, 5-fluorouracil (5-FU), and formazan tetrahydrofolate, Wherein the method comprises at least one administration cycle, wherein the cycle is a 2-week period, and wherein for each cycle: (a) the aliline irinotecan is administered at a dose of 80 mg/m ² on the first day of each cycle Administration to patients who are not homozygous for the UGT1A1*28 allele, and at a dose of 60 mg/m ^{2 on} day 1 of cycle 1 and between 60 mg/m ² and 80 mg on day 1 of each subsequent cycle A dose in the range of m ² (for example, 60 mg/m ² or 70 mg/m ² or 80 mg/m ² ) is administered to a patient who is homozygous for the UGT1A1*28 allele; (b) is administered at a dose of 2400 mg/m ² 5-FU; and (c) to 200mg / m ² (l or L form of methyl tetrahydrofolate XI) or 400mg / m ² (l + d outside the racemic form) is administered in doses of acyl methyl tetrahydrofolate.

In another aspect, a liplipid irinotecan formulation for co-administration with 5-fluorouracil (5-FU) and formazan tetrahydrofolate in at least one cycle is provided, wherein the cycle is for a 2 week period The irinotecan formulation is an irinotecan liposome formulation, and wherein: (a) the lipid irinotecan is administered at a dose of 80 mg/m ² on the first day of each cycle for UGT1A1*28 A patient with an allelic non-homogeneous junction, and administered at a dose of 60 mg/m ² on the first day of cycle 1 and at a dose of 60 mg/m ² or 80 mg/m ² on the first day of each subsequent cycle for UGT1A1 * 28 allele isotype engaging the patient; (b) at 2400mg / m ² doses administered with the 5-FU; and (c) to 200mg / m ² (l or L form of methyl tetrahydrofolate XI) or 400mg / m A dose of ² ( l + d racemic form) is administered to formamidine tetrahydrofolate.

In one embodiment, after a period, and administered to patients UGT1A1 * 28 allele isotype of the engagement increases for irinotecan liposome Kang dose to 80mg / m ^2. In another embodiment, the alipid irinotecan is administered intravenously over 90 minutes. In another embodiment, the 5-FU is administered intravenously over a 46 hour period. In another embodiment, formazan tetrahydrofolate is administered intravenously over 30 minutes.

In another embodiment, the patient is premedicated with dexamethasone and/or a 5-HT3 antagonist or another antiemetic agent prior to each administration of the lipophilic irinotecan.

In another embodiment, the irinotecan liposome formulation is irinotecan sucrose octasulfate liposome injection. MM-398 is an FDA-approved irinotecan liposome injection recently under the trade name ONIVYDE ^® (Irinotecan liposome injection). MM-398 irinotecan liposome injection contains the topoisomerase 1 inhibitor irinotecan, which is encapsulated in a lipid bilayer vesicle or liposome with sucrose octasulfate and formulated for intravenous use. Internal investment. MM-398 is indicated for use in combination with fluorouracil and formazan tetrahydrofolate for the treatment of patients with metastatic adenocarcinoma of the pancreas whose disease has evolved following gemcitabine-based therapy.

Provided herein are safe and effective therapies for the treatment of metastatic adenocarcinoma of the pancreas of patients previously treated with gemcitabine-based therapy using irinotecan liposome formulations. The therapy consists of administering to patients with pancreatic cancer every two weeks: 70 mg/m ² of irinotecan encapsulated in MM-398 irinotecan liposome and a therapeutically effective amount of antitumor agent A combination of hydrogen folic acid and 2,400 mg/m ² of the antitumor agent 5-fluorouracil, and no other antitumor agent for treating pancreatic cancer.

This therapy safely and effectively delivers patients with metastatic adenocarcinoma diagnosed with pancreas after disease progression based on gemcitabine-based therapy. The amount of formazan tetrahydrofolate administered can be selected to provide the desired effect of 5-fluorouracil (for example, the amount of formazan tetrahydrofolate comprises 200 mg/m ² of levodomethyltetrahydrofolate, for example 400 mg/m ² (l +d) Racemic form of formazan tetrahydrofolate). For example, a patient may be treated with an anti-tumor therapy (referred to herein as "MM-398+5-FU/LV (70 mg/m ² MM-398 q2w regimen)): 70 mg/m ² encapsulated in Irinotecan in MM-398 irinotecan liposome (for example, as a 90-minute intravenous infusion), followed by 400 mg/m ² antitumor agent (l+d) racemic formamidine tetrahydrofolate (for example, as 30 minutes intravenous infusion), followed by 2,400 mg/m ² antitumor agent 5-fluorouracil (for example, as a 46-hour intravenous infusion), and not administered any other anti-neoplastic agent for the treatment of pancreatic cancer (eg , do not vote for gemcitabine).

Unless otherwise indicated, the amounts of irinotecan administered herein refer to the amount of irinotecan free base (molecular weight of about 587 g/mol) administered. When indicated, the amount of irinotecan can also be expressed as the amount of irinotecan hydrochloride trihydrate (molecular weight of about 677 g/mol) providing a given amount of irinotecan free base: for example, 80 mg/m ² irinotene Kang hydrochloride trihydrate (e.g., such as a non-liposome irinotecan product CAMPTOSAR ^® approved) contains 70mg / m MM-398 liposomal formulation ² of the of irinotecan approximately equal amounts Alternate dose Yasuyuki Iraq Litenko.

The therapy was evaluated in the NAPOLI-1 human clinical trial described herein in an international randomized, phase 3 trial of patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy. In the NAPOLI-1 human clinical trial, analysis of the ITT (intent to treat) patient group showed overall survival (OS) of MM-398+5-FU/LV (70 mg/m ² MM-398 q2w regimen) relative to individual The 5-FU/LV was statistically significantly increased (Figures 4A and 4B), ranging from 6.1 months to 4.2 months. A significant increase in OS was also observed in the non-evolved survival (PFS), objective response rate (ORR), and tumor marker response (CA19-9) reactions (Figure 5). In contrast, MM-398 (120 mg/m ² q3w protocol) as a single agent did not show a significant difference in OS. In addition, the forest plot sensitivity analysis of the NAPOLI-1 human clinical trial compared MM-398+5-FU/LV to 5-FU/LV in the prognostic subgroup, tumor characteristics, and prior treatment (Figure 6 and 7). In the NAPOLI-1 human clinical trial, the eligible (PP) patient population (described in Figure 8) (patients receiving 6 weeks of treatment), compared to 5.1 months in the 5-FU/LV group, MM-398 The +5-FU/LV combination protocol achieved a 8.9 month median OS (stratification hazard ratio (HR): 0.47, p = 0.0018; Figures 9A and 9B). The observed patient safety profile is manageable and graded 3 had the most frequent adverse events, including neutropenia, fatigue, and GI effects such as diarrhea and vomiting (Figure 12).

Figure 1 provides a combination of irinotecan liposome injection monotherapy or irinotecan liposome injection with 5-fluorouracil and formazan tetrahydrofolate compared to 5-FU/LV active control. The overall survival of the patient in the assessment of clinical efficacy and safety of irinotecan liposome injection +5-FU/LV.

Figure 2 is a flow chart representation of the NAPOLI-1 study design.

Figure 3 is a table providing baseline characteristics of a population of intentional treatment (ITT) (all randomized patients). In this table, CA19-9 at baseline is unknown in 3% of patients. (hereinafter referred to as "Paragraph A")

Figures 4A and 4B are graphical representations of MM-398+5-FU/LV versus overall survival (ITT population) in MM-398 or 5-FU/LV alone. The data presented is a preliminary cut of the data analysis of the 305 event definitions. "**" means no stratification HR: 0.67 (0.49-0.92), p = 0.0122; "***" means no stratification HR: 0.99 (0.77-1.28), p = 0.9416.

Figure 5 is a table providing tumor response and control data (interpretation of preliminary analysis data for protocol definitions). The overall response rate is calculated according to RECIST version 1.1. The CA19-9 reduction response was defined as the baseline CA19-9 value in patients with a baseline value of >30 U/mL and at least one post-baseline CA19-9 measurement. 50% reduction.

Figure 6 is a forest map of overall survival of patients receiving MM-398 + 5FU/LV treatment relative to 5FU/LV alone. The results presented in the table are taken from the data analysis of the preliminary analysis of the protocol definition by a non-hierarchical log-rank test.

Figure 7 is another forest map of the overall survival of patients receiving MM-398 + 5FU/LV treatment relative to treatment with 5FU/LV alone. The results presented in the table are taken from the data analysis of the preliminary analysis of the protocol definition by a non-hierarchical log-rank test.

Figure 8 is a flow chart illustrating the ITT (all randomized patients) and PP (compliant) populations. The compliant program group included the protocol definition treatment during the first 6 weeks of treatment Qualified patients with 80% dose density.

Figures 9A and 9B are graphical representations of overall survival (OS) for a population of patients in a protocol (PP) versus a non-compliant (non-PP) patient population. The results presented in the figure are taken from the data interception of the preliminary analysis of the program definition. A compliant population is defined as a patient who receives at least 80% of the protocol-defined treatments during the first 6 weeks of treatment and does not have a protocol bias for inclusion/exclusion criteria (either forbidden or not randomized). Figure 9A shows the PP population and Figure 9B shows the non-PP population.

Figure 10 is a table providing demographic characteristics of a population of patients in accordance with a protocol (PP) versus a population of non-compliant (non-PP) patients. CA19-9 only included patients who had been measured for CA19-9 prior to treatment. "**" indicates a statistically significant difference (p value) 0.01) The result. "***" indicates the median (1st quartile, 3rd quartile).

Figure 11 is a table providing dose modification and treatment exposure. The duration of exposure is (the date the study drug was last administered + the estimated number of days the study drug was administered to the next dose - the date of the first study drug administration) / 7 time.

Figure 12 is a table providing the safety data (adverse events) of the study. In the table, (1) the safety group system refers to patients who receive at least one dose of the study drug; (2) the percentage of the group with adverse events (AE) is provided according to CTCAE version 4; and (3) blood Adverse events included only those patients who had at least one post-baseline assessment.

Figure 13 is an image representation of nanolipid irinotecan (nal-IRI).

Figure 14 provides a pharmacokinetic analysis of prolonged circulation of irinotecan and SN38 metabolites relative to irinotecan HCl after administration of irinotecan in liposomes in patients with gastric cancer.

Figure 15 provides irinotecan and SN38 levels in tumor tissue and plasma 72 hours after treatment with nal-IRI.

Figure 16A is a graphical representation of overall survival (OS) corresponding to treatment with nal-IRI + 5-FU/LV versus 5-FU/LV alone.

Figure 16B is a graphical representation of overall survival (OS) corresponding to treatment with nal-IRI versus 5-FU/LV alone.

Figure 17A is a graphical representation of no evolution survival (PFS) corresponding to treatment with nal-IRI + 5-FU/LV versus 5-FU/LV alone.

Figure 17B is a graphical representation of progression free survival (PFS) corresponding to treatment with nal-IRI versus 5-FU/LV alone.

Figure 18 is a Kaplan-Meier plot of overall survival (OS) in the NAPOLI-1 assay.

Figure 19 provides a correlation between baseline CA 19-9 values and overall survival (OS) for patients treated with Nal-IRI+5-FU/LV (shaded bars) or 5-FU/LV (open bars). Bar chart, hazard ratio (HR) is shown by its 95% CI.

Figure 20 is a graph showing baseline CA 19-9 values and no evolution survival rate (PFS) for patients treated with Nal-IRI+5-FU/LV (shaded bars) or 5-FU/LV (open bars). For the associated bar chart, the hazard ratio (HR) is shown at 95% CI.

Figure 21 is a graph showing the antitumor activity of MM-398 in a positive pancreatic tumor model (L3.6pl) showing luciferase.

Figure 22 is a graph showing the accumulation of SN-38 in tumors after treatment with free irinotecan or lipid irinotecan (MM-398).

Figure 23 is a graph showing the effect of MM-398 on carbonic anhydrase IX staining in the HT29 xenograft model.

Figure 24 shows the effect of MM-398 on small molecule Hoechst stain perfusion.

Figure 25 summarizes the pharmacokinetics of MM-398 of q3w (irinotecan, liposome + free drug).

Figure 26 summarizes the pharmacokinetics of q3w MM-398.

Figure 27 is a test evolution diagram.

Figure 28 is a table providing demographic and baseline characteristics (PRO population).

Figure 29 is a graphical representation of the proportion of patients with improved overall status and functional scale score improvement, stabilization or deterioration (nal-IRI + 5-FU/LV, n = 71; 5-FU/LV, n = 57).

Figure 30 is a graphical representation showing the proportion of patients with improved, stable or worsened symptom scale scores (nal-IRI + 5-FU/LV, n = 71; 5-FU/LV, n = 57).

Figure 31 is the median change in overall health status and functional scale scores from baseline to week 12 (nal-IRI + 5-FU/LV, n=71 at baseline; 5-FU/LV, n=57 at baseline) Graphical representation.

Figure 32 is a graphical representation of the change in mean value from baseline to week 12 (nal-IRI + 5-FU/LV at baseline n = 71; 5-FU/LV at baseline n = 57).

Figure 33 is a table providing emergency treatment adverse event events from a preliminary analysis of the NAPOLI-1 trial.

Figure 34 is a table providing demographic and baseline characteristics (security groups).

Figure 35 is a table providing TEAEs by age.

Figure 36 is a table providing TEAEs according to ethnic groups.

Figure 37 is a table providing TEAEs according to the UGT1A1*28 allele (TA7/TA7 genotype).

Figure 38 is a table providing TEAE based on albumin content.

Figure 39 is a table providing TEAEs based on KPS scores.

As provided herein, irinotecan is used as irinotecan sucrose sulfate liposome injection (also known as "irinotecan sucrose octasulfate microlipid injection" or "irinotecan sulphate micro Administration in a liposome formulation of a liposome injection), referred to herein as "MM-398" (also known as PEP02, see US 8,147,867). MM-398 can be provided as a sterile injectable parenteral fluid for intravenous injection. The desired amount of MM-398 can be diluted, for example, in 500 mL of 5% dextrose injection USP and infused over a 90 minute period.

MM-398 microlipid system is a single-layer lipid bilayer vesicle with a diameter of about 80-140 nm, which encapsulates an aqueous space containing irinotecan compounded in a gelled or precipitated state with a salt of sucrose octasulfate. . The lipid membrane of the liposome is composed of phospholipid choline, cholesterol and polyethylene glycol-derived phospholipid-ethanolamine in an amount of about 200 phospholipid molecules per polyethylene glycol (PEG) molecule.

This stable liposome formulation of irinotecan has several properties that provide an improved therapeutic index. Controlled and sustained release improves the activity of this time-dependent drug by extending the duration of exposure of the tumor tissue to the drug, which allows it to be used during the S-phase of the cell cycle when DNA unwinding is required as a DNA replication process In the preparatory steps, it is stored in a higher proportion of cells. Long-circulating pharmacokinetics and high intravascular drug retention in the liposomes promote enhanced permeability and retention (EPR) effects. EPR allows the deposition of liposomes at multiple sites, such as malignant tumors, where the normal integrity of the vascular system (especially the capillaries) is impaired, causing particles such as liposomes to leak out of the capillary lumen. EPR can thereby facilitate site-specific drug delivery of liposomes to solid tumors. The EPR of MM-398 can cause subsequent reservoir effects, in which the liposome accumulates in tumor-associated macrophages (TAM), which metabolize irinotecan and locally convert it to a significantly more cytotoxic SN. -38. This localized biological activation is believed to cause a decrease in drug exposure at potentially toxic sites and an increase in exposure to cancer cells within the tumor.

In one embodiment, the lipid irinotecan microlipid irinotecan, such as MM-398. MM-398 Irinotecan liposome injection is a topoisomerase 1 inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1 reduces the torsional strain of DNA by inducing a single strand break. Irinotecan and its active metabolite SN-38 reversibly bind to the topoisomerase 1-DNA complex and prevent re-ligation of single-strand breaks, resulting in exposure time-dependent double-strand DNA damage and cell death. In mice with human tumor xenografts, a similar SN-38 intratumoral exposure was achieved with irinotecan liposome administered at an equivalent dose lower than irinotecan HCl. .

