TW201701880A - Methods for improving the pharmacokinetics and therapeutic index of sustained release drug therapies - Google Patents

Abstract

Provided are methods for improving the pharmacokinetics of drug therapy. In one aspect methods are provided for co-administration of a liposomally encapsulated, PEGylated, or protein-conjugated drug via a parenteral route and the same drug in free (non-encapsulated, PEGylated, or protein-conjugated) form via an enteral or parenteral route. In another aspect, methods are provided for treating a cancer in a patient by co-administering liposomal irinotecan and free irinotecan, optionally in further combination with additional therapeutic agents.

Description

Method for improving pharmacokinetics and therapeutic index of sustained release drug therapy Cross-reference to related applications

The present application claims the benefit of U.S. Provisional Application Serial No. 62/147,389, filed on Apr.

Colorectal cancer accounts for 10 to 15% of all cancers and is the second leading cause of cancer death in Western countries. About half of the patients develop metastatic disease. Even if palliative chemotherapy has been able to prolong survival and improve quality of life with the best supportive care, the prognosis of these patients is poor. Accordingly, there is still a great need to further improve therapy to extend patient life while maintaining quality of life, especially where colorectal cancer often or becomes resistant to current therapeutic modalities.

Providing a method of improving a pharmacokinetic profile of a drug treatment in a patient, such as a human patient, the method comprising administering to the patient a therapeutically effective amount of a drug, wherein the therapeutically effective amount is administered in a manner that is not The intestine is administered a first amount of the drug in a sustained release dosage form and a second amount of the same drug is administered to the patient via the enteral or parenteral immediate release dosage form. Advantageously, the first amount plus the second amount is equal to the therapeutically effective amount of the medicament. The drug can be taken by one day or more or one week, two weeks or three weeks or one month or one month The above spaced apart doses (each dose comprising the first amount and the second amount) are administered. In some embodiments, the first amount of the drug is administered parenterally in a form that provides sustained release (eg, via liposomal encapsulated form), and the same drug is parenterally administered in a second amount, eg, at the same interval And, the pharmacokinetic profile is improved. Advantageously, the drug achieves a therapeutic level at the site of action faster than when administered only in sustained release (e.g., via liposome encapsulation), and is administered at the site of action only at the same interval as immediate release. Maintain a longer level of treatment.

The immediate release form can be in the form of free (non-encapsulated, unpegylated, and non-protein bound), and the sustained release dosage form can be liposomal encapsulated, PEGylated, or protein bound (eg, albumin binding) )form. The co-administration results in an improvement in the pharmacokinetic profile of the drug, or a therapeutic index of the drug, in combination with the first amount and the second amount of the injectable dosage form administered to the matched patient. Efficacy and safety ratio) or improved therapeutic synergy.

The unencapsulated drug and the drug in a sustained release dosage form (e.g., encapsulated, PEGylated, or protein bound in liposome) can be administered sequentially or simultaneously. The sustained release and immediate release dosage forms can all be included in a single formulation for simultaneous injection. In one embodiment, the second amount of immediate release injectable dosage form is at least 10% of the first amount of sustained release injectable dosage form. The drug can be an anticancer drug. In one embodiment, the sustained release dosage form is in the form of a liposome, a hyaluronate or a pegylated form, and the immediate release dosage form is in the form of a hydrochloride or other salt solution or an analog or derivative thereof.

In various embodiments, the drug is an anti-cancer drug. The anticancer drug may be selected from a topoisomerase inhibitor (such as a topoisomerase I inhibitor or a topoisomerase II inhibitor), an anti-microtubule agent (such as a taxane, a vinca alkaloid) , a vinca alkaloid derivative), an antimetabolite (such as an antifolate, fluoropyrimidine, deoxynucleoside analog or thiopurine), a platinum salt, an alkylating agent (such as nitrogen mustard gas, nitrosourea) , tetrazine, aziridine, organoplatinum, procarbazine or hexamethylmelamine, anti-angiogenic agents or cytotoxic antibiotics. The topoisomerase I inhibitor can be, for example, camptothecin, irinotecan, SN-38 or topotecan; the topoisomerase II inhibitor can be, for example, (pixantrone), mitoxantrone or anthracycline (eg, doxorubicin, daunorubicin, bleomycin, actinomycin D (dactinomycin) ), epirubicin or idarubicin, or it may be, for example, etoposide or teniposide; the taxane may be, for example, paclitaxel , docetaxel, cabazitaxel or tesetaxel, for example, vincristine alkaloids such as vincristine, vinblastine or vinorelbine, the platinum salt For example, oxaliplatin, cisplatin or carboplatin, the alkylating agent may be, for example, bendamustine, butabuban, carbos Carmustine, chlorambucil, cyclophosphamide, ifosfamide, lomustine, a Mechlorethamine, melphalan, streptozocin, thiotepa or uramustine, the antimetabolite may be, for example, 5-FU, capecitabine (capecitabine), cytarabine, gemcitabine, methotrexate, pemetrexed or tegafur, and the anti-angiogenic agent can be, for example, shellfish Favacizumab (bevacizumab). The liposome encapsulated Irinotecan Irinotecan can be sugar esters of sulfur liposome injection ^{(nal-IRI, ONIVYDE TM,} MM-398).

Exemplary combinations include: liposomal irinotecan (eg, MM-398 or IHL-305) co-administered with SN-38 or free irinotecan (eg, CAMPTOSAR®); hyaluronic acid irinotecan (HA-irilide) Co-administered with SN-38 or irinotecan; PEGylated irinotecan (eg, NKTR-102) is co-administered with SN-38 or irinotecan; cyclodextrin camptothecin (eg CRLX101) Co-administered with camptothecin; or PEGylated SN-38 (eg NK102 or EZN2208) co-administered with SN-38 or irinotecan. Liposomal cranberries (for example, DOXIL®, CAELYX®, MYOCET®) co-administered with cranberries; liposomal daunorubicin (eg DAUNOSOME®) with daunorubicin, bleomycin, actinomycin D, epirubicin, AI Dataumycin or mitoxantrone is co-administered. Albumin-bound paclitaxel (eg, ABRAXANE®) is co-administered with paclitaxel; liposomal docetaxel is co-administered with docetaxel; cyclodextrin docetaxel and docetaxel are co-administered; Ethylene glycolated docetaxel is co-administered with docetaxel. The liposomal vincristine (such as MARQIBO®) was co-administered with vincristine; the liposomal vinorelbine was co-administered with vinorelbine; the liposomal vinblastine was co-administered with vinblastine. Liposomes or PEGylated or protein-bound oxaliplatin co-administered with oxaliplatin; liposomes or PEGylated or protein-conjugated cisplatin co-administered with cisplatin; liposomes or PEGylated or The protein is combined with carboplatin and carboplatin.

Also provided is a method for treating a cancer (a tumor, such as an unresectable tumor) in a patient (eg, a human patient) comprising providing an effective amount of each drug according to a particular clinical dosage regimen, co-administering liposomal irinotene to the patient Kang (e.g. ONIVYDE ^TM) and free irinotecan (i.e., in unencapsulated form of a solution or suspension, e.g. CAMPTOSAR®), optionally co-administered with 5-fluorouracil (5-FU) and leucovorin compositions A XI Further, depending on the situation, it is combined with bevacizumab. Compositions adapted for use in such methods are also provided.