MM-398 is a topoisomerase inhibitor formulated with irinotecan hydrochloride trihydrate as a liposome dispersion for intravenous use. The chemical name of irinotecan hydrochloride trihydrate is ( S )-[1,4'bipiperidinyl-1'-carboxylic acid 4,11-diethyl-3,4,12,14-tetrahydro- 4-hydroxy-3,14-di- oxy 1H-pyrano[3',4':6,7]-pyridazino[1,2 b]quinolin-9-yl ester monohydrochloride Hydrate. The empirical formula is C ₃₃ H ₃₈ N ₄ O ₆ . HCl. 3H ₂ O and molecular weight 677.19 g / mol. The molecular structure is: structural formula:

The chemical name of irinotecan is ( S )-[1,4'bipiperidinyl]-1'-carboxylic acid 4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14 - Bi-oxy 1H-pyrano[3',4':6,7]-pyridazino[1,2b]quinolin-9-yl ester. The empirical formula is C ₃₃ H ₃₈ N ₄ O ₆ and the molecular weight is 586.68 g/mole. The molecular structure of irinotecan is: Structural formula:

MM-398 system has recently tradename ONIVYDE ^TM (irinotecan liposome injection) of approval by the FDA irinotecan liposome injection. MM-398 is a topoisomerase I inhibitor indicated for the treatment of metastatic adenocarcinoma of the pancreas following disease progression after gemcitabine-based therapy. MM-398 (Irinotecan liposome injection) in combination with fluorouracil and formazan tetrahydrofolate is indicated for the treatment of patients with metastatic adenocarcinoma of the pancreas whose disease has evolved following gemcitabine-based therapy. MM-398 was administered prior to formazan tetrahydrofolate and fluorouracil. MM-398 was not indicated as a single agent for the treatment of metastatic adenocarcinoma of the pancreas. MM-398 does not replace other drugs containing irinotecan hydrochloride or irinotecan hydrochloride trihydrate non-lipidate formulations.

A dose based on irinotecan hydrochloride trihydrate is converted to a dose based on irinotecan free base by multiplying the dose based on irinotecan hydrochloride trihydrate by the molecular weight of irinotecan free base (586.68 g) /mol) is completed in a ratio of the molecular weight of irinotecan hydrochloride trihydrate (677.19 g/mol). This ratio is 0.87, which can be used as a conversion factor. For example, a dose of 80 mg/m ² based on irinotecan hydrochloride trihydrate is equivalent to a dose of irinotecan free base of 69.60 mg/m ² (80 x 0.87). This was rounded to 70 mg/m ² in the clinic.

Unless otherwise indicated, the dose of irinotecan liposome (including MM-398 or PEP02 irinotecan liposome) as indicated herein in mg/m ² refers to the corresponding weight of irinotecan hydrochloride. The amount of irinotecan in salt trihydrate. For example, a dose of 80 mg/m ² of irinotecan liposome refers to a dose of irinotecan liposome providing 80 mg/m ² of irinotecan hydrochloride trihydrate ("hydrochloride dose") . Alternatively, the dose of irinotecan liposome can be expressed as the amount of irinotecan free base encapsulated in irinotecan liposome ("free base dose"). In the ONIVYDE irinotecan liposome product, the dose of irinotecan liposome is expressed in terms of the free base dose of irinotecan. Unless otherwise indicated, the irinotecan liposome dose free base doses listed in the US Prescribing Information for ONIVYDE can be converted to the irinotecan liposome hydrochloride dose according to the following table.

The recommended dose of MM-398 is 80 mg/m ² (salt) (70 mg/m ² free base) intravenously via 90 minutes (ie, 70 mg of irinotecan free base/m ² patient in irinotecan liposome) The surface area contains approximately equal amounts of irinotecan as may be present in 80 mg/m ² of irinotecan hydrochloride trihydrate. Preferably, the recommended dose of MM-398 is 80 mg/m ² administered by intravenous infusion over 90 minutes every 2 weeks. Corticosteroids and antiemetics are preferably administered to the patient 30 minutes prior to MM-398.

MM-398 is available as the product ONIVYDE (Irinotecan liposome for injection) (Merrimack Pharmaceuticals, Inc, Cambridge, MA) as a sterile white to pale yellow opaque isotonic liposome dispersion. Each 10 mL single dose vial contained 43 mg irinotecan free base at a concentration of 4.3 mg/mL. A single-layered lipid bilayer vesicle having a diameter of about 110 nm, which encapsulates an aqueous space containing gelation or sedimentation. The yttrium state is irinotecan which is sucrose octasulfate (also known as "threte"). The vesicles are composed of 6.81 mg/mL 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 2.22 mg/mL cholesterol, and 0.12 mg/mL methoxy-terminal polyethylene. Alcohol (MW 2000)-distearoylphosphatidylcholine ethanolamine (MPEG-2000-DSPE) composition. Each mL also contains 4.05 mg/mL 2-[4-(2-hydroxyethyl)hexahydropyrazin-1-yl]ethanesulfonic acid (HEPES) as a buffer and 8.42 mg/mL sodium chloride as an isotonic reagent. .

For the preparation of MM-398, follow the applicable special handling and disposal procedures. MM-398 can be supplied as a single dose vial containing 43 mg irinotecan in a 10 mL single dose vial. Irinotecan is encapsulated in a liposome. The calculated volume of MM-398 was taken from the vial. MM-398 was diluted in 500 mL of 5% dextrose injection USP or 0.9% sodium chloride injection USP and the diluted solution was mixed by gentle inversion. Prevent the diluted solution from seeing light. The diluted solution was administered within 4 hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigeration conditions [2 ° C to 8 ° C (36 ° F to 46 ° F)]. The diluted solution was allowed to reach room temperature before administration. Not frozen. The diluted solution was intravenously infused over 90 minutes. No line filters are used. Discard the unused portion. Injection: 43 mg/10 mL irinotecan free base as a white to pale yellow opaque microlipid dispersion in a single dose vial. MM-398 can be obtained in a single dose vial containing 43 mg of irinotecan free base at a concentration of 4.3 mg/mL: 69171-398-01. The MM-398 was refrigerated at 2 ° C to 8 ° C (36 ° F to 46 ° F). Not frozen. Prevent it from seeing light. MM-398 is a cytotoxic drug. Follow the applicable special handling and disposal procedures.

MM-398 dose and administration

The lipid irinotecan can be administered in combination with 5-fluorouracil and formazan tetrahydrofolate to treat pancreatic cancer. The pancreatic cancer may be a pancreatic cancer secreted from a group consisting of acinar cell carcinoma, adenocarcinoma, adenosquamous carcinoma, giant cell tumor, intraductal papillary mucinous neoplasm (IPMN), mucinous cyst Cancer, pancreatic blastoma, serous cystadenocarcinoma and solid pseudopapillary tumor. In one embodiment, a patient treated using the methods and compositions disclosed herein is Evidence of recurrent or persistent pancreatic cancer after initial chemotherapy. In another embodiment, the patient has previously performed at least one platinum-based chemotherapy regimen for managing a primary or recurrent disease, such as a chemotherapy regimen comprising carboplatin, cisplatin or another organoplatinum compound and fails. In another embodiment, the patient has previously been treated with gemcitabine and failed or became resistant to gemcitabine. In one embodiment, the resistant or refractory tumor is one in which the patient having the tumor has a tumor-free progression of less than 6 months after completion of the treatment (eg, due to cancer recurrence) or where tumor progression occurs during the course of treatment . In another embodiment, the pancreatic cancer of the patient undergoing treatment is advanced pancreatic cancer, which is a pancreatic tumor that exhibits either or both of distal metastases or peripancreatic expansion of the tumor. The compositions and methods disclosed herein can be used to treat all pancreatic cancers, including pancreatic cancer that is refractory or resistant to other anti-cancer therapies.

In one embodiment, the alipid irinotecan is administered prior to 5-FU and formazan tetrahydrofolate to treat pancreatic cancer. In another embodiment, the formazan tetrahydrofolate is administered prior to 5-FU. In another embodiment, the alipid irinotecan is administered intravenously over 90 minutes. In another embodiment, the 5-FU is administered intravenously over a 46 hour period. In another embodiment, formazan tetrahydrofolate is administered intravenously over 30 minutes. In various embodiments, the lipid irinotecan is MM-398.

In another aspect, a liplipid irinotecan formulation for co-administration with 5-fluorouracil (5-FU) and formazan tetrahydrofolate in at least one cycle is provided, wherein the cycle is for a 2 week period The irinotecan formulation is an irinotecan liposome formulation, and wherein: (a) the lipid irinotecan is administered at a dose of 80 mg/m ² on the first day of each cycle for UGT1A1*28 A patient with an allelic non-homogeneous junction, and administered at a dose of 60 mg/m ² on the first day of cycle 1 and at a dose of 60 mg/m ² or 80 mg/m ² on the first day of each subsequent cycle for UGT1A1 * 28 allele isotype engaging the patient; (b) at 2400mg / m ² doses administered with the 5-FU; and (c) to 200mg / m ² (l or L form of methyl tetrahydrofolate XI) or 400mg / m A dose of ² ( l + d racemic form) is administered to formamidine tetrahydrofolate.

In another embodiment, the 5-FU is administered intravenously over a 46 hour period.

In another embodiment, formazan tetrahydrofolate is administered intravenously over 30 minutes.

In another embodiment, the patient is premedicated with dexamethasone and/or a 5-HT3 antagonist or another antiemetic agent prior to each administration of the lipophilic irinotecan.

5-fluorouracil is a pyrimidine antagonist that interferes with nucleic acid biosynthesis. The deoxyribonucleotide of the drug inhibits thymidine nucleotide synthetase, thereby inhibiting the formation of thymidylate from deoxyuridine, thereby interfering with the synthesis of DNA. It also interferes with RNA synthesis.

Formazan tetrahydrofolate (also known as aldehyde folate) is used as a biochemical cofactor for 1-carbon transfer reactions in the synthesis of purines and pyrimidines. The conversion of formazan tetrahydrofolate to tetrahydrofolate requires no enzyme dihydrofolate reductase (DHFR). Hyperthyroidism inhibits the effects of methotrexate and other DHFR antagonists. Formazan tetrahydrofolate enhances the cytotoxic effects of fluorinated pyrimidines (ie, fluorouracil and fluorouridine). After 5-FU is activated intracellularly, it is accompanied by folic acid coenzyme and inhibits the enzyme thymidine nucleotide synthetase, thereby inhibiting pyrimidine synthesis. Formazan tetrahydrofolate increases the folate pool, thereby increasing the binding of folate coenzyme and active 5-FU to thymidine nucleotide synthetase.

Formazan tetrahydrofolate has dextrorotatory and levorotatory isomers, and only levorotatory isomers are pharmacologically useful. Therefore, the biologically active levorotatory isomer ("levopyrazine tetrahydrofolate") has also been approved by the FDA for the treatment of cancer. The dose of levoameptine tetrahydrofolate is usually one half of the racemic mixture of both the dextrorotatory ( d ) and levorotatory ( 1 ) isomers.

FU and formazan tetrahydrofolate will be stored and manipulated according to country-specific packaging inserts.

The enzyme UDP-glucuronosyltransferase 1 produced by the UGT1A1 gene is responsible for bilirubin metabolism and also mediates SN-38 glucuronidation, the initial of the main metabolic clearance pathway of this active metabolite of irinotecan step. In addition to its anti-tumor activity, SN-38 sometimes causes severe toxicity associated with irinotecan therapy. Therefore, acidification of SN-38 glucuron to an inactive form of SN-38 glucuronide is an important step in the regulation of irinotecan toxicity.

Mutational polymorphisms in the promoter of the UGT1A1 gene have been described in which a variable number of thymine adenine (ta) repeats are present. The promoter containing 7 thymine adenine (ta) repeats (found in the UGT1A1*28 allele) has been found to be less active than the wild type 6 repeats, resulting in UDP-glucuronosyltransferase 1 Performance is reduced. Patients carrying the two defective alleles of UGT1A1 exhibited reduced glucuronidation of SN-38. Some case reports have shown that the UGT1A1*28 allele is homozygous (called the UGT1A1 7/7 genotype, since both alleles are UGT1A1*28 alleles containing 7 ta repeats, Individuals with opposite fluctuations in serum bilirubin (eg, Gilbert's Syndrome patients) can be accepted in comparison with wild-type UGT1A1 6/6 genotypes in which two alleles contain six ta repeats. The standard dose of irinotecan has a greater risk of toxicity. This indicates a correlation between homozygous zygosity, bilirubin content and irinotecan toxicity of the UGT1A1*28 allele.

The metabolic conversion of MM-398 to SN-38 (eg, in plasma) involves two key steps: (1) release of irinotecan from the liposome and (2) conversion of free irinotecan to SN-38. Although not intended to be bound by theory, it is believed that once irinotecan leaves the liposome, it is alienated by the same metabolic pathway as the conventional (free) irinotecan. Therefore, the genetic polymorphisms predicting the toxicity and efficacy of irinotecan and MM-398 in humans can be considered similar. However, due to the smaller tissue distribution, lower clearance, higher systemic exposure, and longer elimination half-life of SN-38 in the MM-398 formulation compared to free irinotecan, defective genetic polymorphism can be shown and severe More relevance of adverse events and/or efficacy.

Individuals with the UGT1A1*28 allele homotypic junction (UGT1A1 7/7 genotype) have been shown to have an increased risk of neutropenia after initiation of irinotecan treatment. Based on information about irinotecan (CAMPTOSAR ^® ), in a study of 66 patients receiving a single agent irinotecan (350 mg/m2 once every 3 weeks), patients who were homozygous for the UGT1A1*28 allele The incidence of grade 4 neutropenia was as high as 50%, and the incidence was 12.5% in patients with this allelic heterozygous (UGT1A1 6/7 genotype). Importantly, no grade 4 neutropenia was observed in patients with wild-type allele homotypic junctions (UGT1A1 6/6 genotype). In other studies, the lower prevalence of life-threatening neutropenia was described. Therefore, patients enrolled in the Phase 3 study described in the Examples herein and for the UGT1A1*28 allele homotypic junction (UGT1A1 7/7 genotype) will have less than one (eg, UGT1A1 6/7) or 2 ( UGT1A1 6/6) The dose of patients with wild-type alleles was initiated by MM-398. .

Although the UGT1A1*28 allele is relatively common in Caucasians (estimated at 10%), the prevalence rate varies among other ethnic groups. In addition, other UGT1A1 genotypes have been found to have a high prevalence in, for example, Asian populations and these genotypes are important for the metabolism of irinotecan in such populations. For example, the UGT1A1*6 allele is more prevalent in Asians. This allele is not related to the ta repeat, but is associated with a Gly71Arg mutation that reduces enzyme activity. In the previous and ongoing MM-398 study, pharmacogenetic information on selected patients has been collected. In a study called the PEP0203 study, the relationship between the genetic polymorphism of the UGT1A family and DPYD (dihydropyrimidine dehydrogenase, an enzyme involved in the catabolism of 5-FU) and the pharmacokinetic parameters and toxicity of MM-398 No clear association was provided due to the small sample size of the subjects assessed. However, patients with UGT1A1*6/*28 combination polymorphism were observed to have a higher SN-38 dose normalized AUC and experienced DLT.

The recommended starting dose of MM-398 in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m ² administered by intravenous infusion over 90 minutes. The MM-398 dose was increased to a tolerable 70 mg/m ² in subsequent cycles. In one embodiment, after a period, and administered to patients UGT1A1 * 28 allele isotype of the engagement increases for irinotecan liposome Kang dose to 80mg / m ^2. In another embodiment, the alipid irinotecan is administered intravenously over 90 minutes.

In some embodiments, a method of administering MM-398 to a patient having one or more characteristics can include reducing or otherwise modifying the agent administered MM-398 according to the embodiments herein. the amount. In some embodiments, the dose of MM-398 is modified according to Table 2.

Irinotecan is a subject of extensive metabolic conversion of multiple enzyme systems, including esterases to form the active metabolite SN-38, and UGT1A1 mediates the uronic acidification of SN-38 to form inactive glucuronide metabolites SN -38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism into several inactive oxidation products, one of which can be hydrolyzed by a carboxyl esterase to release SN-38. In a population pharmacokinetic analysis using the results of a subset of the UGT1A1*28 genotype test (where the analysis is directed to the lower dose adjusted for patients who are homozygous for the UGT1A1*28 allele), for this The mean steady-state concentrations of total SN-38 in patients with homozygous (N=14) and non-synchronous (N=244) were 1.06 [95% CI: 0.9-1.25] and 0.95 [95% CI: 0.9-0.99, respectively). ]ng/mL.