In one aspect, a method for treating (eg, effectively treating) a cancer (eg, an unresectable cancer) in a patient, the method comprising: administering to the patient an effective amount of irinotecan, wherein the effective amount comprises The liposomal irinotecan is co-administered with free (non-encapsulated) irinotecan, wherein the method comprises at least one cycle, wherein the cycle is a two-week period, and wherein for each cycle, the liposome irinotene The patient is administered to the patient at a dose of 60 mg/m ² or 80 mg/m ² and the free irinotecan is administered to the patient at a dose of 90 mg/m ² or 120 mg/m ² .

In one embodiment, the cancer is a gastrointestinal cancer, such as colorectal cancer (CRC). In another embodiment, the cancer is a metastatic CRC. In another embodiment, the cancer is pancreatic cancer. In yet another embodiment, the patient has previously been treated with first-line standard care therapy cancer.

In another aspect, a method for treating CRC (optional unresectable late CRC) in a patient, the method comprising: co-administering to a patient an effective amount of each liposome irinotecan, free irinotene Kang, 5-fluorouracil (5-FU), formazan tetrahydrofolate, and optionally bevacizumab, wherein the method comprises at least one co-administration cycle, wherein the period is two weeks, and wherein for each cycle: a) the liposome irinotecan is administered to the patient once at a dose of 60 mg/m ² or 80 mg/m ² ; (b) the free irinotecan is administered to the patient once at a dose of 90 mg/m ² or 120 mg/m ² ; (c) formazan tetrahydrofolate is administered to the patient once at a dose of 400 mg/m ² ; (d) 5-FU is administered once to the patient at a dose of 2400 mg/m ² ; and (e) bevacizumab is administered at 5 mg The dose of /kg or 10 mg/kg is administered to the patient once as appropriate.

In one embodiment, the liposomal irinotecan is administered intravenously over 90 minutes. In another embodiment, the 5-FU is administered intravenously over a period of 46 hours. In another embodiment, the formazan tetrahydrofolate is administered intravenously over 2 hours. In another embodiment, the bevacizumab is administered intravenously over 30-90 minutes. In another embodiment, the liposomal irinotecan is administered intravenously over 60 minutes or 90 minutes. In another embodiment, the free irinotecan is administered intravenously over 60 minutes.

In other embodiments, the liposomal irinotecan is administered prior to the free irinotecan. In one embodiment, the formazan tetrahydrofolate and 5-FU are administered sequentially. The formazan tetrahydrofolate and 5-fluorouracil can be administered after two formulations of irinotecan, wherein the formazan tetrahydrofolate is administered prior to administration of the 5-FU. In another embodiment, the bevacizumab is administered prior to the liposome irinotecan, the free irinotecan, the formazan tetrahydrofolate, and the 5-FU.

In still other embodiments, treating the patient results in a positive result, wherein the positive result is a pathological complete response (pCR), a complete response (CR), a partial response (PR), or a stable disease (SD). In one embodiment, the combination therapy with the liposomes irinotecan, free irinotecan, 5-FU, and formazan tetrahydrofolate results in a therapeutic synergy.

In other embodiments, the liposome formulations of Irinotecan irinotecan liposome injection ^{(MM-398, ONIVYDE TM)} . MM-398 may also be referred to as irinotecan HCl liposome injection because irinotecan HCl is an effective pharmaceutical ingredient for loading irinotecan into liposomes containing sucrose triethylammonium sulphate to prepare MM-398 Liposomes. Even if the irinotecan HCl hydrochloride ion is reacted with the triethylammonium ion of sucrose triethylammonium sulphate, triethylammonium chloride (triethylamine hydrochloride) which is diffused from the liposome is obtained. This nomenclature can still be used to leave irinotecan sulphate coated in the MM-398 liposomes.

In another aspect, a formulation of liposomal irinotecan (eg, MM-398) is provided for co-administration with free irinotecan in at least one cycle, wherein the cycle is two weeks, and wherein: (a) The liposome irinotecan is administered at a dose of 60 or 80 mg/m ² ; and (b) the free irinotecan is administered at a dose of 90 or 120 mg/m ² .

In another aspect, a formulation of liposomal irinotecan is provided for co-administration with free irinotecan, 5-fluorouracil (5-FU), formazantetrahydrofolate, and bevacizumab in at least one cycle, Wherein the cycle is two weeks, and wherein: (a) the liposome irinotecan is administered at a dose of 60 or 80 mg/m ² ; (b) the free irinotecan is administered at a dose of 90 or 120 mg/m ² ; c) formazan tetrahydrofolate was administered at a dose of 400 mg/m ² ; (d) 5-fluorouracil was administered at a dose of 2400 mg/m ² ; and (e) bevacizumab was administered at a dose of 5 mg/kg.

Optionally, the liposomal irinotecan is administered intravenously over 90 minutes, and/or the 5-FU is administered intravenously over a period of 46 hours, and/or the formazan tetrahydrofolate is administered intravenously 2 Hourly invested. In an alternative embodiment, the liposomal irinotecan is administered intravenously over 6 minutes or 90 minutes, and/or the free irinotecan is administered intravenously over 60 minutes.

In another aspect, the camptothecin topoisomerase I inhibitor is irinotecan, and the sustained release dosage form is in the form of a liposome, a hyaluronic acid or a PEGylated form, and the immediate release dosage form is Irinotecan hydrochloride solution or an analog or derivative thereof. In one embodiment, the period is two weeks and is used for each co-administration: (a) the liposomal irinotecan sulphanate is administered at a dose ranging between 60 and 100 mg/m ² ; b) the irinotecan hydrochloride is administered at a dose ranging between 90 and 180 mg/m ² ; (c) the formazan tetrahydrofolate is administered at a dose of 400 mg/m ² ; (d) the 5-fluorouracil is A dose of 2400 mg/m ² was administered; and (e) the bevacizumab was co-administered at a dose of 5 mg/kg every 2 weeks or 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks.

In another aspect, a kit for treating a CRC in a patient (eg, an unresectable CRC, a metastatic CRC, or a metastatic unresectable CRC) is provided, the kit comprising a first container and at the first A second container and a third container in the container, the second container containing a dose of liposomal irinotecan and the third container containing a dose of free irinotecan. The kit further includes instructions for the use of the liposomes irinotecan, free irinotecan, and optionally 5-FU and formazan tetrahydrofolate, as appropriate, and optionally bevacizumab as described herein.

MM-398 PEGylated liposomes encapsulating irinotecan and sucrose octasulfate are useful as a method for treating unresectable advanced cancer in a human patient, the method comprising administering to the human patient every two weeks during the treatment cycle Cast.

Figures 1A-1C summarize MM-398 pharmacokinetic parameters in HT-29 xenograft studies.

1A and 1B are graphs showing plasma irinotecan and SN-38 levels after administration of free irinotecan and MM-398, respectively. Figure 1C is a graph showing the intratumoral levels of irinotecan and SN-38 after different doses of MM-398.

definition

The term "patient" is a human patient.