Individuals who are homozygous for the UGT1A1*28 allele have an increased risk of neutropenia from irinotecan HCl. In Study 1, patients with homozygous binding of the UGT1A1*28 allele (n=7) started MM-398 with a reduced dose of 50 mg/m ² in combination with 5-FU/LV. The frequency of grade 3 or 4 neutropenia in these patients [2 out of 7 (28.6%)] is similar to the UG-398 receiving the initial dose of 70 mg/m ² for the UGT1A1*28 allele The frequency of patients with non-homogeneous junctions [30 of 110 (27.3%)].

Pharmacokinetics of MM-398

Preferably, the irinotecan liposome is characterized by the pharmacokinetic parameters in Table 3 (eg, MM-398 irinotecan liposome), or bioequivalent, when administered to a human patient once every two weeks. The irinotecan liposome (eg, irinotecan liposome is characterized by one or more values, one or more of the values _Cmax , AUC, and t1 _/2 in Table 3 below) 80%-105%).

Using population pharmacokinetic analysis in patients with cancer (these patients received MM-398 as a single agent or as part of a combination chemotherapy at a dose between 50 and 150 mg/m ² ) and 353 with cancer Plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients. The pharmacokinetic parameters of total irinotecan and total SN-38 after administration of 70 mg/m ² as a single agent or a combination of chemotherapeutic treatments are presented in Table 3, or Cmax and AUC values are attributable to The 80 mg/m ² (salt) q2w dose was administered within 80-125% of the value observed by MM-398. Overview of the mean (± standard deviation)

The pharmacokinetic parameters of total irinotecan and total SN-38 after administration of 70 mg/m ² as part of a single agent or combination chemotherapy are presented in Table 3.

In the dose range of 50 to 150 mg/m ² , the Cmax and AUC of total irinotecan increased with dose. In addition, the _{Cmax of} total SN-38 increased proportionally with dose; however, the AUC of total SN-38 increased proportionally with dose. The association of SN-38 C _max with the lipid irinotecan dose has not previously been established. Higher plasma SN-38 _{Cmax is} associated with an increased likelihood of experiencing neutropenia.

The _{Cmax of} SN-38 increased proportionally with the dose of aliline irinotecan, but the AUC of SN-38 increased proportionally with dose, enabling a new dose adjustment method. For example, the value of the parameter ( _Cmax ) associated with the adverse effect is reduced to a greater extent than the value associated with the therapeutic effectiveness (AUC). Therefore, when an adverse effect is seen, a reduction in the administration of the lipophilic irinotecan can be performed, thereby maximizing the difference between the decrease in _{Cmax and the} decrease in AUC. This finding means that in a treatment regimen, a given SN-38 AUC can be achieved with very low SN-38 _Cmax . Similarly, a given SN-38 _Cmax can be achieved with a very high SN-38 AUC.

Direct measurements of irinotecan liposomes showed that 95% irinotecan remained encapsulated with liposomes and the ratio between total and encapsulated form did not change over time from 0 to 169.5 hours after administration. The average distribution volume is summarized in Table 3.

In some embodiments, the lipid irinotecan can be MM-398 or a bioequivalent product with MM-398. In some embodiments, the aliline irinotecan can be characterized by the parameters in Table 4, including the Cmax and/or AUC values of 80-125% of the corresponding values in Table 3. The pharmacokinetic parameters of the total irinotecan of various alternative lipid irinotecan formulations administered 70 mg/m ² irinotecan free base once every two weeks are provided in Table 4.

C _max : maximum plasma concentration AUC _0-∞ : extrapolated to infinite time plasma concentration curve area under t _1⁄2 : terminal elimination half-life

<0.44% of the total irinotecan in the plasma protein binding line MM-398.

The plasma clearance of total irinotecan from 70 mg/m ² MM-398 was 0.077 L/h/m ² and the terminal half-life was 26.8 h. After administration of 125 mg/m ² irinotecan HCl, the plasma clearance of irinotecan was 13.3 L/h/m ² and the terminal half-life was 10.4 h.

The disposal of MM-398 has not yet been elucidated in humans. After administration of irinotecan HCl, the urinary excretion of irinotecan was 11% to 20%; SN-38 <1%; and SN-38 glucuronide was 3%. In the 48-hour period after administration of irinotecan HCl in 2 patients, the accumulation of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) was between biliary excretion and urinary excretion. 25% (100 mg/m ² ) to 50% (300 mg/m ² ).

Group pharmacokinetic analysis showed that age (28 to 87 years) had no clinically significant effect on irinotecan and SN-38 exposure.

Population pharmacokinetic analysis showed that gender (196 males and 157 females) had no clinically significant effect on irinotecan and SN-38 exposure after adjustment for body surface area (BSA).

Mild to moderate renal impairment after adjustment for BSA in population pharmacokinetic analysis The injury had no effect on the exposure of total SN-38. The analysis included 68 patients with moderate (CLcr 30-59 mL/min) kidney injury, 147 patients with mild (CLcr 60-89 mL/min) kidney injury, and 145 with normal renal function (CLcr >90 mL/ Min) patients. The data in patients with severe renal impairment (CLcr < 30 mL/min) is not sufficient to assess its effect on pharmacokinetics.

Group pharmacokinetic analysis showed that Asians (East Asians) had an average steady-state concentration of irinotecan that was 56% lower than Caucasians and a mean steady-state concentration of 8% of total SN-38.

The pharmacokinetics of irinotecan liposomes have not been studied in patients with liver damage. In the population pharmacokinetic analysis, patients with a baseline bilirubin concentration of 1-2 mg/dL (n=19) had a mean steady-state concentration of total SN-38 compared to patients with a baseline bilirubin concentration <1 mg/dL (n =329) increased by 37%; however, elevated ALT/AST concentrations had no effect on total SN-38 concentration. No data were obtained from patients with bilirubin > 2 mg/dL.

In the population pharmacokinetic analysis, the pharmacokinetics of total irinotecan and total SN-38 were not altered by co-administration of fluorouracil/hyperthymidine.

The moderate CYP3A4 inducer dexamethasone did not alter the pharmacokinetics of irinotecan after administration of irinotecan HCl.

In vitro studies indicate that irinotecan, SN-38, and another metabolite, aminopentanecarboxylic acid (APC), do not inhibit cytochrome P-450 isozymes.

Safety and tolerance

MM-398 is a cytotoxic drug. In some embodiments, the method of administering MM-398 includes certain precautions. For example, a patient may have or have suffered from neutropenia, diarrhea, or interstitial lung disease.

In some embodiments, MM-398 is administered without causing severe or fatal neutrophilia or neutropenic sepsis. MM-398 can cause severe and fatal neutropenia/neutropenic sepsis. In Study 1, the incidence of neutropenic sepsis was 0.8% among patients receiving MM-398, at 117 One patient with MM-398 plus fluorouracil/hyperthyroid tetrahydrofolate (MM-398/5-FU/LV) and one patient with 147 patients receiving MM-398 as a single agent Among the patients with the disease. Twenty-seven percent of patients receiving MM-398/5-FU/LV developed severe or life-threatening neutropenia, compared with fluorouracil/hyperthyroid tetrahydrofolate (5-FU/LV) The patient was 2%. 3% of patients receiving MM-398/5-FU/LV developed grade 3 or 4 neutropenic fever/neutropenic sepsis and did not occur in patients receiving 5-FU/LV .

Among patients receiving MM-398/5-FU/LV, the incidence of grade 3 or 4 neutropenia was in Asia compared with Caucasian patients [13 out of 73 (18%)] Patients were higher [18 out of 33 (55%)]. Neutrophilic fever/neutropenic sepsis occurred in 6% of Asian patients compared to 1% of whites.

Thus, in some embodiments, MM-398 is administered while monitoring the whole blood count on the first and eighth days of each cycle, and more frequently if clinically indicated. Clinical indications include an assessment of the likelihood that a patient may have neutropenia. Patients with an increased risk of neutropenia include those with non-wild type UGT1A1 and/or Asians. In some embodiments, the methods disclosed herein comprise the step of performing blood counts more frequently when the patient is Asian and/or has a non-wild type UGT1A1 allele. In some embodiments, the blood count is performed at one of: one or more days of days 1, 2-7, one or more of days 8 and 9-14, such as where Blood count: 2 days or more on Day 1, Day 2-7, Day 2 and Days 2-14 or more; wherein Blood Count is performed at: Day 1 3 days or more of days 2-7, 3 days or 3 days or more of days 9-14; wherein blood counts are performed at: 1st, 2nd-7th 4 days or more of 4 days or more, 8th day and 9-14 days; wherein the blood count is performed at: 1st day, 5th day of 2nd-7th or more Five days or more of days, days 8, and days 9-14; for example, where blood counts are performed on each of days 1-14. In some embodiments, the blood cell counting detector neutrophil thrombocytopenia, for example, wherein the absolute neutrophil count of less than ^1500/3 mm, the detected neutrophil thrombocytopenia. In some embodiments, a subsequent dose of aliline irinotecan is reduced upon detection of neutropenia. In some embodiments, the reduced dose is not zero.

MM-398 is discontinued if the absolute neutrophil count (ANC) is below 1500/mm ³ or if neutrophilic fever occurs. When the ANC is 1500/mm ³ or higher, the MM-398 is restored. For grade 3-4 neutropenia or neutropenic fever, the MM-398 dose is reduced after recovery in subsequent cycles. The measurement of the reduced dose usage can be taken into account in the discussion of paragraph A. When, for example, neutrophils observed in Asian patients thrombocytopenia, the liposomes may reduce the dosage of irinotecan Kang to reduce adverse effects associated with the SN-38C _max. However, based on the comparison, the reduction in effect (based on AUC) can be extremely high and treatment effectiveness can still be expected. Thus, the inventors' findings suggest that the clinician has previously determined the need in many of the assumptions that the previous SN-38 C _max and SN-38 AUC are related in the same manner to the aliline irinotecan dose. In the case of complete cessation of treatment, treatment can continue. In other words, the relationship between these parameters and the administration of aliline irinotecan causes the reduction in the dose of aliline irinotecan to reduce SN-38 C _max below the threshold for adverse effects, but maintain SN-38 AUC is higher than the threshold for obtaining treatment outcome. Thus, in some embodiments of the methods disclosed herein, the method comprises determining whether the patient has neutropenia (or will experience another adverse effect) or may have neutropenia (or another adverse effect) When the step of reducing the dose of aliline irinotecan is reduced. In some embodiments, the dose is reduced, but the aliline irinotecan treatment is not stopped (ie, the reduced dose is not 0).

By blood count analysis and the study population of SN-38 C _max, the relationship can be determined between the neutrophil thrombocytopenia and SN-38 C _max, and C _max to thereby calculate the threshold value, exceeding said threshold Limits indicate that neutropenia has occurred or will occur. This threshold can be used as a predetermined threshold in subsequent tests for other patients. Accordingly, in some embodiments, the methods disclosed herein include the step of monitoring SN-38 _Cmax and, if appropriate, changing the dose of the aliquot of irinotecan. As noted above, SN-38 C _max is proportional to the relationship between the administered lipid irinotecan, meaning that the patient's SN-38 C _{max can be} more than known to be associated with neutropenia. The extent of the limit is calculated as the desired reduction in the dose of the aliline irinotecan, but at this dose reduction the AUC parameter exceeds the threshold for the observed therapeutic effect. A similar analysis can be performed to eliminate the risk of interstitial lung disease or severe allergic reactions and indeed other adverse effects before the onset of physical symptoms.

In some embodiments, MM-398 is administered without causing severe or life-threatening diarrhea. MM-398 can cause severe and life-threatening diarrhea. Do not administer MM-398 to patients with intestinal obstruction. Severe or life-threatening diarrhea follows one of two modes: delayed diarrhea (within 24 hours after chemotherapy) and early onset diarrhea (other symptoms that occur within 24 hours of chemotherapy, sometimes with choline) Happen together). Individual patients can experience both early onset and delayed onset diarrhea.

In Study 1, grade 3 or grade 4 diarrhea occurred in 13% of those who received MM-398/5-FU/LV, compared with 4% who received 5-FU/LV. Among patients who received MM-398/5-FU/LV, the incidence of grade 3 or grade 4 delayed diarrhea was 9%, compared with 4% of patients receiving 5-FU/LV. Among patients who received MM-398/5-FU/LV, the incidence of grade 3 or grade 4 early onset diarrhea was 3%, compared with no grade 3 or 4 in patients receiving 5-FU/LV. Early onset diarrhea. Of the patients who received MM-398/5-FU/LV in Study 1, 34% received loperamide for delayed diarrhea and 26% received atropine for early-onset diarrhea.

In some embodiments, the method of treatment comprises discontinuing MM-398 due to grade 2-4 diarrhea. The starting loperamide is used for delayed diarrhea of any severity. 0.25 to 1 mg atropine (unless clinically contraindicated) is administered intravenously or subcutaneously for any severity of early onset diarrhea. After returning to grade 1 diarrhea, use MM-398 at a reduced dose.

In some embodiments, MM-398 is administered to a patient without causing severe or fatal interstitial lung disease. Irinotecan HCl can cause severe and fatal interstitial lung disease (ILD). In patients with new or progressive dyspnea, cough and fever, in the diagnosis The MM-398 is deactivated during the evaluation. MM-398 was discontinued in patients with confirmed ILD.

In some embodiments, MM-398 is not administered to a patient experiencing a severe allergic reaction to irinotecan. Irinotecan HCl can cause severe allergic reactions, including allergic reactions. MM-398 was permanently discontinued in patients experiencing severe allergic reactions.

In some embodiments, MM-398 is not administered to a pregnant or lactating patient. Based on the animal data using irinotecan HCl and the mechanism of action of MM-398, MM-398 can cause fetal damage when administered to pregnant women. Observation of irinotecan HCl after administration to pregnant rats and rabbits during organogenesis at doses that resulted in irinotecan exposure lower than those achieved with 70 mg/m ² MM-398 in humans To embryo toxicity and teratogenicity. Inform pregnant women about the potential risks to the fetus. It is recommended that women with reproductive potential use effective contraception during treatment with MM-398 and one month after the final dose. Based on the animal data using irinotecan HCl and the mechanism of action of MM-398, MM-398 can cause fetal damage when administered to pregnant women. Information available in non-pregnant women. Observed after treatment with irinotecan HCl administered to pregnant rats and rabbits during organogenesis at doses that caused irinotecan exposure to be lower than those achieved in humans with 70 mg/m ² MM-398 Embryo toxicity and teratogenicity. Inform pregnant women about the potential risks to the fetus.

In the US general population, the estimated background risk of major birth defects and clinically recognized abortions during pregnancy is 2-4% and 15-20%, respectively. Animal studies have not been performed to assess the effects of irinotecan liposomes on reproduction and fetal development; however, irinotecan HCl has been used for research. Irinotecan is administered intravenously through the rat placenta. Intravenous administration of irinotecan to rats and rabbits at a dose of 6 mg/kg/day during the organogenesis phase resulted in an increase in post-implantation loss and a decrease in the number of live fetuses. In rats of a separate study, based on the area under the curve (AUC), this dose leads to irinotecan exposure is about 0.002 times to 70mg / m ² dose administered to the patient MM-398 of the of irinotecan exposure of the. At doses greater than 1.2 mg/kg/day (based on AUC, about 0.0002 times the clinical exposure of irinotecan in MM-398), administration of irinotecan HCl resulted in structural abnormalities and growth delay in rats. Teratogenic effects include a variety of external, visceral, and skeletal abnormalities. Administration of irinotecan HCl to rat dam at a dose of 6 mg/kg/day from organogenesis to weaning stage resulted in decreased learning ability and decreased female body weight.

There is no information on the presence of irinotecan liposome, irinotecan or SN-38 (active metabolite of irinotecan) in human milk or on breast-feeding infants or on lactation. Irinotecan is present in the milk of rats. Due to the potential of MM-398 to cause serious adverse reactions in breast-fed infants, it is recommended that lactating women do not breastfeed during treatment with MM-398 and one month after the final dose. Radioactivity was visualized in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan HCl and concentrated up to 65 times relative to plasma concentration 4 hours after administration.

MM-398 can cause fetal damage when administered to pregnant women. It is recommended that women with reproductive potential use effective contraception during treatment with MM-398 and one month after the final dose. Due to the potential for genotoxicity, men with female spouses with reproductive potential are advised to use condoms during treatment with MM-398 and for 4 months after the final dose.

For patients with serum bilirubin above the upper limit of normal, there is no recommended dose of MM-398. The safety and efficacy of MM-398 has not been established in pediatric patients. No known therapeutic intervention can effectively control the overdose of MM-398.

In some embodiments, the method of administering MM-398 comprises informing a patient to select one or more risks selected from the group consisting of:

‧ Allergic to irinotecan HCl or MM-398: inform patients of the potential risk of severe allergies and MM-398 is contraindicated in patients with a history of severe allergic reactions to irinotecan HCl or MM-398. Instruct patients to seek immediate medical attention for signs of severe allergic reactions such as chest tightness; shortness of breath; wheezing; dizziness or fainting; or swelling of the face, eyelids or lips;

‧ Severe neutropenia : Inform patients that neutropenia is at risk of serious and life-threatening infections and that blood counts need to be monitored. Instruct patients to contact their health care provider immediately if they experience signs of infection, such as fever, chills, dizziness or shortness of breath (see "WARNINGS AND PRECAUTIONS: Severe Neutropenia").

‧ Severe diarrhea : Inform patients of the risk of severe diarrhea. Patients are advised to contact their health care provider if they experience the following symptoms: persistent vomiting or diarrhea; melena or bloody stools; or dehydration symptoms such as dizziness, dizziness or fainting;

‧Interstitial lung disease : inform patients of the potential risk of ILD. Patients are advised to contact their health care provider as soon as possible for new coughing or difficulty breathing;

‧ Choline reaction: Inform patients of the risk of biliary reactions occurring within 24 hours of MM-398 administration. Patients are advised to contact their health care provider if they experience the following symptoms: rhinitis, increased salivation, flushing, bradycardia, dilated pupils, tearing, sweating, and excessive peristalsis with abdominal cramps and early onset diarrhea;

‧ Embryo-fetal toxicity : Inform women of reproductive potential of the potential risk to the fetus, use effective contraception during treatment and one month after the final dose, and inform their health care provider of known or suspected pregnancy;

‧ Contraception : It is recommended that male patients with female spouses with reproductive potential use condoms during treatment with MM-398 and 4 months after the final dose

‧ Lactation : It is recommended that women do not breastfeed during the treatment with MM-398 and one month after the final dose.

In some embodiments, MM-398 is not administered to a patient having a severe allergic reaction to MM-398 or irinotecan HCl, a patient having an allergic reaction to MM-398, or some having reproductive potential or having a pair Female patients with potential risks to the fetus, or breast-feeding female patients.

After administration of non-lipid irinotecan (ie, irinotecan HCl), it simultaneously receives CYP3A4 enzyme-induced anticonvulsant phenytoin, phenobarbital Exposure to irinotecan or its active metabolite SN-38 was significantly reduced in adult and pediatric patients (phenobarbital), carbamazepine or St. John's wort. Avoid strong CYP3A4 inducers if possible (eg, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John's wort) . Non-enzymatic induction therapy was replaced at least 2 weeks prior to initiation of MM-398 therapy.

In some embodiments, MM-398 is not administered to a patient receiving a strong CYP3A4 inducer. After administration of non-lipid irinotecan (ie, irinotecan HCl), patients receiving both ketoconazole (CYP3A4 and UGT1A1 inhibitors) had increased irinotecan and its active metabolite SN-38. Exposed. MM-398 and other CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, Nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole or UGT1A1 inhibitors (eg, atazanavir (atazanavir) ), co-fibrozil, and indinavir may be added to systemic exposure in irinotecan or SN-38. Avoid strong CYP3A4 or UGT1A1 inhibitors if possible. The strong CYP3A4 inhibitor was discontinued at least 1 week prior to the start of MM-398 therapy. In some embodiments, MM-398 is administered to a patient who has received a strong CYP3A inducer by replacing the strong CYP3A inducer with non-enzymatic induction therapy for at least 2 weeks prior to initiation of MM-398. In some embodiments, MM-398 is not administered to a patient receiving a strong CYP3A4 inhibitor. In some embodiments, MM-398 is administered to a patient who has received a strong CYP3A4 inhibitor by replacing the strong CYP3A4 inhibitor with non-enzymatic induction therapy at least 1 week prior to initiation of MM-398. Do not administer MM-398 to patients with intestinal obstruction. MM-398 was discontinued for 2-4 grade diarrhea. Administration of loperamide for delayed diarrhea of any severity. Atropine is administered for early-onset diarrhea of any severity.

Studies have not been conducted to assess the carcinogenicity, genotoxicity or damage of irinotecan liposomes The potential to harm fertility. Intravenous administration of irinotecan hydrochloride to rats once a week for 13 weeks and subsequent recovery from 91 weeks resulted in a combined incidence of irinotecan HCl dose with uterine horn endometrial stroma and endometrial stromal sarcoma. Significant linear trend between the two. Irinotecan HCl is cleavable in vitro (chromosomal aberrations in Chinese hamster ovary cells) and in vivo (small nuclear test in mice). Irinotecan and its active metabolite SN-38 were not mutagenic in the in vitro Ames assay.

Special fertility studies have not been performed with irinotecan liposome injection. A total of 6 doses of irinotecan liposome were administered at a dose equal to or greater than 13 mg/kg every 3 weeks (about 3 times the clinical exposure of irinotecan after administration of MM-398 administered at 70 mg/m ² ). Atrophy of male and female reproductive organs was observed in dogs injected with body fluids. No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan HCl to rats at doses up to 6 mg/kg/day; however, in rodents at 20 mg/kg (at Casting about 0.007 times the clinical irinotecan exposure after MM-398 at 70 mg/m ² and 0.4 mg/kg in the dog (0.0005 times the clinical exposure of irinotecan after administration of MM-398) Male genital atrophy was observed after multiple daily doses of irinotecan HCl.

Example 1: NAPOLI-1 clinical trial

NAPOLI-1 is an international randomized human phase 3 clinical trial that evaluates the use of irinotecan liposome MM-398 in patients with a diagnosis of metastatic pancreatic cancer who have previously been treated with gemcitabine-based therapy. The NAPOLI-1 test is outlined below.

NAPOLI-1 is an open tag, randomized, based on albumin (<4.0g/dL relative to 4.0g/dL), Karnofsky physical state (KPS) (70 and 80 relative to 90) and stratification of ethnic groups (Caucasians versus East Asians relative to others). Preliminary analysis was performed by comparing the OS of each treatment group with its corresponding 5-FU/LV control by a non-hierarchical log-rank test; the Family I error rate was controlled to a bilateral 0.05 degree using the Bonferroni-Holm method. Preliminary analysis was planned with at least 305 death events with an 85% weighting to detect HR=0.67 and 98% weighting in the MM-398 group to detect HR=0.50 in the MM-398+5-FU/LV group. Implement a supportive stratification analysis that explains the random packet layer.

The primary endpoint of the NAPOLI-1 study was overall survival; and the key secondary endpoints were progression-free survival (PFS), objective response rate (ORR), tumor marker response (CA19-9), and safety. Once the safety information on the combination is available, the study was modified to increase the MM-398+5-FU/LV group. Only the patients (N=119) who were enrolled in the 5FU/LV group after the correction were used as controls for the combination group.

The key inclusion criteria for the NAPOLI-1 trial are: adenocarcinoma of the pancreatic exocrine; measurable or unmeasurable metastatic disease; evolution after previous gemcitabine or gemcitabine therapy; KPS 70; appropriate bone marrow, liver (bilirubin in the normal range of the body and albumin 3g/dL) and renal function.

Sixty-six patients with PP were in the MM398+5-FU/LV group of NAPOLI-1 and 71 patients with PP were in the 5-FU/LV group of NAPOLI-1. The NAPOLI-1 study is well balanced. Patients in the MM-398+5FU/LV and 5FU/LV groups were consistent between the following patient characteristics: prognostic factors, demographics (age, gender, ethnicity), tumors, and pre- and post-treatment characteristics. The post-study anticancer therapy was 31% in the MM-398+5-FU/LV group and 38% in the 5-FU/LV group.

The overall survival results from the ITT patient group in the NAPOLI-1 clinical trial are shown in Figures 4A and 4B. Figure 4A shows that the median overall survival of the MM-398+5-FU/LV group was 6.1 months (95% CI 4.8-8.9) and the overall survival of the 5-Fu/LV group was 4.2 months (95% CI). 3.3-5.3) and the stratified HR is 0.57 (95 CI 0.41-0.8), p=0.0009. Figure 4B shows that the median overall survival of the MM-398 group was 4.9 months (95% CI 4.2-5.6) and the median OS of the 5-Fu/LV group was 4.2 months (95% CI 3.6-4.9) and The layer HR was 0.93 (95 CI 0.71-1.21), p=035545.

Analysis of the ITT (intent to treat) patient group showed that the overall survival (OS) of MM-398+5-FU/LV (MM-39880 mg/m ² q2w regimen) was statistically significant relative to 5-FU/LV alone. Increase (Figures 4A and 4B), 6.1 months to 4.2 months. Figure 8 is a flow diagram illustrating a population of intent-to-treat (ITT) patients (all randomized patients) who do not meet the protocol (NPP) and PP (conformity) groups. The compliant program group included the protocol definition treatment during the first 6 weeks of treatment Qualified patients who are 80% dose density and do not have the following protocol violations; receive any prohibited therapy as defined in the protocol, do not receive treatment on a random basis, or deviate from the inclusion/exclusion criteria.

A significant increase in OS was also observed in the non-evolved survival (PFS), objective response rate (ORR), and tumor marker response (CA19-9) reactions (Figure 5). In contrast, MM-398 (120 mg/m ² q3w protocol) as a single agent did not show a significant difference in OS. In addition, the forest map sensitivity analysis of the NAPOLI-1 human clinical trial favored MM-398+5-FU/LV relative to 5-FU/LV between the prognostic subgroup, tumor characteristics, and prior treatment (Figures 6 and 7). It is worth noting that in the NAPOLI-1 human clinical trial, the eligible (PP) patient population (described in Figure 8) (patients receiving 6 weeks of treatment), compared to 5.1 months in the 5-FU/LV group, The MM-398+5-FU/LV combination protocol achieved a 8.9 month median OS (stratification hazard ratio (HR): 0.47, p=0.0018; Figures 9A and 9B).

Security profile is manageable and rated 3 had the most frequent adverse events, including neutropenia, fatigue, and GI effects such as diarrhea and vomiting (Figure 12).

The overall survival results for the PP and non-PP populations are shown in Figures 9A and 9B, respectively. Figure 9A shows the median overall survival of the PP population; the median OS of the MM-398+5-FU/LV group was 8.9 months (95% CI 6.4-10.5) and the median OS rate of the 5-Fu/LV group It was 5.1 months (95% CI 4.0-7.2) and the stratified HR was 0.47 (95 CI 0.29-0.77), p = 0.0018. Figure 9B shows the median overall survival of the non-PP population; the median OS of the MM-398+5-FU/LV group was 4.4 months (95% CI 3.3-5.3) and the 5-Fu/LV group median OS The rate was 2.8 months (95% CI 1.7-3.2) and the stratified HR was 0.56 (95 CI 0.33-0.97), p=0.365.

A dosage of 200 mg/m ^{2 of} formazan tetrahydrofolate as used herein is understood to mean (1) mirror image isomer of 200 mg/m ² formazan tetrahydrofolate and a dose of 400 mg/m ² formazan tetrahydrofolate is required. It is understood that 400 mg/m ² of the (l+d) racemate of formazan tetrahydrofolate is required. It is to be further understood that the dose of (1) mirror image isomer having 200 mg/m ^{2 of} formazan tetrahydrofolate and the dose of (l+d) racemate having 400 mg/m ^{2 of} formazan tetrahydrofolate contain equivalents. The medicinal activity (1) form of the amount of formazan tetrahydrofolate.

The efficacy of MM-398 was evaluated in Study 1 in patients with metastatic pancreatic adenocarcinoma with documented disease progression after gemcitabine or gemcitabine-based therapy, a three-group, randomized, open-label trial. Key eligibility criteria include Karnofsky Physical State (KPS) 70, serum bilirubin within normal institutional limits, and albumin 3.0g/dL. Patients were randomized to receive MM-398 plus fluorouracil/mercaptotetrahydrofolate (MM-398/5-FU/LV), MM-398, or fluorouracil/mercaptotetrahydrofolate (5-FU/LV). Randomization was based on ethnic groups (whites versus East Asians versus others), KPS (70-80 versus 90-100), and baseline albumin content ( 4 g/dL is layered relative to 3.0-3.9 g/dL). Patients randomized to MM-398/5-FU/LV received 70 mg/m ² MM-398 intravenously for 90 minutes every 2 weeks, followed by intravenous administration of 400 mg/m ² formazan tetrahydrofolate over 30 minutes. Thereafter, 2400 mg/m ^{2 of} fluorouracil was intravenously administered over 46 hours. The MM-398 dose of 70 mg/m ^{2 in} Study 1 was based on irinotecan as a free base (equivalent to 80 mg/m ² of irinotecan as the hydrochloride trihydrate).

Patients randomized to MM-398 as a single agent received 100 mg/m ² MM-398 via a 90-minute intravenous infusion every 3 weeks. Patients randomized to 5-FU/LV received 200 mg/m ² formazan tetrahydrofolate intravenously for 30 minutes, followed by intravenous administration of 2000 mg/m ² fluorouracil over 24 hours, at the first, eighth, and fifth weeks of the 6-week cycle. And 22 days to vote. For patients with homozygous binding of the UGT1A1*28 allele, reduce the dose (if administered with 5-FU/LV, 50 mg/m ² MM-398 or 70 mg/m ² as a single agent, MM-398), start MM- 398. 5-FU is also discontinued or discontinued when MM-398 is discontinued or interrupted due to adverse reactions. When the dose of MM-398 was reduced due to adverse reactions, the dose of 5-FU was reduced by 25%. Continue treatment until disease progression or unacceptable toxicity.

The primary efficacy outcome measures were overall survival (OS) and two pairwise comparisons: MM-398 vs. 5-FU/LV and MM-398/5-FU/LV vs. 5-FU/LV. Other performance result measures Survival without evolution (PFS) and objective response rate (ORR). Tumor status assessment was performed every 6 weeks after baseline and thereafter. The test series was initiated as a two-group study and modified to include the third group (MM-398/5-FU/LV) after initiation. The comparison between the MM-398/5-FU/LV and the 5-FU/LV group was limited to patients enrolled in the 5-FU/LV group after this protocol was modified.

417 patients were randomized to: MM-398/5-FU/LV (N=117), MM-398 (N=151) or 5-FU/LV (N=149). After the third group was added to the study, the baseline demographic and tumor characteristics of 236 patients randomized to MM-398/5-FU/LV or 5-FU/LV (N=119) were median age 63. Aged (34-81 years old) and 41% of age 65 years old; 58% male; 63% Caucasian, 30% Asian, 3% black or African American, and 5% other ethnic groups. The mean baseline albumin content was 3.97 g/dL and the baseline KPS was 90-100 in 53% of patients. Disease characteristics included liver metastases (67%) and lung metastases (31%). In the lead/assisted case only a total of 13% of patients received gemcitabine, 55% of patients had one prior line therapy for metastatic disease, and 33% had 2 or more times for metastatic disease Previous therapy. All patients received prior gemcitabine (alone or in combination with another agent); 54% received prior gemcitabine in combination with another agent, and 13% received prior gemcitabine in combination with albumin-binding paclitaxel (nab-paclitaxel).

Study 1 shows a statistically significant improvement in overall survival of the MM-398/5-FU/LV group relative to the 5-FU/LV group, as outlined in Table 5 and shown graphically in Figure 1.

Overall survival was not improved in the MM-398 group relative to the 5-FU/LV group (hazard ratio = 1.00, p-value = 0.97 (bilateral log-rank test)).