The term "effective treatment" refers to the treatment of a beneficial effect, such as amelioration of at least one symptom of a disease or condition. A beneficial effect may be in an improved form beyond the baseline, i.e., an improvement over the measurement or observation performed prior to the initiation of the therapy according to the method. Favorable effects may also be in the form of halting, slowing, delaying or stabilizing the harmful progression of cancer markers. Effective treatment can mean alleviating at least one symptom of cancer. The effective treatment can, for example, reduce pain in the patient, reduce the size and/or number of lesions, reduce or prevent cancer metastasis of cancerous tumors, and/or can slow the growth of cancerous tumors. Effective treatment with a drug or composition can: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, delay, slow, and prevent cancer cells from infiltrating into peripheral organs to some extent; Inhibiting (ie, slowing down and preventing to some extent) tumor cancer metastasis; (v) inhibiting tumor growth; (vi) preventing or delaying tumor emergence and/or recurrence; and/or (vii) reducing to some extent One or more symptoms associated with cancer.

The terms "combination therapy", "co-administration" or "co-administered" (or minor variations of such terms) include the simultaneous administration of at least two therapeutic agents to a patient or The therapeutic agents are administered sequentially over a period of time during which the therapeutic agent administered the second time is administered while the first dose of the therapeutic agent is still present in the patient.

The term "monotherapy" refers to the administration of a single pharmaceutical formulation containing a single drug to treat the same disease or condition in the absence of co-administration of any other drug or therapeutic agent to treat the disease or condition.

"Dose" refers to a parameter used to administer a pharmaceutical formulation to a patient in a defined amount per unit time (eg, hourly, daily, weekly, monthly, etc.). These parameters include, for example, medicine The amount of the substance in each dose or administration. These parameters also include configurations of each dose, which may be administered in one or more unit forms, such as each using a single administration, such as injection (eg, in infusion or rapid injection). The parameters further include the frequency of administration of the respective dose, wherein the frequency can change over time.

By "dosage form" is meant a form and/or formulation of a drug provided for use, such as a free aqueous solution, an aqueous suspension, a liposomal suspension, a single dose vial, a pill, a capsule, and the like.

"Dose" means the amount of drug administered in a single administration.

The terms "resistance" and "resistance" refer to the continued growth or division of tumor cells during treatment with a therapeutic agent. The cells may initially respond to the therapeutic agent (e.g., not grow or divide), but then exhibit reduced reactivity during treatment.

"Therapeutic synergy" refers to the phenomenon in which a patient is treated with a combination of therapeutic agents (eg, a combination of co-administered different drugs or a co-administered combination of different agents of the same drug) to show that treatment is better than The results achieved by the individual components of the combination of doses are more excellent results. In this context, a therapeutically superior result is the result in which patient a) exhibits a reduced incidence of adverse events while receiving individual components equal to or greater than the combination in a monotherapy form to be administered separately at the same dose as the combination. The therapeutic benefit, or b) does not exhibit dose-limiting toxicity, while receiving greater than the ingredients administered in the same dose in the combination, such as when administered as an individual component, the therapeutic benefit of treatment with the individual components of the combination. In a xenograft model, the amount of tumor growth reduction achieved by administering a combination at maximum tolerated dose (where each of the components will typically be present at a dose not exceeding their individual maximum tolerated dose) is greater than This combination shows a therapeutic synergy when the decrease in tumor growth of the optimal component when the component is administered alone.

II. Overview of pharmacokinetics for improved drug therapy

Unencapsulated drugs usually provide rapid exposure to high drug levels, but often cannot be sustained over a long period of time. In a complementary manner, the encapsulation of the drug can be engineered to provide Sustained release of pharmacokinetic profiles for sustained exposure over extended periods of time. However, the encapsulated drug can take longer to reach the therapeutic level at the site of action than the free drug.

III. Irinotecan and MM-398

Irinotecan is ( S )-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-[1,4'dipiperidine]-1'-formate, which is a camptothecin derivative topography Isomerase I inhibitor.

MM-398 (see, for example, US 8,147,867) is a stable liposome formulation, also known as irinotecan liposome injection, irinotecan sucrose octasulfate liposome injection or irinotecan sulpholipid liposome injection (also known as liposome injection) For PEP02 and ONIVYDE ^TM ). MM-398 can be provided for intravenous injection in the form of a sterile injectable parenteral aqueous liquid. The required amount of MM-398 can be diluted, for example, in 250 mL of 5% dextrose injection USP, and for example, infusion over a period of 90 minutes.

The MM-398 liposome is a single-layer lipid bilayer vesicle of 80-140 nm in diameter, which encapsulates an aqueous space containing irinotecan which is in a gelled or precipitated state and which is in salt form with sucrose octasulfate. The lipid membrane of the liposome comprises phospholipid choline, cholesterol and polyethylene glycol-derivatized phospholipid-ethanolamine in an amount of about one polyethylene glycol (PEG) molecule per 200 phospholipid molecules. This stable liposome formulation of irinotecan has several properties that provide an improved therapeutic index. Controllable and sustained release improves the time-course dependent drug irinote by increasing the duration of exposure of the tumor tissue to either or both of the drug (irinotecan and its more active metabolite SN-38) Kang's activity, when DNA melting (mediated by topoisomerase) requires an initial step in DNA replication, allows the drug to be present in a higher proportion of cells during the S phase of the cell cycle.

Long-circulating pharmacokinetics and high intravascular drug retention of liposomes (e.g., MM-398 liposomes) may provide other benefits, such as those derived from enhanced permeability and retention (EPR). In some other parts of the tumor and pathology (such as the site of infection, the site of inflammation, or the site of infection and inflammation), the normal integrity of the vascular structure (especially the capillary) is impaired. Vascular permeation causes leakage of nanoparticle, such as liposomes, from the capillary lumen, which can then remain and accumulate at the leak site. This enhanced permeability and retention can thus facilitate better delivery and accumulation of liposomes in tumors and inflamed or infected sites. The EPR of MM-398 can lead to subsequent accumulation effects in which lipids are aggregated (eg, in tumor-associated macrophages), which can metabolize irinotecan for local conversion to substantially more cytotoxic SN-38 And release the drug as the liposome ruptures. This preferred localized biological activation and delivery is believed to result in increased exposure at cancer cells within the tumor and reduced exposure of the drug elsewhere (eg, at potentially toxic sites).

IV.5-fluorouracil (5-FU) and formazan tetrahydrofolate,

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

Formazan tetrahydrofolate enhances the cytotoxic effects of fluorinated pyrimidines such as 5-FU and fluorouridine. For example, after 5-FU is activated intracellularly, it associates with a folate cofactor and mediates cytotoxicity by inhibiting the enzyme thymidylate synthase. Formazan tetrahydrofolate increases the folate pooling, thereby increasing the binding of folate cofactor and active 5-FU to thymidylate synthase, resulting in increased cytotoxicity.

V. bevacizumab

Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). VEGF-A is a cytokine that stimulates angiogenesis in a variety of diseases, particularly cancer. Bevacizumab is usually administered at a dose of 5 mg/kg or 10 mg/kg every 2 weeks, or typically at a dose of 15 mg/kg every 3 weeks.

VI. Casting

The liposome irinotecan is combined with free irinotecan, and is further co-administered with 5-fluorouracil (5-FU) and, if appropriate, bevacizumab in combination with methotrexate. Intravenous administration with the combination. In one embodiment, free irinote Kang was administered before liposome irinotecan. In another embodiment, the free irinotecan and liposomal irinotecan are administered prior to 5-FU and formazan tetrahydrofolate. In another embodiment, formazan tetrahydrofolate is administered prior to 5-FU. In another embodiment, bevacizumab is administered prior to liposomal irinotecan, free irinotecan, formamidinetetrahydrofolate, and 5-fluorouracil. In another embodiment, the liposomal irinotecan is administered intravenously over 60 minutes or 90 minutes. In another embodiment, the free irinotecan is administered intravenously over 60 minutes. In another embodiment, 5-FU is administered intravenously over a period of 46 hours. In another embodiment, formazan tetrahydrofolate is administered intravenously over 2 hours. In another embodiment, bevacizumab and formazan tetrahydrofolate are each administered over 120 minutes. In another embodiment, bevacizumab is administered over 30-90 minutes. In various embodiments, the liposome irinotecan is MM-398.

VII. Patient group

The compositions and methods disclosed herein are useful for treating patients suffering from a variety of cancers, including unresectable cancers and cancers that are resistant or resistant to other anti-cancer therapies.

CRC

In one embodiment, a patient treated with the methods and compositions disclosed herein has a histologically proven cancer.

The treated patient may have advanced or metastatic disease that is not suitable for complete surgical resection (eg, unresectable cancer).

The treated patient may have colorectal cancer (CRC).

The treated patient may have an unresectable or metastatic CRC.

The CRC can be adenocarcinoma, squamous cell carcinoma, leiomyosarcoma, carcinoid or gastrointestinal matrix tumors.

In various CRC embodiments, the patient has at least one or all of the following:

a. Histologically proven cancer,

b. Advanced or metastatic disease not documented for complete surgical resection

c. measurable lesions according to RECIST v1.1 guidelines

d. ECOG performance status is 0-1

e. Bone marrow is retained as evidenced by:

● ANC without hematopoietic growth factor 1.5×10 ⁹ /L

Platelet 100×10 ⁹ /L

● Hemoglobin > 9g / dL (can be infused to maintain or exceed this level)

f. International Standardized Ratio (INR) 1.5; aPTT < 1.5 x UNL; in addition: patients undergoing complete anticoagulation must have an INR (between 2 and 3) within the range due to VTE.

g. Sufficient renal function as demonstrated by:

●Serum creatinine: <150μmol/l

• Calculated creatinine elimination rate >50 ml/min. (Recommendation: Calculated according to the MDRD formula)

h. overall bilirubin <1.0 x upper normal limit (ULN), or

i. Normal ECG, or ECG without any clinically significant findings.

In various CRC embodiments, the patient does not have one or more of the following:

a. Active central nervous system cancer metastasis (eg by clinical symptoms, cerebral edema, steroid requirements or progressive disease indication)

b. bone disease only

c. Clinically significant gastrointestinal conditions (other than CRC), including liver disease, bleeding, inflammation, GI blockage or diarrhea > Level 1

d. Patients who are resistant to irinotecan (ie, previously exposed to irinotecan-based therapies, which have the best response to progressive disease)

e. Known DLT response to irinotecan

f. Patients known to be homozygous for UGT1A1 *28

g. History of any second malignant disease in the last 3 years; patients with a prior history of orthotopic cancer or basic or squamous cell skin cancer are eligible. If the patient has continued Patients who have a history of other malignant diseases for at least 3 years without disease are eligible

h. Previously exposed to MM-398

i. Known allergies to any of MM-398 components or other liposome products

j. Parallel disease of relative contraindications for trial participation, such as active heart disease or liver disease

●Severe arterial thromboembolic events (myocardial infarction, unstable angina, stroke) less than 6 months before enrollment

● NYHA class III or IV congestive heart failure, ventricular arrhythmia

k. Active infection or unexplained fever >38.5 °C during the screening visit or on the first day of dosing (dose at the discretion of the investigator, patients with tumor fever may participate), from the perspective of the investigator Can damage patients' participation in trials or influence research results

l. prior chemotherapy administered within 3 weeks or at intervals less than 5 half-lives of the agent, whichever is longer, before the first day of dosing in this study

m. Uncontrolled hypertension (defined as persistent systolic blood pressure >150 mmHg and / or diastolic blood pressure >100 mmHg), or history of hypertensive crisis or hypertensive encephalopathy

n. Have received radiation therapy in the last 14 days

o. Major surgery or traumatic injury in the last 28 days

p. The investigator believes that it is likely to interfere with the patient's ability to sign informed consent, collaborate and participate in the research, or any other medical or social condition that interferes with the interpretation.

q. Pregnancy or breastfeeding; women who are pregnant may have to test pregnancy negative based on a urine or serum pregnancy test. Male and female patients with reproductive potential must agree to use reliable birth control methods for up to 3 months during the study period and after the most recent dose of study drug.

r. Co-op with St John Wort

s. Accompanying live attenuated virus vaccines, such as yellow fever vaccines

In other embodiments, the patient has pancreatic cancer, such as exocrine pancreatic cancer. In one such embodiment, the pancreatic cancer is selected from the group consisting of acinar cell carcinoma, adenocarcinoma, adenosquamous carcinoma, giant cell tumor, intraductal papillary mucinous neoplasm (IPMN), mucinous sac Adenocarcinoma, pancreatoblastoma, serous cystadenocarcinoma, and solid and pseudopapillary tumors. The treated patient may have recurrent or persistent pancreatic cancer after primary chemotherapy. Patients with pancreatic cancer may have previously used at least one platinum-based chemotherapy regimen for managing primary or recurrent disease, for example, including oxaliplatin, carboplatin, cisplatin Or a chemotherapy regimen of another organoplatinum compound, and failed. Alternatively, patients with pancreatic cancer who previously treated with gemcitabine may fail or become resistant to gemcitabine.

VIII. Combination therapy

In accordance with the present invention, the drug in encapsulated form in liposomes and the same drug in unencapsulated and unmodified (free) form are administered to a patient in need thereof. This co-injection improves the pharmacokinetic profile of the drug in the patient. The patient can have cancer. The drug can be irinotecan.

In one embodiment, the liposomal irinotecan is co-administered with free irinotecan to a patient having cancer according to a particular clinical dosing regimen, such as the dosing regimens described herein. In another embodiment, the patient has an unresectable cancer. In another embodiment, the patient has colon cancer. In another embodiment, the patient has unresectable colon cancer.

In another embodiment, the liposomal irinotecan is co-administered to a cancer patient in combination with free irinotecan, 5-fluorouracil (5-FU), formazan tetrahydrofolate, and, optionally, bevacizumab. Each of these combinations should be administered to a patient having cancer according to a particular clinical dosing regimen, such as the dosing regimen described herein. The liposome irinotecan can be MM-398. The patient may have an unresectable cancer. The patient may have CRC. The CRC can be unresectable. The patient may have metastatic cancer. The patient may have a metastatic CRr. Patient can suffer Unresectable metastatic CRC.