^† 5-FU / LV = 5-fluorouracil / formazan tetrahydrofolate; CI = confidence interval MM MM-398 dose of 70 mg / m ² based on the free base irinotecan (equivalent to 80mg / m ² as the hydrochloride salt trihydrate of irinotecan).

Table 5 shows that the overall overall survival of MM-398/5-FU/LV was 6.1 months. The median overall survival was used to indicate survival. It is in MM-398/5-FU/LV of Study 1 described herein (presented in Table 5), after which time 50% of patients in the study group died and 50% survived for the amount of time. The life expectancy (months) from the start of treatment with the MM-398/5-FU/LV treatment regimen as disclosed herein is defined by the parameter t _surv . In some embodiments, the treated individual has at least ² / ₃ of the t _surv median overall survival rate ( 4.1 months (to a decimal place (dp))), such as at least ⁵ / ₆ of the median overall survival ( 5.1 months (1dp)) or at least median overall survival ( 6.1 months). In some embodiments, the treated subject has a t _surv less than 2 times the median overall survival (<12.2 months (1 dp)), eg, less than 1.5 times the median overall survival (<9.15 months (2 dp)) or Less than 1.2 times the median overall survival (<7.32 months (1dp)). In some embodiments, the individual values of t in the treatment of overall survival based _surv of at least _^2/3 and less than twice the median overall survival, for example less than 1.5 times the median overall survival of less than or median overall survival of 1.2 times. In some embodiments, the individual values of t in the treatment of overall survival based _surv of at least _^5/6 and less than 2 times the median overall survival, for example less than 1.5 times the median overall survival of less than or median overall survival of 1.2 times. In some embodiments, the t _surv of the treated individual is at least a median overall survival and less than 2 times the median overall survival, such as less than 1.5 times the median overall survival or less than 1.2 times the median overall survival.

Since the clinical trials were carried out under widely varying conditions, the adverse reaction rates observed in the clinical trials of MM-398 were not directly comparable to the adverse reaction rates in clinical trials of other drugs, and were not reflected in practice. The rate of adverse reactions.

The safety data described below is derived from Study 1, which is an open-label trial of international, randomized, active controls in which patients who have previously undergone metastatic adenocarcinoma of the pancreas treated with gemcitabine-based therapy receive protocol-specific therapy. One part is as follows: 70 mg/m ² MM-398 and 400 mg/m ² formazan tetrahydrofolate and 2400 mg/m ² fluorouracil (MM-398/5-FU/LV; n=117) every 46 weeks. 3 weeks 100mg/m ² MM-398 (n=147), or 200mg/m ² formazan tetrahydrofolate and 2000mg/m ² fluorouracil for 24 hours per week for 4 weeks, then rest for 2 weeks (5-FU/ LV; n = 134). Entry into the study requires serum bilirubin within the normal range of the institution, albumin 3g/dL, and Karnofsky physical state (KPS) 70. The median exposure duration was 9 weeks in the MM-398/5-FU/LV group, 9 weeks in the MM-398 monotherapy group, and 6 weeks in the 5-FU/LV group.

The most common adverse reactions of MM-398 ( 20%) are diarrhea, fatigue/inability, vomiting, nausea, loss of appetite, stomatitis and fever. The most common laboratory abnormalities ( 10% grade 3 or grade 4) is a neutropenia and neutropenia. The most common serious adverse reactions of MM-398 ( 2%) vomiting, diarrhea, neutropenic fever or sepsis, nausea, fever, anemia, pneumonia, sepsis, dehydration, septic shock, acute renal failure, thrombocytopenia, and intestinal obstruction.

The most common adverse reactions in patients receiving MM-398 ( 20%) is diarrhea, fatigue / weakness, vomiting, nausea, loss of appetite, stomatitis and fever. Severe (21%) or life-threatening (7%) neutropenia or neutropenic septicemia (of which 1% leads to septic shock) occurs in MM-398 with fluorouracil and formazan tetrahydrofolate In combination with patients. In some embodiments, MM-398 is discontinued from patients with absolute neutrophil counts below 1500/mm ³ or with neutrophilic fever. Preferably, the patient's blood count is monitored periodically during treatment. Severe or life-threatening diarrhea occurs in 13% of patients who receive MM-398 in combination with 5FU and formazan tetrahydrofolate.

In study 1 described herein, severe or life-threatening neutropenia occurred in 27% of patients receiving MM-398/5-FU/LV, compared with 2% receiving alone. In patients with fluorouracil/hyperthyroid tetrahydrofolate (5-FU/LV). The expected likelihood (%) of severe or life-threatening neutropenia during treatment with MM-398/5-FU/LV in the protocol used in Study 1 is expressed as the parameter P _{ae n} . In some embodiments, P _{ae n} <50%. In some embodiments, <45%, such as <40%, <35%, <30% or 27%.

In Study 1, grade 3 or grade 4 diarrhea occurred in 13% of patients receiving MM-398/5-FU/LV, compared with 4% of patients receiving 5-FU/LV. The expected likelihood (%) of grade 3 or grade 4 diarrhea was expressed as the parameter P _{ae d} during treatment with MM-398/5-FU/LV in the protocol used in Study 1. In some embodiments, P _{ae d} <50%. In some embodiments, <45%, such as <40%, <35%, <30%, <25%, <20%, <15% or 13%.

In some embodiments, t _serv 6.1 months, P _{ae n} 27% and P _{ae d} 13%.

In 11% of patients receiving MM-398/5-FU/LV, adverse reactions resulted in permanent Broken MM-398; the most common adverse reactions leading to discontinuation of MM-398 were diarrhea, vomiting, and sepsis. The MM-398 dose was reduced by adverse reactions in 33% of patients receiving MM-398/5-FU/LV; the most common adverse reactions requiring dose reduction were neutropenia, diarrhea, nausea and anemia. In 62% of patients receiving MM-398/5-FU/LV, MM-398 was discontinued or delayed due to adverse reactions; the most common adverse reactions requiring interruption or delay were neutropenia, diarrhea, and fatigue. , vomiting and thrombocytopenia.

Table 6 provides a higher incidence (level 1-4) in patients receiving MM-398/5 FU/LV compared to patients receiving the 5-FU/LV group in Study 1. 5% difference or 3-4 level 2% difference) The frequency and severity of adverse reactions that occur.

^* NCI CTCAE v4.0 ^† early-onset diarrhea: ^‡ delayed onset of diarrhea in the MM-398 administered 24 hours: After MM-398 administered> 1 day attack ^§ includes stomatitis, aphthous stomatitis, mouth ulcers, mucosal inflammation. Includes febrile neutropenia.

Choline reaction : MM-398 can cause choline reaction, manifested as rhinitis, increased salivation, flushing, bradycardia, dilated pupils, tearing, sweating and excessive peristalsis of abdominal cramps and early onset diarrhea. In Study 1, grade 1 or grade 2 choline symptoms in addition to early onset diarrhea occurred in 12 (4.5%) MM-398 treated patients. Six of the 12 patients received atropine; in one of the six patients who received atropine, atropine was administered for biliary symptoms other than diarrhea.

Infusion : In 3% of patients receiving MM-398 or MM-398/5-FU/LV, it was reported that MM-398 was administered on the same day with allergic reactions, rash, urticaria, periorbital edema or pruritus. Infusion reaction.

Other clinically significant adverse events that occurred in <10% of patients treated with MM-398/5-FU/LV:

Cardiovascular : severe hypotension

Compared with the 5-FU/LV group ( 5% difference), laboratory abnormalities occurring at higher incidence rates in the MM-398/5 FU/LV group are summarized in Table 7 below.

* NCI CTCAE v4.0, showing the worst level # based on the percentage of patients with baseline and at least one post-baseline measurement.

Of the 264 patients in study 1 who received MM-398 as a single agent or in combination with 5-FU and formazan tetrahydrofolate, 49% 65 years old and 13% 75 years old. No overall differences in safety and efficacy were observed between these patients and younger patients.

Example 2: Overall survival analysis of the Napoli-1 Phase 3 study.

NAPOLI-1 is a global, randomized, phase 3 study evaluating nal-IRI with or without 5-FU/LV in 417 patients with metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. (Nanolipid irinotecan). The initial survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs. 4.2 mo; vs. 5-FU/LV (no stratification hazard ratio [HR]=0.67; P= 0.012). The primary endpoint was supported by improved non-evolved survival, time to treatment failure, objective response, and CA19-9 tumor marker response rate and manageable toxicity. An updated analysis of OS, 6-month and 12-month survival estimates and safety presentations.

Methods: An updated descriptive analysis of OS based on 378 events, including data from all randomized patients in the 3 groups.

RESULTS: After 378 OS events, nal-IRI+5-FU/LV (n=117) retained OS advantage over 5-FU/LV (n=119): 6.2 mo (95% confidence interval [CI], 4.8-8.4) vs. 4.2 mo (95% CI, 3.3-5.3), and no stratification HR was 0.75 (P=0.0417). In contrast, nal-IRI monotherapy (n=151) had no OS advantage over 5-FU/LV (n=149): 4.9 mo [95% CI, 4.2-5.6] vs. 4.2 mo [95% CI , 3.6-4.9], HR=1.08; P=0.5. The 6-month survival of nal-IRI+5-FU/LV was estimated to be 53% (95% CI, 44-62%), compared to 38% of 5-FU/LV (95% CI, 29-47%); The 12-month survival of nal-IRI+5-FU/LV was estimated to be 26% (95% CI, 18-35%), compared to 16% (95% CI, 10-24%) of 5-FU/LV. For events in almost all patients, the OS curve met at approximately 20 months and 19 patients (16.2%) survived for more than 20 months. This is the reason why the HR estimate and the non-hierarchical logarithmic rank p value decrease. In the nal-IRI-containing group The most common grade 3+ adverse events that occur at 2% incidence are neutropenia, diarrhea, vomiting, and fatigue.

Conclusions: In the update analysis, nal-IRI+5FU/LV was maintained relative to 5-FU/LV median OS benefit with a similar safety profile. Nal-IRI+5-FU/LV can be the new standard of care for patients with mPAC previously treated with gemcitabine-based therapy.

In another embodiment, the pancreatic cancer is selected from the group consisting of pancreatic exocrine cancers of the group consisting of acinar cell carcinoma, adenocarcinoma, adenosquamous carcinoma, giant cell tumor, intrapancreatic papillary mucinous neoplasm (IPMN) ), mucinous cystadenocarcinoma, pancreatic blastoma, serous cystadenocarcinoma, and solid pseudopapillary tumor. Metastatic pancreatic cancer (mPAC) represents a significant unmet need, and approximately 80% of patients with mPAC die of disease within 12 months.

In another embodiment, the irinotecan liposome formulation is irinotecan sucrose octasulfate liposome injection.

Nal-IRI (ONIVYDE® [Irinotecan liposome injection]; MM-398) is a nano-lipid formulation of irinotecan for intravenous use and is a topoisomerase inhibitor (Figure 13). Pharmacokinetic analysis revealed an extended cycle of irinotecan in mice with gastric cancer (Figure 14). The liposome promotes drug deposition in the tumor via enhanced permeability and retention effects. nal-IRI promoted local activation and release of active metabolites of irinotecan, and at 72 hours after nal-IRI infusion, SN-38 levels were five times higher in biopsies than in plasma (Figure 15).

Based in part on the results of a preliminary analysis of the large (N=417) Phase 3 NAPOLI-1 trial in this case, the US Food and Drug Administration recently approved a combination of nal-IRI and 5-FU/LV for the treatment of gemcitabine-based therapies. Patients with mPAC after progression of the disease.

Median overall survival (OS) was significantly increased with nal-IRI+5-FU/LV versus 5-FU/LV (6.1 vs. 4.2 months; no stratification hazard ratio [HR]=0.67 [95% confidence interval ( CI), 0.49-0.92]; P = 0.012) (Fig. 18).

Median OS did not differ between patients assigned to nal-IRI monotherapy and patients assigned to 5-FU/LV (4.9 versus 4.2 months; no stratification HR = 0.99 [95% CI, 0.77-1.28] ;P=0.94).

No median survival with nal-IRI+5-FU/LV compared with 5-FU/LV alone (PFS; 3.1 versus 1.5 months; no stratification HR=0.56 [95% CI, 0.41- 0.75]; P = 0.0001) and objective response rate (ORR; 16% vs. 1%; P < 0.0001) were also improved.

nal-IRI+5-FU/LV shows a predictable and manageable safety profile; most often reported Level 3 Emergency Treatment Adverse Event (TEAE) is neutropenia, fatigue, diarrhea, and vomiting.

The current descriptive analysis of the NAPOLI-1 trial aims to assess the robustness of previously observed OS treatment effects of nal-IRI+5-FU/LV versus 5-FU/LV controls using data from longer follow-up, and Assess the long-term safety and tolerability of nal-IRI.

method

Research design:

NAPOLI-1 is an international, open label, randomized, phase 3 trial (Figure 2). Patients were first randomized to nal-IRI monotherapy or 5-FU/LV. Once the safety data for the combination was obtained from a parallel study in autotransferable colorectal cancer, the protocol was modified to increase the third group of nal-IRI+5-FU/LV combinations. The decision to add the third group was made shortly after the initial trial, and 63 patients were enrolled according to the 1st edition, after which all locations were converted to the 2nd edition. Combination therapy was compared to patients in their 5-FU/LV control group who were randomized after protocol revision.

Randomized stratification based on baseline albumin content, Karnofsky physical state (KPS), and ethnic groups.

Analysis of primary endpoint (OS) Each treatment group was compared to its corresponding 5-FU/LV control by a non-stratified log-rank test; the Family I-type error rate was controlled to a bilateral 0.05 degree using the Bonferroni-Holm method. Has happened A preliminary analysis was planned for 305 death events with an 85% weighting to detect a HR of 0.67 in the nal-IRI group and a 98% weighting to detect a HR of 0.50 in the nal-IRI+5-FU/LV group. Supportive stratification analysis explaining the random packet layer is also implemented.

The results presented in this paper are based on unapproved data from snapshots of updated data after 378 OS events.

Key inclusion criteria:

Patients must have/dose: metastatic pancreatic ductal adenocarcinoma (measurable or unmeasurable); in presumptive, adjuvant (only when distal metastases occur within 6 months of completion of adjuvant therapy), local advanced or metastatic Disease progression after previous gemcitabine or gemcitabine therapy; KPS 70; appropriate hematology (including absolute neutrophil count > 1,500 / μL), liver (including normal serum total bilirubin and albumin content 3.0g/dL) and renal function; and age 18 years old.

Patient characteristics

A total of 417 patients were enrolled in 76 locations in 14 countries between January 2012 and September 2013. Patient demographics and baseline clinical characteristics were well balanced between treatment groups (Table 8).

Treatment exposure

The mean duration of treatment exposure was 18.5 weeks in the nal-IRI+5-FU/LV group (median, 8.7 weeks; range, 2-115 weeks), and 12.3 weeks in the nal-IRI group (median, 8.9) Week; range, 3-69 weeks) and 10.8 weeks in the 5-FU/LV control group (median, 6.0 weeks; range, 1-68 weeks).

The mean relative dose strength of nal-IRI was 83% in the combination group and 90% in the monotherapy group.

naI-IRI is a nanolipid irinotecan; 5-FU is 5-fluorouracil; LV is hyperthyroidism; IQR is interquartile; KPS is Karnofsky physical state; CA19-9 is carbohydrate antigen 19- 9. ^a includes patients who have been measured for CA19-9 values only prior to treatment. Data were lost in 3 patients in the nal-IRI+5-FU/LV group and in 5 patients in the ral-IRI monotherapy and 5-FU/LV groups. ^b Patients received lead, adjuvant or locally advanced treatment, but no previous treatment for metastatic disease was performed.

efficacy

After 378 events, nal-IRI+5-FU/LV retained OS advantages over 5-FU/LV (Table 9 and Figure 16A).

For events in almost all patients, the Kaplan-Meier OS curve met at approximately 20 months and 19 (16.2%) patients survived for more than 20 months.

No OS advantages were observed relative to 5-FU/LV using nal-IRI monotherapy (Figure 16B).