The liposome irinotecan can be combined with free irinotecan, 5-fluorouracil (5-FU) and formazan tetrahydrofolate according to a particular clinical dosing regimen, such as the dosing regimen described herein, to the pancreas Patients with cancer are co-invested.

In all of the above examples, the exemplary liposome irinotecan is MM-398. The liposome irinotecan can be administered simultaneously or sequentially with free irinotecan. Alternatively, the liposome irinotecan can be co-administered with free irinotecan, 5-FU and formazan tetrahydrofolate, wherein the liposomes irinotecan, 5-FU and formazan tetrahydrofolate are each formulated for use. Each voted and was given in order. For example, liposomes and free irinotecan can be administered first, followed by (eg, immediately following) administration of formazan tetrahydrofolate, followed by 5-FU. In another embodiment, the free irinotecan and the liposomal irinotecan are administered prior to 5-FU, formazan tetrahydrofolate, and bevacizumab. In another embodiment, bevacizumab is administered prior to liposomal irinotecan, free irinotecan, formamidinetetrahydrofolate, and 5-fluorouracil.

The liposomes irinotecan, free irinotecan, 5-FU, formazan tetrahydrofolate and bevacizumab were each formulated for intravenous administration. In an exemplary embodiment, the patient is administered an effective therapy comprising administering to the liposomal irinotecan, free irinotecan, 5-fluorouracil (5-FU), and formazan tetrahydrofolate, Wherein the treatment comprises at least one cycle wherein the period is a period of 2 weeks, and wherein for each cycle: (a) liposomal irinotecan is administered at a dose of 60 or 80 mg/m ² ; (b) free irinotecan at 90 Or a dose of 120 mg/m ² ; (c) formazan tetrahydrofolate is administered at a dose of 400 mg/m ² ; and (d) 5-fluorouracil is administered at a dose of 2400 mg/m ² . The therapy can further comprise administering bevacizumab at a dose of 5 mg/kg or 10 mg/kg.

Alternatively, the patient is administered an effective therapy comprising administering liposomal irinotecan without administration of formazan tetrahydrofolate or 5-FU and optionally without bevacizumab. And each of the free irinotecans, wherein the treatment comprises at least one cycle, wherein the period is 2 weeks, and wherein for each cycle: (a) the liposomal irinotecan is administered at a dose of 60 or 80 mg/m ² And (b) free irinotecan is administered at a dose of 90 or 120 mg/m ² .

IX. Results

Preferably, the co-administered liposomal irinotecan and free irinotecan exhibit therapeutic synergy, or co-administered liposomal irinotecan, free irinotecan, 5-fluorouracil (5-FU) and formazan tetrahydrogen Folic acid exhibits therapeutic synergy, or co-administered liposomal irinotecan, free irinotecan, 5-fluorouracil (5-FU), formazan tetrahydrofolate, and bevacizumab exhibit therapeutic synergy.

This co-administration of these combinations produces an additive to suppress tumor growth compared to monotherapy with irinotecan encapsulated only with liposomes or with other formulations in the absence of liposomal irinotecan therapy. Super cumulative effect. "Accumulate" means that the result is greater than the best individual outcome achieved by monotherapy with the individual components, and "super-accumulation" is used to indicate that the result exceeds the sum of the individual outcomes to a greater extent. . In one embodiment, the additive effect is measured to slow or prevent tumor growth. The additive effect can also be measured, for example, by a decrease in tumor size, a decrease in tumor mitotic index, a decrease in the number of metastatic lesions over time, an increase in overall response rate, or an increase in median survival or overall survival, or asymptomatic or symptomatic symptoms. The frequency and/or duration of fewer hours increases.

One non-limiting example of measuring the effect of therapeutic treatment can be quantified by calculating the log10 cell kill rate, which is determined according to the following equation: log10 cell kill rate = T C (days) / 3.32 x Td

Wherein TC represents the delay time of cell growth, which is the average time in days of the tumor of the treatment group (T) and the tumor of the control group (C) reaching a predetermined value (for example, 1 g or 10 mL), and Td represents a control animal. The time required in days for the tumor volume to double. When this measurement is applied, the product is considered active if the log10 cell kill rate is greater than or equal to 0.7, and if the log10 cell kill rate is greater than 2.8, the product is considered to be extremely active. Using this measurement, log10 cell killing rate is greater than log10 cell killing of the best component alone. At the value of the rate, a combination of its own maximum tolerated dose, wherein each of the ingredients is present at a dose that is typically less than or equal to its maximum tolerated dose, exhibiting therapeutic synergy. In an exemplary case, the combined log10 cell kill rate exceeds the combined optimal component log10 cell kill rate value by at least 0.1 log cell kill rate, at least 0.5 log cell kill rate, or at least 1.0 log cell kill. rate.

Responses to therapy may include: pathological complete response (pCR): there is no invasive cancer in the breast and lymph nodes after primary systemic treatment.

Complete response (CR): All target lesions disappeared. Any pathological lymph node (regardless of target or non-target) is reduced by <10 mm on the short axis; partial response (PR): the total size of the target lesion is reduced by at least 30%, taking the baseline total diameter as a reference; stable disease (SD): The reduction is not sufficient to identify a partial response, the increase is not sufficient to identify a progressive disease, and the minimum sum diameter is used as a reference; or, at the same time, non-CR/non-PD indicates that one or more non-target lesions persist and/or maintain Above the normal limit of tumor marker levels.

Progressive disease (PD) indicates an increase in the sum of the size of the target lesion by at least 20%, taking the smallest sum in the study (if it is the minimum of the study, this includes the baseline sum) as a reference. In addition to the relative increase of 20%, the sum must also exhibit an absolute increase of 5mm. The appearance of one or more new lesions is also considered to be progress; in exemplary results, a patient treated according to the methods disclosed herein can experience an improvement in at least one cancer sign.

In one embodiment, the patient so treated exhibits pCR, CR, PR or SD.

In another embodiment, the patient so treated exhibits a shrinking tumor and/or a decrease in growth rate, i.e., tumor growth is suppressed. In another embodiment, tumor cell proliferation is reduced or inhibited. In yet another embodiment, one or more of the following may occur: the number of cancer cells is Reduction; tumor size can be reduced; cancer cells can be inhibited, delayed, slowed or prevented by infiltration into peripheral organs; tumor cancer metastasis can be slowed down or inhibited; tumor growth can be inhibited; tumor recurrence can be prevented or delayed; One or more symptoms can be reduced to some extent.

In other embodiments, the improvement is measured by measurable reduction in the number and/or size of tumor lesions.

In some embodiments, co-administering an effective amount of liposomal irinotecan and free irinotecan according to any of the methods provided herein produces at least one therapeutic effect selected from the group consisting of: tumor size reduction Small, over time, showing a reduction in the number of metastatic lesions, complete remission, partial remission, stable disease, increased overall response rate, or pathological complete response. In some embodiments, the provided treatment produces a comparable clinical benefit rate (CBR=CR+PR+SD 6 months), which is better than the clinical benefit rate achieved by the same combination of anticancer agents administered without MM-398 administration. In other embodiments, the improvement in clinical benefit rate is about 20%, 30%, 40%, 50%, compared to an anticancer agent that is administered in the same combination as administered without MM-398 administration. 60%, 70%, 80% or more.

In other embodiments, co-administering an effective amount of liposomal irinotecan, free irinotecan, 5-FU, formazan tetrahydrofolate, and bevacizumab according to any of the methods provided herein produces at least A therapeutic effect selected from the group consisting of: reduced tumor size, reduced size of unresectable colorectal tumors, decreased number of metastatic lesions over time, complete remission, partial remission, stable disease, overall response rate Increase or pathological complete response. In some embodiments, the provided treatment produces a comparable clinical benefit rate (CBR=CR+PR+SD 6 months), which is better than the clinical benefit rate achieved by the same combination of anticancer agents administered without MM-398 administration. In other embodiments, the improvement in clinical benefit rate is about 20%, 30%, 40%, 50%, compared to an anticancer agent that is administered in the same combination as administered without MM-398 administration. 60%, 70%, 80% or more.

The following examples are illustrative and are not to be construed as limiting the scope of the invention in any way.

Instance Example 1: MM-398 preclinical pharmacokinetics

The pharmacokinetic properties of free irinotecan and MM-398 were evaluated in the HT-29 colon subcutaneous xenograft model. Tumor-bearing mice were injected with different doses of MM-398 (5, 10, 20 mg/kg) followed by a single injection, plasma and tissue samples at multiple time points (1, 4, 8, 24, 48, 72, 168 hours) collection. HPLC analysis was used to measure the level of irinotecan and its metabolite SN-38 in these samples. The PK characteristic curve of MM-398 was compared with the PK characteristic curve of free irinotecan (at 10 and 40 mg/kg).

Both irinotecan and SN-38 were eliminated from the plasma very rapidly (within 8 hours) and then administered free irinotecan. However, the MM-398 elimination rate was significantly slower, as shown in Figure 1A, with a half-life of about 48 hours; since >90% of irinotecan was encapsulated throughout the plasma, the irinotecan level reflected the MM-398 concentration. Although Cmax levels were reduced after MM-398 administration, SN38 plasma exposure was also greater, indicating that irinotecan liposome formulations have advantages in prolonging exposure and half-life (Fig. 1B). The accumulation of irinotecan and SN-38 in the tissue continued for an extended period of time (at least 1 week after MM-398 was administered). Accumulation was also observed to be dose dependent (Fig. 1C).

When free irinotecan is administered, irinotecan is activated by the liver into SN38 as the main pathway for SN38 tumor accumulation. In contrast, these data indicate that when MM-398 is administered, tumor accumulation in MM-398 and subsequent liposome decomposition and local conversion of irinotecan to SN38 result in enhanced tumor exposure to SN38. Current research has focused on identifying cell types that are located in tumors that cause liposome breakdown and MM-398 activation.

Example 2: Phase I study of MM-398 plus irinotecan in unresectable advanced cancer. aims

The primary objective of this study was to determine the safety, tolerability, and extent of the tolerated combination dose, and to define the recommended dose (RD) for further evaluation in Phase II studies. 1) Determine the safety, tolerability and extent of the tolerated combination dose. 2) Define the recommended dose (RD) for further evaluation in Phase II studies.

The secondary objective of this study was to describe the pharmacokinetics of MM-398 plus irinotecan combination therapy (Group A). MM-398 plus irinotecan and LV/5-FU combination therapy (Group B) dynamics. The clinical activity of MM-398 plus irinotecan combination therapy (Group A) was determined. The clinical activity of MM-398 plus irinotecan and LV/5-FU combination therapy (Group B) was determined.

The exploratory goal of this study was to evaluate the pharmacokinetic response in colorectal tumors after combination therapy, in potential tissue and plasma/serum pharmacokinetic markers (tumor-associated macrophages (TAM), tumor irinotecan, tumors) Correlation between SN-38, tumor SN38G levels, plasma cytokines, plasma lipoproteins or other plasma components) and tumor response, drug elimination rate and safety.

Test design

This is a dose escalation and therapeutic exploratory phase I multicenter, open-label study of MM-398 plus irinotecan patients with unresectable advanced cancer.

This study will enroll approximately 6-36 patients in both groups.

• Group A, patients with unresectable advanced non-colorectal cancer will receive MM-398 and free irinotecan every two weeks (q2w).

● Group B, patients with metastatic colorectal cancer will receive MM-398 and free irinotecan and bevacizumab 5 mg/kg every two weeks, formazan tetrahydrofolate 400 mg/m ² 2h infusion and 5-fluorouracil 2400mg/m ² 46h infusion was co-administered.

There are three periods in this study: 1) Screening period (up to 28 days): Patients are screened to determine compliance with study conditions. 2) MM-398 treatment period (C1D1 until intolerable toxicity and/or progression): The patient is treated every 2 weeks and undergoes biopsy and other required assessments. 3) Tracking period After the most recent dose of MM-398, the patient was assessed for 30 days for final safety assessment, and overall survival tracking was performed every 2 months thereafter.

Dose-limiting toxicity

Dose-limiting toxicity (DLT) is defined as any of the following events that may, likely or are explicitly attributable to the combination of MM-398 and irinotecan, and are considered clinically significant. After the first dose of study treatment, DLT for dose escalation purposes was evaluated during the 28 day period. This includes two treatment cycles. Each treatment cycle is 2 weeks. Toxicity was graded and recorded according to NCI CTCAE (v4.0).

Non-blood dose-limiting toxicity is defined as: • Any grade 3 or grade 4 non-hematologic toxicity, with the following specific exclusions: ○ Level 3 nausea, vomiting, diarrhea, mucositis/oral caused by response to maximum supportive care within 3 days Inflammation; ○ level 3 liver enzyme elevation, including returning to the level before the next treatment cycle time 1 or baseline ALT/AST/GGT; and ○ level 3 fever or infection

● An allergic reaction that forces the study drug to stop.

Blood dose limiting toxicity is defined as:

● Level 4 neutropenia (absolute neutrophil count, ANC) lasts > 7 days, platelets count <10.000/mm ³ on separate 2 days, or platelets need to be separated for 2 days in 7 days Infusion

● Toxicity causes a delay of >14 days between treatment cycles.

● Fecal neutropenia occurs even with secondary prevention of G-CSF

Definition of dose escalation and maximum tolerated dose

In the case of a limited number of patients, the goal of dose escalation defines the safety and toxicity characteristics of free irinotecan to MM-398. The dose escalation will follow the 3+3 dose escalation step as described in Table 1. Need to study before defining a new dose and starting the next group Evaluation of the safety data format for a minimum of 3 patients who had completed 28 days of dosing. Safety data were assessed after the last patient in each group completed the DLT evaluation period, including the collected laboratories, all adverse events (AEs), and any other relevant information. Dosing will continue to the next level after agreement between the investigator, sponsor, and medical monitor. Patients were enrolled in a cohort of 3 patients for each dose level. Dose escalation continues between groups and does not allow for intra-patient dose escalation. If none of the first 3 patients experienced DLT, the dose escalation continued for the next group of patients. If one of the 3 patients developed DLT, the group was expanded to 6 patients. If no more than one of the 6 patients experienced DLT, the progression was increased to the next dose level. If 2 of 3 patients or 2 of 6 patients developed DLT at a certain dose level, the dose escalation was stopped and the previous dose level was verified as the maximum tolerated dose (MTD). A minimum of 6 evaluable patients are treated at the MTD dose level, and no more than 1 of the 6 patients should undergo DLT at this dose level. If the highest dose level was evaluated in the initial 3 patients without DLT, then an additional 3 patients were enrolled. This shows MTD if no more than 1 of the 6 patients experience DLT at the highest dose level.