The median PFS for nal-IRI+5-FU/LV was 3.1 months, 1.5 months vs. 5-FU/LV combination control, and nal-IRI monotherapy was 2.6 months compared to 5-FU The /LV monotherapy control was 1.6 months (Table 9 and Figure 17).

nal-IRI+5-FU/LV (difference 16% [95% CI, 9-24]) and nal-IRI monotherapy (difference 5% [95% CI, 1-9]; Table 9) The ORR is higher than the 5-FU/LV control.

naI-IRI system nano-lipid irinotecan; 5-FU 5-fluorouracil; LV-based hyperthyroidism; OS system overall survival; CI-based confidence interval; HR-based hazard ratio; PFS-free evolutionary survival; The objective response rate. ^a does not stratify HR and log rank P values. The designation of the ^b response does not require confirmation and is based solely on the investigator's assessment using the RECIST v1.1 guidelines. ^c The shortest duration of stable disease from baseline since the randomization date is 6 weeks. ^d Patients who do not have a measurable (target) disease at baseline may have the best overall response to a non-complete/non-partial response.

Safety / tolerance

The safety profiles of nal-IRI+5-FU/LV and nal-IRI monotherapy as described in the current update analysis were not significantly different from those reported in the preliminary analysis.

Most frequently reported in the nal-IRI group Grade 3 TEAE was neutropenia, diarrhea, vomiting and fatigue (Table 10).

TEAE caused dose delay in 73% of patients in the nal-IRI+5-FU/LV group, 56% of patients in the nal-IRI monotherapy group, and 37% of patients in the 5-FU/LV group , reduce and / or interrupt.

The most common causes of dose reduction in the nal-IRI+5-FU/LV and nal-IRI monotherapy groups were gastrointestinal events (12% and 17%, respectively) and neutropenia (18% and 10%). .

The treatment interruption rate due to TEAE was 12% for nal-IRI+5-FU/LV, 14% for nal-IRI, and 8% for 5-FU/LV; neutropenia, diarrhea and Vomiting was the most common cause of interruption in the nal-IRI group.

Grade 3 febrile neutropenia occurred in 2 (2%) patients who received nal-IRI+5-FU/LV and 6 (4%) patients who received nal-IRI; 1 and 5 Patients required a dose reduction, but no patients discontinued treatment for febrile neutropenia.

Additional deaths due to treatment-related TEAE were not reported since the initial analysis.

TEAE is an emergency treatment for adverse events; nal-IRI is a nanolipid irinotecan; 5-FU is 5-fluorouracil; LV is hyperthyroidism. The table includes any treatment group 5% of all reported cases Level 3 TEAE. ^a neutropenia including granule globule deficiency, febrile neutropenia, granule globule reduction, neutropenia, neutropenic sepsis, neutrophil count reduction and all Hematocrit.

In this analysis from the updated data from the NAPOLI-1 trial, nal-IRI+5-FU/LV maintained the previously described OS and PFS benefits compared to 5-FU/LV alone. The OS curve rendezvous at 20 months (and 19 [16%] patients survived for more than 20 months) may be responsible for the observed OSHR estimates and the decrease in the non-stratified log-rank P value. No new safety issues were detected for nal-IRI as monotherapy or in combination with 5-FU/LV.

Example 3: Alternative analysis of the NAPOLI-1 study: Effect of baseline carbohydrate antigen 19-9 (CA 19-9) content on overall survival in a NAPOLI-1 Phase 3 study

The current analysis of the NAPOLI-1 trial is aimed at assessing the potential predictability between baseline CA19-9 values and efficacy in patients receiving nal-IRI+5-FU/LV versus 5-FU/LV alone and/or Prognostic effect.

CA19-9 assessment

Blood samples were taken every 6 weeks after baseline and until disease progression, initiation of new anti-tumor therapy, or withdrawal of informed consent, and CA19-9 levels were assessed by central laboratories to assess their predictive and prognostic effects.

CA19-9 quartile analysis

The results of the baseline CA19-9 measurements were divided into quartiles (Q1-Q4). Treatment comparisons were performed by a non-stratified Cox proportional hazard regression model to estimate the hazard ratio of baseline CA19-9 values to OS, PFS, and ORR and the corresponding 95% CI.

The quartile range was based on 404 available baseline CA19-9 values from 417 randomized patients in NAPOLI-1. Of the 236 patients randomized to receive nal-IRI+5-FU/LV or 5-FU/LV alone (after revision of the protocol), 218 were treated with study and had baseline CA19-9 measurements, and Included in this analysis (Table 11).

CA19-9 series carbohydrate antigen 19-9; nal-IRI system nanolipid irinotecan; 5-FU 5-fluorouracil; LV system formazan tetrahydrofolate

Association of baseline CA19-9 values with efficacy

The results show a higher therapeutic effect of higher CA19-9 content relative to 5-FU/LV on OS. The CA19-9 response (>50% drop from baseline) was superior to nal-IRI‧5-FU/LV compared to 5-FU/LV (29% versus 9%; P=0.0006). Nal-IRI alone did not show statistical improvement in survival. A larger therapeutic effect of nal-IRI+5-FU/LV versus 5-FU/LV on OS and PFS was observed at higher baseline CA19-9 values (U/mL) (Figure 19 and Figure 20 and Table 12). ).

Between all quartiles of baseline CA19-9 values, the objective response rate (ORR) was higher in the nal-IRI+5-FU/LV group compared to the 5-FU/LV group (Table 13).

CA19-9 series carbohydrate antigen 19-9; nal-IRI system nanolipid irinotecan; 5-FU 5-fluorouracil; LV system formazan tetrahydrofolate

In the NAPOLI-1 test of patients with mPAC after gemcitabine-based therapy, nal-IRI+5-FU/LV significantly improved OS and PFS compared to the 5-FU/LV control. The results show a greater therapeutic effect on OS at higher CA-19-19 levels relative to 5-FU. Between the patients with the highest baseline CA 19-9 values, nal-IRI+5-FU/LV had the greatest benefit from OS and PFS observed with respect to 5-FU/LV. In the overall population, the ORR of nal-IRI+5-FU/LV was larger relative to the 5-FU/LV control, and there was no significant trend in the effect of ORR on baseline CA 19-9. These results indicate that baseline CA 19-9 values are associated with therapeutic effects observed in the combination of nal-IRI + 5-FU/LV in mPAC patients, and that CA19-9 serum levels provide important information about overall survival. .

Example 4: Activity of MM-398 in a positive pancreatic tumor model (L3.6pl) showing luciferase

The anti-tumor activity of MM-398 was evaluated in a positive pancreatic cancer model (L3.6pl, a pre-clinical tumor model with high hypoxia). About 2.5 x 10 ^-5 L3.6 pl pancreatic tumor cells were implanted by direct injection into the pancreas. Bioluminescence images (BLI) were tracked over time for tumor burden detection/quantification. MM-398 and free irinotecan were administered at a dose of 20 mg/kg/dose per week for 3 weeks. As shown in Figure 1, MM-398 (microlipid CPT11) has significant anti-tumor activity as compared to control (HBS) and free CPT11.

Example 5: Accumulation of SN-38 in tumors after treatment with free irinotecan or aliline irinotecan (MM-398)

It is hypothesized that the anti-tumor activity observed in the orthotopic pancreatic cancer model is due to the effect of macrophages in the local conversion of irinotecan to the more active SN-38. To test this hypothesis, human colon cancer cells (HT-29) were injected subcutaneously into SCID mice, and 40 mg/kg of free irinotecan or MM-398 was injected intravenously at a tumor size of 1000 mm ³ . Tumor-bearing mice were sacrificed at different time points, tumors from both groups were extracted and SN-38 concentrations were measured.

As shown in Figure 2, tumor AUC _{SN-38 of} MM-398 was increased 20-fold compared to free irinotecan. Long exposure durations allow for slow proliferative cancer cells to prolong their exposure to active metabolites as they progress through the cell cycle. In addition, it is also assumed that this activity results from a decrease in hypoxia within the tumor and subsequent downstream effects on the angiogenesis, metastasis and immunosuppressive environment in the tumor.

Example 6: Effect of MM-398 on carbonic anhydrase IX staining in HT29 xenograft model

To test whether MM-398 reduced hypoxic markers, experiments were performed in a human colon cancer cell (HT-29) model. Specifically, HT-29 cells were subcutaneously injected into nude mice, and PBS control or 1.25, 2.5, 5, 10 or 20 mg/kg MM-398 was intravenously injected on the 13th day. MM-398 was administered at the indicated dose once a week for 4 weeks. Tumors were extracted from both groups (n=5) 24 hours after the last dose. Immunohistochemical staining of carbonic anhydrase IX (CAIX) was performed using frozen tumor sections. Quantification of GAIX staining was performed using Definiens ^® (Definiens AG, Munich) software.

As shown in Figure 3, MM-398 reduced the hypoxic marker. In particular, the graph in Figure 3 shows the percentage of CAIX-stained cells that were moderate (middle one-third) or high (highest one-third) intensity. Representative samples and group mean (mean +/- stdev) for each group are shown. MM-398 treatment alters the tumor microenvironment by reducing the percentage of medium and high CAIX positive cells in a dose dependent manner. Due to hypoxia resistance and the hallmark of invasive disease, it is expected that the reduction in hypoxia will make tumor cells more sensitive to chemotherapy.

Example 7: MM-398 increases the perfusion of Hurst staining

In addition to altering the chemosensitivity of tumor cells by altering the tumor microenvironment, reducing hypoxia may indicate improved tumor angiogenesis, which may facilitate delivery of small molecule therapies. Treatment with MM-398 resulted in an increase in microvessel density 6 days after treatment, as measured by CD31 (platelet endothelial cell adhesion molecule) staining in the HT29 xenograft study. To further evaluate the effect of MM-398 on small molecule tumor angiogenesis, a Hoechst 33342 perfusion experiment was performed. Specifically, primary pancreatic tumors were grown in NOD-SCID mice and given one dose of MM-398 (20 mg/kg). After 24 hours, Hoechst 33342 staining was administered and the animals were sacrificed after 20 minutes. As shown in Figure 4, the increase in staining intensity in treated mice was statistically significant, p < 0.001. These data indicate that MM-398 should be more sensitive to agents such as 5-FU/LV by reducing tumor hypoxia and increasing small molecule perfusion. Ways to change the tumor microenvironment.

Example 8: Pharmacokinetics of MM-398 in Humans (Phase I)

In the Phase I clinical study (PEP0201), MM-398 single agent drug was studied at a dose of 60, 120 or 180 mg/m ² in a phase II clinical trial in a gastric cancer patient (PEP0206) at 120 mg/m ² Dynamics overview. The plasma levels of total irinotecan, SN-38, and encapsulated irinotecan were measured in these studies.

For 120 mg/m ² MM-398, the peak serum concentration of total irinotecan (C _max ) ranged from 48-79 μg/ml, which was about 50-fold higher than 125 mg/m ² free irinotecan. The total irinotecan half-life (t _1/2 ) of MM-398 ranged from 21 to 48 hours, which was about 2-3 times higher than 125 mg/m ^{2 of} free irinotecan. In conclusion, total irinotecan exposure at 1 week (AUC 0-T) at a dose of 120 mg/m ² MM-398 ranged from 1200-3000 (μg*h/ml) compared to 300 mg/m ² free Litenko is about 50-100 times higher. In contrast, in SN38 C _max value of 120mg / m ² MM-398 is between 9 to 17ng / ml range, which than 125mg / m ² irinotecan free about 50% lower. Overall, SN38 exposure at 1 week (AUC 0-T) ranged from 474 to 997 ng*/ml and was only 1-2 times higher than that achieved with 300 mg/m ² free irinotecan. For both SN38 and total irinotecan, the AUC increased in proportion to the MM-398 dose. The PK parameters of encapsulated irinotecan are almost equivalent to total irinotecan, indicating that most of the irinotecan remains encapsulated in the liposomes during the cycle. The MM-398 PK parameters did not change significantly when combined with 5-FU/LV. Figures 5 and 6 summarize the PK findings in the previous MM 398 study.

Example 9: Phase 1 dose escalation study

In a phase 1 trial of solid tumors, a combination of fluorouracil, formazantetrahydrofolate, and MM-398 was studied in 16 subjects (5 of whom were patients with pancreatic cancer). Objective tumor response rate, duration of response, and disease control rate are the efficacy endpoints of the study. Of the 15 efficacy-evaluable patients, 2 (13.3%) had confirmed PR, 9 (60.0%) had SD, and 4 (26.7%) had PD. The overall disease control rate was 73.3%. A partial response was observed in one gastric cancer patient (at a dose of 80 mg/m ² ) and one breast cancer patient (at a dose of 100 mg/m ² ), and the duration of the reaction was 142 days and 76 days, respectively. There were 1 PR, 4 SD, and 1 PD between 6 patients receiving an MTD dose of 80 mg/m ² . The tumor response rate and disease control rate were 16.7% and 83.3%, respectively. The main DLT is grade 3 diarrhea, leukopenia, neutropenia, and febrile neutropenia. The MTD of MM-398 is 80 mg/m ² .

In a phase 1 dose escalation study (PRP0203) of MM-398 and 5-FU/LV combination in advanced solid tumors, a total of 401 AE episodes were reported from 16 treated subjects (safety population), of which 74 (18.4%) is a grade 3 or higher CTC. Between AEs, 231 (57.6%) were considered by the investigator to be related to treatment. The most common treatment-related AEs included nausea (81.3%), diarrhea (75.0%), vomiting (68.8%), fatigue (43.8%), mucositis (43.8%), leukopenia (37.5%), neutrophils Reduction (37.5%), weight loss (37.5%), anemia (31.3%) and dislocation (31.3%). Acute biliary diarrhea is rarely observed. Table 14 is based on the maximum CTC level and based on causality (incidence rate) 20%) provide an incidence of emergency treatment adverse events, as seen in the PEP0203 study. Table 15 provides the incidence of grade 3 or higher emergency treatment adverse events seen in 5 pancreatic cancer patients treated in the PEP0203 study.

^1: If the subject reports the adverse event, the severity rating uses the highest rating ² rated for each subject ^: defined as the subject who has experienced or not dependent on the AE associated with the study drug.

Example 10: Time course for selecting an emergency treatment adverse event (TEAE) in NAPOLI-1: nal-IRI (MM-398) ± in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy Phase 3 study of 5-fluorouracil and formazantetrahydrofolate (5-FU/LV) versus 5-FU/LV

BACKGROUND: U.S. approved aliline irinotecan (nal-IRI, ONIVYDE®, MM-398) plus 5-FU/LV for patients with previous mPAC (pt) treated with gemcitabine-based therapy. A preliminary analysis from NAPOLI-1 (NCT01494506) showed a significant median survival advantage of nal-IRI+5-FU/LV versus 5-FU/LV (6.1 vs. 4.2 mo; HR 0.67; 95% CI 0.49-0.92; P = 0.012); Wang-Gillam et al., Lancet. 2016). The most common TEAEs include diarrhea, vomiting, nausea, loss of appetite, fatigue, neutropenia, and anemia. The incidence and prevalence of TEAEs selected in NAPOLI-1 over time are reported here.

Methods: Pt was randomly assigned to nal-IRI+5-FU/LV, nal-IRI or 5-FU/LV. In this post hoc analysis (data deadline, February 14, 2014), through the treatment phase (first 6 weeks [stage 1], second 6 weeks [stage 2] and beyond the second 6 weeks [ Stage 3]) Analyze the incidence (ie, first occurrence) and prevalence (ie, first occurrence, ongoing event, or recurrence) of the selected TEAE. Percentage of pts of risk concentration during each phase of the percentage (for morbidity: pt that is still in treatment without previous events; for prevalence: all safety evaluable pt).

RESULTS: 398 pt were treated with nal-IRI+5-FU/LV (n=117), nal-IRI (n=147) or 5-FU/LV (n=134). In the nal-IRI+5-FU/LV group, neutropenia, diarrhea, nausea, and vomiting occurred as early as the first 6 weeks of treatment, and the incidence and severity usually decreased afterwards (Table 16). ). Similarly, prevalence and severity are highest in the first 6 weeks and tend to decline over time. A similar trend was observed in the nal-IRI and 5-FU/LV groups.

CONCLUSIONS: Neutropenia, diarrhea, nausea, and vomiting usually occur early in the early stages of nal-IRI+5-FU/LV and often decrease in incidence and severity.