After sequential dose escalation of MM-398 and CPT11, the final MTD will be considered the recommended dose for the Phase II study. Patients who underwent DLT discontinued the study. Replacement non-compliance with research The patient was discontinued during the DLT evaluation period due to reasons other than toxicity.

efficacy

Tumor response was evaluated every 8 weeks after starting treatment. Response Evaluation Criteria in Solid tumors (RECIST version 1.1; Eisenhauer, EA et al. (2009), EJC, 45(2), 228-47) for this study for target tumor response assessment Use, including confirmation of the response within 28 days. The best overall response is the best response recorded from the start of treatment until the treatment fails, taking the minimum measured values recorded for the onset of progressive disease as a reference. The survival period is from the randomization date to the patient's death date, for any reason, or to the last date of the known patient's survival. Patients who did not report death at the time of analysis were examined using the last date known to survive. PFS (progression free survival) is the time from the date of the first dose of study drug to the date of progressive disease (RECIST criteria) or death (any cause). Death is considered a progression event in their patients. At the time of the final analysis, the patient was examined at the date of his last target tumor assessment without recording the progress of the target.

Patient population

Patients must meet all of the following criteria that meet the study criteria.

Selected criteria:

a. Age 18-75 years old

b. Histologically proven cancer

c. Recorded advanced or metastatic disease not suitable for complete surgical resection

d. measurable lesions according to RECIST v1.1 guidelines

e. ECOG performance status is 0-1

f. Bone marrow is retained as evidenced by:

● ANC without hematopoietic growth factor 1.5×10 ⁹ /L

Platelet 100×10 ⁹ /L

● Hemoglobin > 9g / dL (can be infused to maintain or exceed this level)

g. International Standardized Ratio (INR) 1.5; aPTT < 1.5 x UNL; Exception: Patients undergoing complete anticoagulation must have a range of INRs (usually between 2 and 3).

h. Sufficient renal function as demonstrated by:

●Serum creatinine: <150μmol/l

• Calculated creatinine elimination rate >50 ml/min. (Recommendation: Calculated according to the MDRD formula)

i. Overall bilirubin <1.0 × upper limit of normal (ULN)

j. Normal ECG, or ECG without any clinically significant findings

k. Usable regular tracking. Registered patients must be treated and tracked at the participating center.

l. Be able to understand and sign an informed consent form (or have a legal representative that can do so)

m. Registration of the national health system (including the French CMU).

Elimination criteria:

a. Active central nervous system cancer metastasis (indicated by clinical symptoms, brain edema, steroid requirements, or progressive disease)

b. bone disease only

c. Clinically significant gastrointestinal conditions including liver disease, bleeding, inflammation, GI blockage or diarrhea > Level 1

d. Patients who are resistant to irinotecan (ie, previously exposed to irinotecan-based therapies, which have the best response to progressive disease)

e. Known DLT response to irinotecan

f. Patients known to be homozygous for UGT1A1 *28

g. History of any second malignant disease in the last 3 years; patients with a prior history of orthotopic cancer or basic or squamous cell skin cancer are eligible. If the patient has not had a disease for at least 3 years, the patient with a history of other malignant diseases is eligible.

h. Previously exposed to MM-398

i. Known allergies to any of MM-398 components or other liposome products

j. Parallel disease of relative contraindications for trial participation, such as active heart disease or liver disease

●Severe arterial thromboembolic events (myocardial infarction, unstable angina, stroke) less than 6 months before enrollment

● NYHA class III or IV congestive heart failure, ventricular arrhythmia

k. Active infection or unexplained fever >38.5 °C during the screening visit or on the first day of dosing (dose at the discretion of the investigator, patients with tumor fever may participate), from the perspective of the investigator Can damage patients' participation in trials or influence research results

l. prior chemotherapy administered within 3 weeks or at intervals less than 5 half-lives of the agent, whichever is longer, before the first day of dosing in this study

m. Uncontrolled hypertension (defined as persistent systolic blood pressure >150 mmHg and / or diastolic blood pressure >100 mmHg), or history of hypertensive crisis or hypertensive encephalopathy

n. Have received radiation therapy in the last 14 days

o. Major surgery or traumatic injury in the last 28 days

p. The investigator believes that it is likely to interfere with the patient's ability to sign informed consent, collaborate and participate in the research, or any other medical or social condition that interferes with the interpretation.

q. Pregnancy or breastfeeding; women who are pregnant may have to test pregnancy negative based on a urine or serum pregnancy test. Male and female patients with reproductive potential must agree to use reliable birth control methods for up to 3 months during the study period and after the most recent dose of study drug.

r. Co-op with St. John's Wort

s. Accompanying live attenuated virus vaccines, such as yellow fever vaccines

Study treatment discontinuation

The patient may withdraw or be forced to withdraw from the study at any time and for any reason. One Possible reasons for early withdrawal include (but are not limited to) the following: progressive sexually transmitted diseases. Adverse events that prevent further participation. The occurrence of an intervening medical condition may require the prevention of further involvement in concomitant treatment. Disobeying the agreement. The patient withdrew the consent form. The investigator removed the patient from the trial in the best interests of the patient. The organizer terminated the study. Use prohibited combined medications. Lost tracking.

When the patient discontinues treatment, all procedures and assessments required for the 30-day follow-up visit are completed and the patient's overall survival should continue to be tracked. All patients who discontinue the trial due to an adverse event must be followed until the adverse event subsides or stabilizes.

Treatment period

The treatment phase consists of 5 dose levels. Use the "3+3" design. The patient will be treated until disease progression or unacceptable toxicity occurs. Each dose group started with 3 patients. The DLT evaluation period is during the first period and the second period (28-day period).

The irinotecan dose level 60 or 80 mg/m ² was diluted in 250 ml NaCl 0.9% for 1 hour infusion.

The MM-398 dose level of 90 or 120 mg/m ² was diluted in 5% of 250 ml dextrose and infused for 90 minutes. If there is no acute infusion reaction during the first cycle, the MM-398 infusion time can be reduced to 1 hour from the beginning of the second cycle. Group B, patients with metastatic colorectal cancer, except for irinotecan and MM-398, received an infusion of formazan tetrahydrofolate 400 mg/m ^{2 for} 2 hours, and a 5-fluorouracil 2400 mg/m ^{2 for} 46 hours infusion. And bevacizumab 5mg 30-90 minutes infusion therapy.