Example 11: Metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy In patients (mPAC) (pt), nanolipid irinotecan (nal-IRI; MM-398) plus 5-fluorouracil and formazantetrahydrofolate (5-FU/LV) relative to 5-FU/ alone Time for asymptomatic or toxic quality adjustment of LV (Q-TWiST)

In a preliminary analysis of the phase 3 NAPOLI-1 trial, nal-IRI+5-FU/LV was significantly improved relative to 5-FU/LV alone in mPAC patients (pt) previously treated with gemcitabine-based therapy. Overall survival (OS; 6.1 vs. 4.2 months; hazard ratio [HR] = 0.67; P = 0.012) and no evolutionary survival (PFS; 3.1 versus 1.5 months; HR = 0.56; P = 0.0001). Differences in the treatment-adjusted survival of the quality using the Q-TWiST method are reported here.

NAPOLI-1 intends to treat the cohort distributed over 12 months of total survival to have Time for adverse events with grade 3 toxicity (TWiST). The average Q-TWiST is calculated by multiplying the time spent in each health state by its individual effects. In the base case, the effects of toxicity (uTOX), recurrence (uREL), and TWiST (uTWiST) were set at 0.5, 0.5, and 1.0. Derived nonparametric pull-up 95% confidence interval (CI). The relative Q-TWiST gain of nal-IRI+5-FU/LV was calculated relative to the OS of 5-FU/LV. The threshold analysis changed uTOX and uTWiST between 0.1 and 1.0. Scenario analysis was performed using a compliance (PP) group.

They received a significantly longer TWiST time (average 3.4 vs. 2.4 months) than pt (117) receiving nal-IRI+5-FU/LV compared to pt (n=119) receiving 5-FU/LV ) and TOX time (1.0 vs. 0.3 months), but REL time is similar (2.5 vs. 2.7 months). In the base case, nal-IRI+5-FU/LV resulted in Q-TWiST (range 95% CI: 0.4-2.1; 5.1 vs. 3.9) (range threshold analysis (RTA; 0.9-1.6) Month), and the relative Q-TWiST gain is 24% (RTA: 17-31%). In the PP group, Q-TWiST is also significantly better in MM-398+5-FU/LV pt (Q-TWiST gain) = 1.8 months; 95% CI: 0.7-3.0).

In NAPOLI-1, nal-IRI+5-FU/LV resulted in a statistically significant and clinically important quality adjusted survival gain relative to 5-FU/LV alone. This confirmation The clinical outcome benefit of nal-IRI+5-FU/LV in patients with mPAC.

Example 12: Effect of nanolipid irinotecan (nal-IRI; MM-398) ± 5-fluorouracil and formazantetrahydrofolate (5-FU/LV) on quality of life (QoL) in NAPOLI-1; Phase 3 study in patients with metastatic pancreatic adenocarcinoma (mPAC) previously treated with gemcitabine-based therapy (pt)

QoL results from the NAPOLI-1 trial are reported here: a randomized, phase 3 study of nal-IRI plus 5-FU/LV versus 5FU/LV in pt with mPDAC previously treated with gemcitabine-based therapy.

QoL was assessed using the EORTC-QLQ-C30, which included a functional and symptom scale, as well as an overall health and QoL scale. Patients (Pt) completed the questionnaire at the beginning of treatment, every 6 weeks (wk) and 30 days after follow-up. Including providing baselines and Pt of 1 subsequent evaluation. A linear transition is applied to the original score to produce a report score in the range of 0-100. Pt is classified as improved for each subscale (added to the breadth of the time point after the baseline) 10% and at Deterioration (maintained above baseline) during 6 weeks (not meeting the improvement criteria and dying, or decreasing from baseline in the width scale at the time point after baseline) 10%) or stable (does not meet the improvement or deterioration criteria). A pairwise treatment group comparison for response classification was performed for each subscale and for diversity adjustment for 15 comparisons to control the false discovery rate to the extent of 0.05.

The analysis included 154 pt; 69% (49/71) of the nal-IRI+5-FU/LV group and 53% (44/83) of the 5-FU/LV group had evaluable data at 12 weeks. At baseline, the median overall health status score was close to the midpoint of the score range, the median functional scale score was high, and the symptom scale score was low, and the baseline values between the groups were similar. The median health status of the two treatment groups and the following subscale scores were observed at 12 weeks. The median change in scores was 0: role function, emotional function, cognitive function, social function, nausea and vomiting, pain, dyspnea, insomnia Loss of appetite, constipation, diarrhea and financial difficulties. For the subscale scores (nal-IRI+5-FU/LV: body function and fatigue) in which the median change was not 0, the difference between the groups was not significant. There was no significant difference in the proportion of pt classified as improved, worsened or stabilized between treatment groups. different. The adjusted P value was >0.05 (NS) between the subscales.

Conclusion: Although limited by the pt number, pt in nal-IRI+5-FU/LV treatment in this analysis often maintained baseline QoL during 12 weeks. Despite the addition of a second cytotoxic agent, there was no significant difference in QoL response relative to the 5-FU/LV treated pt.

Final result of NAPOLI-1: nal-IRI (MM-398) ± 5-fluorouracil and formazantetrahydrofolate (5-FU/LV) in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy Phase 3 study relative to 5-FU/LV

BACKGROUND: The irinotecan formulation nal-IRI (ONIVYDE, MM-398) plus 5-FU/LV was approved for use in patients with mPAC previously treated with gemcitabine-based therapy (pt). Preliminary analysis of the NAPOLI-1 trial (data cut-off date, February 14, 2014) (NCT01494506) showed a significant improvement in median nal-IRI+5-FU/LV versus 5-FU/LV after 313 events Survival (OS) (6.1 versus 4.2 mo; HR 0.67; 95% CI 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). The final analysis of NAPOLI-1 is reported here (data deadline, November 16, 2015).

Method: 417 pt were randomly assigned to 70 mg/m ² nal-IRI (equivalent to 80 mg/m ² irinotecan HCl trihydrate salt) + 2400/400 mg/m ² 5-FU/LV q2w (n=117 ), 100 mg/m ² nal-IRI (equivalent to 120 mg/m ² irinotecan HCl trihydrate salt) q3w (n=151) or 2000/200 mg/m ² 5-FU per week for 1-4 weeks /LV q6w (n=149). The logarithmic rank P value is bilateral.

RESULTS: After 382 events, nal-IRI+5-FU/LV was compared to 5-FU/LV modified median OS (6.2 vs. 4.2 mo; HR 0.75; 95% CI 0.57-0.99; P = 0.038), However, nal-IRI was not improved relative to 5-FU/LV (4.9 vs. 4.2 mo; HR 1.07; 95% CI 0.84-1.36; P = 0.567). Kaplan-Meier estimates for nal-IRI+5-FU/LV and 5-FU/LV OS were 53% and 38% at 6 months, respectively, and 26% and 16% at 12 months, respectively. The median non-evolved survival of nal-IRI+5-FU/LV was longer relative to 5-FU/LV (3.1 vs. 1.5 mo; HR 0.57; 95% CI 0.43-0.76; P < 0.001), but nal-IRI Not longer than 5-FU/LV (2.7 vs. 1.6 mol; HR 0.81; 95% CI 0.63-1.04; P = 0.111). The response rate of nal-IRI+5-FU/LV according to RECIST v1.1 is higher than that of 5-FU/LV (17% vs. 1%; P <0.001) and nal-IRI vs. 5-FU/LV Higher (6% vs. 1%; P = 0.020). In the nal-IRI group 10% pt Grade 3 emergency treatment adverse events were neutropenia (28%, 15%, and 1% in nal-IRI+5-FU/LV, nal-IRI, and 5-FU/LV groups, respectively), fatigue (14%, 6% and 4%), diarrhea (13%, 21% and 5%), vomiting (12%, 14% and 4%), anemia (9%, 11% and 7%) and hypokalemia Symptoms (3%, 12%, and 2%).

Conclusion: The final results of NAPOLI-1 continue to show the OS benefit of nal-IRI+5-FU/LV versus 5-FU/LV. No new security issues have been identified. nal-IRI+5-FU/LV provides a new treatment option for pt with mPAC previously treated with gemcitabine-based therapy.

Example 13: Effect of nal-IRI (MM-398) ± 5-fluorouracil on quality of life (QoL) in NAPOLI-1: in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy Phase 3 study in patients

Patients with mPDAC frequently experience significant symptom burden. This in turn has a negative impact on its QoL. In a randomized phase 3 study, patients with mPDAC previously treated with gemcitabine-based therapy (NAPOLI-1) were evaluated with respect to 5-FU/LV for irinotecan nanoparticles with or without 5-FU/LV. The liposome formulation nal-IRI. The results showed that nal-IRI+5-FU/LV significantly improved overall survival compared with 5-FU/LV (6.1 vs. 4.2 months; no stratification hazard ratio 0.67; P=0.012) (Wang-Gillam et al., Lancet) 2016). The secondary endpoint of the QoL study.

QoL was assessed using the European Cancer Research and Treatment Tissue Quality of Life Core Questionnaire (EORTC-QLQ-C30), which included functional scales (body, role, cognition, mood, and society); symptom scales (loss of appetite, constipation, diarrhea, and breathing) Difficulties, fatigue, insomnia, nausea and vomiting and pain); and overall health and quality of life. The patient will complete the questionnaire at the beginning of the treatment, every 6 weeks and 30 days after the follow-up. The analyzed population includes all provided baselines and One patient who was subsequently evaluated by EORTC-QLQ-C30. A linear transition is applied to the original score to produce a report score in the range of 0-100. In the responder analysis, the patient was classified as improved for each subscale (increased in the breadth of the time point after the baseline) 10% and at Deterioration (maintained above baseline) during 6 weeks (not meeting the improvement criteria and dying, or decreasing from baseline in the width scale at the time point after baseline) 10%) or stable (does not meet the improvement or deterioration criteria). A comparison of the paired treatment groups for response classification was performed using the Cochran-Mantel-Haenszel test for each subscale, which was adjusted for Benjamini-Hochberg correction for 15 comparisons to control the false discovery rate to 0.05.

NAPOLI-1 is an international, open label, randomized, and phase 3 trial. Patients were first randomized to nal-IRI monotherapy (120 mg/m ² irinotecan hydrochloride trihydrate salt every 3 weeks, equivalent to 100 mg/m ² irinotecan free base) or 5-FU/LV ( 200 mg/m ² LV and 2000 mg/m ² 5-FU per week for the first 4 weeks of the 6-week cycle; version 1 protocol). Once a parallel study of autotransportable colorectal cancer yields safety data for combination therapy, the protocol is modified to include a third group of nal-IRI+5-FU/LV (80 mg/m ² irinotecan hydrochloride per 2 weeks) Hydrate salt, equivalent to 70 mg/m ² irinotecan free base; 400 mg/m ² LV every 2 weeks and 2400 mg/m ² 5-FU; version 2 protocol).

A total of 154 patients (nal-IRI+5-FU/LV, n=71; 5-FU/LV, n=83) constituted the population used for this analysis, with 69% of the nal-IRI+5-FU group (49/71) Patients and 53% (44/83) of the 5-FU/LV group had evaluable data at 12 weeks. At baseline, the median overall health status score was close to the midpoint of the score range, the median functional scale score was high, and the symptom scale score was low, and the baseline values between the groups were similar. The median health status of the two treatment groups and the following subscale scores were observed at 12 weeks. The median change in scores was 0: role function, emotional function, cognitive function, social function, nausea and vomiting, pain, dyspnea, Insomnia, loss of appetite, constipation, diarrhea and financial difficulties. For the subscale scores (nal-IRI+5-FU/LV: body function and fatigue) in which the median change was not 0, the difference between the groups was not significant. In addition, there was no proportion of patients classified as modified, worsened, or stable between treatment groups. Significant difference. The adjusted P value was >0.05 (NS) between the subscales.

In NAPOLI-1, evaluable nal-IRI+5-FU/LV patients with up to 12 weeks of data often maintained baseline QoL during 12 weeks, and despite the addition of a second cytotoxic agent, the QoL response was relative to 5 There were no significant differences between patients treated with -FU/LV. These results are limited by the difference in the number of smaller patients and the QoL sub-measurement score.

As of the data deadline of February 14, 2014 (preliminary analysis), the median survival (OS) of nal-IRI+5-FU/V was significantly increased relative to 5-FU/LV (6.1 vs. 4.2 months; The risk of non-stratification was [HR], 0.67 [95% confidence interval (CI), 0.49-0.92]; P = 0.012), but there was no significant difference between nal-IRI monotherapy and 5-FU/LV (4.9 relative At 4.2 months; no stratification HR 0.99 [95% CI, 0.77-1.28]; P = 0.94).

The median PFS of nal-IRI+5-FU/V was significantly longer than 5-FU/LV (3.1 vs. 1.5 months; non-stratified HR 0.56; 95% CI, 0.41-0.75; P=0.0001) .

The median ORR of nal-IRI+5-FU/V was significantly higher compared to 5-FU/LV (16% vs. 1%; P < 0.0001).

nal-IRI+5-FU/LV exhibits a manageable safety profile; nal-IRI+5-FU/LV occurs more frequently than 5-FU/LV with grade 3/4 adverse events (AE) including neutrophils Ball reduction (27% vs. 1%), fatigue (14% vs. 4%), diarrhea (13% vs. 4%), and vomiting (11% vs. 3%).

71 patients in the nal-IRI+5-FU/LV group (61% of the ITT population randomized according to the 2nd version protocol) and 57 patients in the 5-FU/LV group (ITT randomized according to the 2nd edition protocol) 48% of the group) provide baseline and 1 follow-up EORTC assessment (PRO population). Patient demographics and baseline characteristics were similar between treatment groups.

Significant differences in the proportion of patients showing improved, stable, or worsening QoL in the symptom scale score were not identified between the nal-IRI+5-FU/LV and 5-FU/LV groups.

Baseline overall health status and functional scale scores ranged from 58-83 and were similar between treatment groups. In conclusion, overall health between nal-IRI+5-FU/LV and 5-FU/LV groups The status and functional scale scores did not change significantly from baseline. The observed change in body function score from baseline to week 6 was 6.7 points in both groups; this corresponds to a "minimum" decrease. Baseline symptom scale scores ranged from 0-33 and were similar between treatment groups. In summary, there was no significant change in the symptom scale score between the nal-IRI+5-FU/LV and 5-FU/LV groups from baseline. The change in the fatigue score observed in the nal-IRI+5-FU/LV group from baseline to week 6 was about 11 points, which corresponds to a "moderate" increase.

In patients previously treated with gemcitabine-based therapy with mPDAC, nal-IRI+5-FU/LV significantly improved OS compared to 5-FU/LV. Overall health status and functional scale scores were not significantly different between treatment groups at baseline and showed no significant change over 12 weeks. The median symptom scale score at baseline was in the range of 0-33 (lower symptoms) and showed no significant change during 12 weeks. nal-IRI+5-FU/LV provides new treatment options that do not affect QoL in patients previously treated with gemcitabine-based therapy with mPDAC.

Example 14: Safety between subgroups of NAPOLI-1: nal-IRI (MM-398) ± 5-fluorouracil and formazan tetrahydrogen in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy Phase III study of folic acid relative to 5-fluorouracil and formazan tetrahydrofolate

Nal-IRI+5-FU/LV significantly improved overall survival compared to 5-FU/LV (6.1 vs. 4.2 months; P=0.012) and was generally well tolerated (Wang-Gillam et al., Lancet. 2016). Most common in the nal-IRI+5-FU/LV group Level 3 Emergency Treatment Adverse Event (TEAE) is neutropenia, fatigue, diarrhea, and vomiting. Based on NAPOLI-1, the nal-IRI+5-FU/LV protocol was approved by the US Food and Drug Administration for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression based on gemcitabine-based therapy. Here, the results of the pre-specified safety analysis were presented based on a subset of patients from NAPOLI-1.

For the following pre-designated subgroups, TEAE is rated by NCI CTCAE v4.0 and encoded by MedDRA v14.1: gender, age (<65 vs. 65 years old), ethnic (Caucasian versus Asian), UGT1A1*28 status, previous irinotecan therapy (relative to no) and previous 5-FU therapy (relative to no). All TEAEs are tracked until they resolve or the patient is interrupted. For security groups (ie accept Analysis was performed on each of the 1 dose of the study drug. The results herein are for the nal-IRI+5-FU/LV group unless otherwise stated.

In summary, the incidence and severity of TEAE were similar between males (n=67) and females (n=50). age The incidence of TEAE in patients 65 years of age (n=54) is usually higher than those in patients <65 years old (n=63) (eg, stomatitis: 20.4% vs. 7.9%; anemia: 46.3% vs. 30.2%) , but the most common type of TEAE is similar, regardless of age. In short, Asians (n=33) patients The incidence of grade 3 TEAE was higher than that of Caucasian (n=73) patients (87.9% vs. 69.9%), mainly due to neutropenia (24.2% vs. 12.3%) and decreased neutrophil count ( An increase in the incidence of 33.3% vs. 1.4%); febrile neutropenia was reported in 3.0% of Asian patients and 0 Caucasian patients. Gastrointestinal disorders are also slightly more frequent in Asian patients than in Caucasian patients (any grade: 100% vs. 87.7%), but diarrhea is less frequent and less severe among Asian patients (any grade: 48.5% vs. 61.6%; grade 3: 3.0% vs. 19.2%). The UGT1A1 gene encodes an enzyme responsible for glucuronidation of the active metabolite SN-38 of irinotecan. Patients with homozygous binding of the UGT1A1*28 allele (UGT1A1 7/7 genotype) may have an increased risk of neutropenia due to a decrease in glucuronidation of SN-38 during irinotecan treatment. However, in this analysis, the incidence, type, and severity of TEAE did not differ between patients who were homozygous for the UGT1A1*28 allele (n=7) and those who were not conjugated (n=110). . The incidence or severity of TEAE was between (n=12) and not (n=105) patients who had previously used irinotecan therapy or during (n=50) or not (n=67) previous 5 There were also no significant differences between patients with -FU therapy.

In summary, the safety profile of nal-IRI+5-FU/LV is usually similar between subgroups of patients, but increased in Asian patients. Except for the risk of a grade 3 neutropenia/neutrophil count reduction. The results of this pre-specified subgroup analysis further support nal-IRI+5-FU/LV in previous treatment with gypizine-based therapy with mPAC Tolerance profile in patients.

As of the data deadline of February 14, 2014, the median survival (OS) of nal-IRI+5-FU/LV was significantly increased relative to 5-FU/LV (6.1 vs. 4.2 months; no stratification risk) Ratio [HR], 0.67 [95% confidence interval (CI), 0.49-0.92]; P = 0.012), but there was no significant difference between nal-IRI monotherapy and 5-FU/LV (4.9 vs. 4.2 months; Not stratified HR 0.99 [95% CI, 0.77-1.28]; P = 0.94).

Adverse events leading to dose reduction occurred in 39 (33%) patients in the nal-IRI+5-FU/LV group, 46 (31%) patients in the nal-IRI monotherapy group, and 5-FU Among 5 (4%) patients in the /LV group. Adverse events leading to treatment interruption occurred in 13 (11%) patients in the nal-IRI+5-FU/LV group, 17 (12%) patients in the nal-IRI monotherapy group, and 5-FU Among 10 (7%) patients in the /LV group.

NAPOLI-1 is an international, open label, randomized, and phase 3 trial. Patients were first randomized to nal-IRI monotherapy (120 mg/m ² irinotecan hydrochloride trihydrate salt every 3 weeks, equivalent to 100 mg/m ² irinotecan free base) or 5-FU/LV ( 200 mg/m ² LV and 2000 mg/m ² 5-FU per week for the first 4 weeks of each 6-week cycle. Once the safety of the combination protocol was obtained in a parallel study of autotransportable colorectal cancer, the protocol was modified to include a third group of nal-IRI+5-FU/LV (80 mg/m ² irinotecan salt every 46 weeks for 2 weeks) The acid salt trihydrate salt (equivalent to 70 mg/m ² irinotecan free base), 400 mg/m ² LV and 2400 mg/m ² 5-FU).

The initial nal-IRI dose in the nal-IRI+5-FU/LV group was 60 mg/m ² for patients with homozygous UGT1A1*28 allele (TA7/TA7 genotype) and could be in the absence of drug-related toxic effects. Increase to standard dose (80 mg/m ² ).

Based on baseline albumin content ( 4.0g/dL vs. <4.0g/dL), KPS (70 and 80 vs. 90) and ethnic groups (whites versus East Asians versus all other ethnic groups) will be randomly grouped into layers.

TEAE is rated by the National Cancer Institute's Common Adverse Event Assessment Guidelines Version 4.0 and is coded by the Standard Medical Terminology Set 14.1 of Pharmacy Administration. All TEAEs are tracked until they resolve or the patient is interrupted. Security analysis group includes all acceptances One dose of the study drug patient. The presence of the UGT1A1*28 allele was determined by genotypic testing and identified as a homozygous patient (A7/TA7 genotype).

The UGT1A1 gene encodes an enzyme responsible for glucuronidation of the active metabolite SN-3 of irinotecan. Patients with homozygous binding of the UGT1A1*28 allele may have an increased risk of neutropenia, diarrhea, and other SN-38 exposure-related side effects during irinotecan treatment due to decreased glucuronidation of SN-38.

Information from the nal-IRI+5-FU/LV group (nal-IRI combination group) and the 5-FU/LV group (control group) is presented here (data deadline is February 14, 2014).

Qualification criteria:

Key inclusion criteria; age 18-year-old adult; histologically or cytologically confirmed PDAC; distally metastatic disease that can be measured or unmeasurable (eg, Response Evalution Criteria in Solid Tumors 1.1) Definition); disease progression after prior gemcitabine or gemcitabine-containing therapy in the presence, adjuvant (only when distal metastases occur within 6 months of completion of adjuvant therapy), local advanced or metastatic disease; KPS score 70; appropriate hematology (including absolute neutrophil count > 1.5 × 109 cells / L), liver (including normal serum total bilirubin and albumin content 30g/L) and renal function.

Key exclusion criteria: active central nervous system metastasis; clinically significant gastrointestinal disorders; < severe arterial thromboembolic events in the first 6 months of inclusion; New York Heart Association Class III or IV stagnation heart failure, ventricular arrhythmia or Loss of blood pressure; active infection or uncontrolled fever.

Of the 417 patients included in the treatment-intention group, 398 (95%) accepted 1 dose of any study drug (safety analysis population). Patient demographics and baseline characteristics were well balanced between the nal-IRI combination and the control group.

The median exposure duration of the nal-IRI combination group in nal-IRI was 8.7 weeks (interquartile range [IQR], 5.4-22.0 weeks); the average dose intensity of nal-IRI during 6 weeks was 167.5 mg/m. ² (standard deviation [SD], 52.05 mg/m ² ). The median exposure duration in 5-FU was 8.7 weeks (IQR, 5.4-22.0 weeks) in the nal-IRI combination group and 6.0 weeks (IQR, 5.9-12.1 weeks) in the control group; 5-FU was at The average dose strength during the 6 weeks was 5065.0 mg/m ² (SD, 1539.1 mg/m ² ) and 6718.0 mg/m ² (SD, 1771.18 mg/m ² ), respectively.

Any level in each treatment group and The incidence of grade 3 TEAE in patients <65 years of age and their age Similar between patients aged 65 years. Noteworthy Level 3 TEAE (difference between subgroups) 5%): In the nal-IRI combination group, the incidence of vomiting (14.3% vs. 7.4%) was higher in patients <65 years old; the incidence of nausea (11.1% vs. 4.8%) was Among the 65-year-old patients is higher.

The incidence of TEAE at any level in each treatment group was similar between Caucasian and East Asian patients, with the exception of diarrhea, which occurred less frequently in East Asians. In the control group The incidence of grade 3 TEAE was similar between Caucasian and East Asian patients (56.5% vs. 54.5%), whereas The incidence of grade 3 TEAE was higher in Caucasians than in Caucasians (87.9% vs. 69.9%) in the nal-IRI combination group. Noteworthy Level 3 TEAE (difference between subgroups) 5%). In the nal-IRI combination group, the incidence of diarrhea (19.2% vs. 3.0%), fatigue (19.2% vs. 0%), and vomiting (13.7% vs. 6.1%) was higher in Caucasian patients; anemia ( The incidence of 21.2% vs. 5.5%), neutropenia (54.5% vs. 17.8%) and leukopenia (21.2% vs. 2.7%) was higher in East Asian patients. In the control group, the incidence of abdominal pain (8.2% vs. 2.3%) was higher in Caucasian patients; the incidence of anemia (13.6% vs. 3.5%) was higher in East Asian patients.

UGT1A1*28 allele (TA7/TA7 genotype): Although a low number of patients with the TA7/TA7 genotype make it difficult to compare, any grade and The incidence of grade 3 TEAE appears to be similar between patients with or without the TA7/TA7 genotype. In the nal-IRI combination group, 3 of 7 patients with the TA7/TA7 genotype were able to increase the nal-IRI dose to 80 mg/m ² without dose reduction. One patient raised the dose but needed to reduce the dose back to 60 mg/m ² ; 2 patients maintained the initial dose; 1 patient needed to reduce the dose to 40 mg/m ² ; another patient in the nal-IRI combination group had Patients with the TA7/TA7 genotype discontinued treatment with grade 3 vomiting (no dose reduction).

Any level and The incidence of grade 3 TEAE is in albumin content Patients between 4.0 g/dL or <4.0 g/dL are similar. Noteworthy Level 3 TEAE (difference between subgroups) 5%). In the nal-IRI combination group, the incidence of diarrhea (17.6% vs. 6.4%) and fatigue (16.2% vs. 10.6%) was in albumin content. The patient was 4.0g/dL higher. In the control group, the incidence of diarrhea (8.1% vs. 1.4%) was higher in patients with an albumin content <4.0 g/dL.

Karnofsky physical status: the incidence of TEAE at any level is in the KPS score 90 or <90 patients are similar. In the nal-IRI combination group The incidence of grade 3 TEAE is in the KPS score 90 or <90 patients are similar; in the control group The incidence of grade 3 TEAE is in the KPS score Patients with 90 were lower relative to patients with a KPS score <90 (40.9% vs. 70.6%). Noteworthy Level 3 TEAE (difference between subgroups) 5%): In the nal-IRI combination group, the incidence of decreased appetite (8.3% vs. 1.4%) and abdominal pain (10.4% vs. 4.3%) was higher in patients with KPS score <90; in the control group The incidence of abdominal pain (8.8% vs. 3.0%) was higher in patients with a KPS score <90.

The safety profiles of nal-IRI+5-FU/V and 5-FU/LV are generally similar between patient subgroups; diarrhea, vomiting, and the most common TEAE of nausea. Within the subgroup The incidence of grade 3 TEAE is consistent with the overall population safety profile. Study limitations included the number of smaller patients in some subgroups and the lack of statistical analysis, which made it impossible to draw decisive conclusions. The results of this subgroup analysis further support that nal-IRI+5-FU/LV has a manageable safety profile in patients previously treated with gPAC based on gemcitabine-based therapy.

Claims (24)

A method of treating metastatic adenocarcinoma of the pancreas of a human patient previously treated with an antitumor agent gemcitabine, the method comprising intravenously administering to the patient an anti-tumor therapy consisting of the following: once every two weeks: 80 mg/ m ² antitumor agent MM-398 liplipid irinotecan (irinotecan) combined with 200mg/m ² form of formazan tetrahydrofolate ( 1 ) and 2,400mg/m ² antitumor agent 5-fluorouracil to treat the human The patient's metastatic adenocarcinoma of the pancreas. The method of claim 1, wherein the patient has a baseline CA19-9 content of at least 1,540 U/mL. The method of claim 1, wherein the patient has a baseline CA19-9 content of from about 1542 to about 12,815 U/mL. The method of claim 1, wherein the patient has a baseline CA19-9 content of 12,815 U/mL or higher. The method of any one of claims 1 to 4, wherein the ( 1 ) form of the 200 mg/m ² formamidine tetrahydrofolate is in the form of 400 mg/m ^{2 of} formazan tetrahydrofolate ( l + d ). Cast. The method of any one of claims 1 to 5, wherein the method comprises administering to the human patient at least 3 cycles for metastatic adenocarcinoma of the pancreas. The method of claim 6, wherein the MM-398 liplipid irinotecan, formazan tetrahydrofolate, and 5-fluorouracil are administered to the patient for 48 hours starting on the first day of the 2-week cycle, wherein the method comprises 3 Cycles. The method of claim 7, wherein the ( 1 ) form of the 200 mg/m ² formamidine tetrahydrofolate is administered in a racemic form of 400 mg/m ^{2 of} formazan tetrahydrofolate ( l + d ), and the form The tetrahydrofolate is administered to the patient prior to the 5-fluorouracil. The method of claim 8, wherein the MM-398 liplipid irinotecan is administered to the patient prior to the formazan tetrahydrofolate. The method of claim 9, wherein the MM-398 liplipid irinotecan is administered by a 90-minute infusion, and then the formazan tetrahydrofolate is administered over 30 minutes, after which the 5-fluorouracil is administered over a period of 46 hours. The method of any one of claims 1 to 10, wherein the patient has metastatic pancreatic cancer that has evolved prior to administration of the MM-398 lipolipid irinotecan based on gemcitabine-based therapy. A method of treating metastatic adenocarcinoma of the pancreas of a human patient previously treated with the antitumor agent gemcitabine, the method comprising intravenously administering to the patient an anti-tumor therapy consisting of: 80 mg/m ² every two weeks Antitumor agent MM-398 microlipid irinotecan with 200 mg/m ² formazan tetrahydrofolate ( l ) form or 400 mg/m ² formazan tetrahydrofolate ( l + d ) racemic form and 2,400 mg / A combination of a m ² antitumor agent 5-fluorouracil to treat metastatic adenocarcinoma of the pancreas of the human patient, wherein the method comprises at least 3 cycles. The method of claim 12, wherein the patient has a baseline CA19-9 content of at least 1542 U/mL. The method of claim 12, wherein the patient has a baseline CA19-9 content of from about 1542 to about 12,815 U/mL. The method of claim 12, wherein the patient has a baseline CA19-9 content of at least about 12,815 U/mL. The method of any one of claims 12 to 15, wherein the formazan tetrahydrofolate is administered as a racemic form of ( 1 + d ) of 400 mg/m ^{2 of} formazan tetrahydrofolate. The method of any one of claims 12 to 16, wherein no other anti-neoplastic agent is administered to the human patient for treating metastatic adenocarcinoma of the pancreas. The method of claim 17, wherein the MM-398 liplipid irinotecan, formazan tetrahydrofolate, and 5-fluorouracil are administered to the patient for 48 hours starting on the first day of the 2-week cycle, wherein the method comprises 3 Cycles. The method of claim 18, wherein the ( 1 + d ) racemic form of 400 mg/m ^{2 of} formazan tetrahydrofolate is administered to the patient prior to the 5-fluorouracil. The method of claim 19, wherein the MM-398 liplipid irinotecan is administered to the patient prior to the formazan tetrahydrofolate. The method of claim 20, further comprising pre-administering the patient to dexamethasone and a 5-HT3 antagonist or other antiemetic agent prior to administration of the MM-398 liplipid irinotecan. A method of treating metastatic adenocarcinoma of the pancreas of a human patient having a baseline CA19-9 content of less than 120 U/mL and previously treated with the antitumor agent gemcitabine, the method comprising intravenously administering 80 mg to the patient once every two weeks /m ² anti-neoplastic agent MM-398 microlipid irinotecan with 200mg/m ² formazan tetrahydrofolate ( l ) form or 400mg/m ² formazan tetrahydrofolate ( l + d ) racemic form and A combination of 2,400 mg/m ² of antitumor agent 5-fluorouracil to treat metastatic adenocarcinoma of the pancreas of the human patient. The method of claim 22, wherein the MM-398 liplipid irinotecan is administered by a 90-minute infusion, followed by administration of the formazan tetrahydrofolate for 30 minutes, followed by administration of the 5-fluorouracil over a period of 46 hours. The method of claim 23, wherein the ( 1 ) form of the 200 mg/m ² formamidine tetrahydrofolate is administered as a racemic form of 400 mg/m ^{2 of} formazan tetrahydrofolate ( l + d ).