Time course and dose modification Specific dose modification for irinotecan/MM-398

The patient discontinued the study treatment if they:

●Experience DLT

● Experience any of the toxicity that has not been resolved to baseline within 14 days of the planned start of the next treatment cycle as defined below

● need to reduce more than one dose

If the patient receives a clinical benefit, the patient who meets the above criteria will continue the study. Once the dose is reduced, it cannot be incremented back to the previous level. If the patient experiences grade 3 (>3 days) or grade 4 therapy-related diarrhea even if the patient is maximally using anti-diarrheal medication, the dose of irinotecan/MM-398 is reduced to one as defined by the subsequent cycles for Phase 1. Lower dose level. If grade 3 (>3 days) or grade 4 diarrhea is recorded even if the maximum use of anti-diarrheal drugs or prophylactic antibiotics is recorded, the dose is reduced and the patient leaves the protocol. Patients with grade 3 or 4 thrombocytopenia receive a subsequent cycle at the next lower dose level. When thrombocytopenia is normalized to level 2 or better, re-treatment with such lower doses begins. Patients with grade 4 neutropenia or febrile neutropenia with >7 days duration receive a subsequent cycle at a lower dose level and receive prophylactic bone marrow growth factor therapy. When the neutropenia is normalized to level 2 or better, re-treatment with such lower doses begins. For non-hematologic toxicity that meets the definition of DLT (other than the definition of their DLTs specifically listed above), subsequent cycles of therapy are administered at a lower dose level.

Management of infusion reaction

Therapeutic modifications for patients with an infusion response to MM-398 follow the procedure outlined in Table 2:

Dosing for 5-fluorouracil (Group B)

Dosing for bevacizumab (Group B)

The dose of bevacizumab will neither decrease nor increase. If significant bevacizumab-related toxicity is present, bevacizumab will be temporarily or definitely suspended. Any grade 3 toxicity attributable to bevacizumab will require treatment with modified or discontinued bevacizumab. If the toxicity is resolved within 4 weeks Level 1, the treatment will start again (on the scheduled date). It is not permitted to reduce the dose of bevacizumab. The missing dose of bevacizumab and combination chemotherapy will not be included. Any patient with any of the following toxicities attributable to bevacizumab should not receive additional bevacizumab: Level 4 toxicity; level 3 toxicity up to level 1 or below 1 is not resolved within 4 weeks Arterial thromboembolic events; gastrointestinal perforation. If certain levels of adverse events are outlined as outlined in the table below, the time course for the study drug administration will be modified.

Concomitant therapy

All concurrent medical conditions and complications of potentially malignant diseases are judged according to acceptable local medical standards. The patient receives an analgesic, an antiemetic, an antibiotic, an antipyretic, and an optional blood product. Although warfarin-type anticoagulant therapy is permitted, careful monitoring of coagulation parameters is essential to avoid any possible complications of drug interaction. All combined medications, including infusions of blood products, are recorded in the form of a suitable case report. Dexamethasone and 5-HT3 blockers (such as ondansetron or granisetron) were administered to all patients as preoperative medication unless contraindicated for individual patients. Antiemetics are specified by clinical indications during the study period. Granule ball community stimulating factor (G-CSF) is recommended for the treatment of patients with neutropenia or neutrophil reduction heat. Prophylactic G-CSF is only approved for at least one episode of grade 3 or 4 neutropenia or neutropenic fever when receiving study therapy, or has been recorded when receiving previous antibiotic therapy Among patients with grade 3 or 4 neutropenia or neutropenic fever. Acute diarrhea and abdominal cramps that occur during the 24-hour period or within 24 hours after MM-398 administration can occur as part of the choline-induced syndrome. The syndrome was treated with atropine. Prophylactic or therapeutic administration of atropine is contemplated for use in patients experiencing choline-induced symptoms during the study, unless clinically contraindicated.

Diarrhea can be debilitating and can be life-threatening in a few occasions. Guidelines for the improvement of chemotherapeus-induced diarrhea by the ASCO group have been published (Benson AB et al. (2004), J. Clin. Oncol. 2004; 22: 2918-2926 and Wadler, S. et al. (1998), J. Clin. Oncol. 1998; 16(9): 3169-3178). The proposed pharmacological method consists of oral administration of loperamide to irinotecan-induced diarrhea at an initial 4-mg dose followed by a 2-mg dose every 2 hours; 2 mg for 5-FU every 4 hours Induced diarrhea. At night, patients can take 4 mg of irinotecan-induced diarrhea every 4 hours. Continue until no diarrhea continues 12 hours. This dose and regimen are suitably effective. No more than 16mg per day.

If loperamide fails to control diarrhea within 24 hours of onset, then octreotide is considered for administration in a dose ranging from 100 micrograms twice daily to 500 micrograms three times daily, with maximum resistance The dose was 2000 micrograms per day for 3 times in a 5 day protocol.

Antibiotics such as cefpodoxime and cefixime are contemplated for use in patients with grade 3 or 4 gastrointestinal (GI) toxicity following irinotecan + MM-398 therapy [42]. Antibiotics were started 5 days before the start of MM-398 therapy only when the patient experienced grade 3 or 4 colitis, dehydration, diarrhea, abdominal pain, weight loss or vomiting during the previous treatment with MM-398. If cefpodoxime or cefixime is not practicable 5 days prior to treatment with MM-398, provide at least 1 full day of cefpodoxime or cefixime before starting the MM-398 course of treatment. It is recommended that the patient be treated throughout ( Drink more water in 21/day.

Excision of the lesion is allowed under the following conditions: the previous assessment of the tumor response is after at least 4 cycles of treatment (2 months).

It is intended to achieve complete surgical resection (R0). After R0 or R1 secondary surgery (complete resection), the patient will be removed from the study. In the case of incomplete resection (R2), the patient remains in the study and should receive treatment based on the treatment assignment.

Prohibited therapy

The following drugs are mentioned in the irinotecan prescription information for interaction with irinotecan: St. John's Wort, CYP3A4-induced anticonvulsants (eg phenytoin, phenobarbital) And carbamazepine, ketoconazole, itraconazole, treleandomycin, erythromycin, diltiazem, verapamil ( Verapamil). Try to avoid treatment with these agents and any other agents that interact with irinotecan.

MM-398

MM-398 is irinotecan (also known as CPT-11) in the form of sucrose octasulfate in the form of irinotecan encapsulated in a nanoliposome drug delivery system. It was supplied as a sterile single use vial containing 9.5 mL of MM-398 at a concentration of 5 mg/mL. The vial contained an excess of 0.5 mL to help extract the amount of label from each 10 mL vial.

The label has the required management instructions. The frequency at which the MM-398 is supplied to the individual centres applies to the participation rate of the centre and takes into account the expiration date of the MM-398. MM-398 is delivered to a hospital pharmacist according to local requirements. When receiving the MM-398, the pharmacist compiled the MM-398 inventory and completed the shipping form. The MM-398 must be stored at a safe limit between 2 and 8 ° C in near-refrigeration and protected from light. No need to be protected from light during infusion. MM-398 should not be frozen. Responsible individuals should check the vial content of the granular material before and after they take the drug from the vial into the syringe. The hospital pharmacist is responsible for the proper storage of MM-398 at the research center. MM-398 must be diluted prior to administration. The diluted solution is physically and chemically stable for 6 hours at room temperature (15-30 ° C), but it is preferably stored at refrigeration temperature (2-8 ° C) and protected from light. The diluted solution cannot be frozen. Since microbial contamination may occur during dilution, it is reasonable to use a diluted solution within 24 hours if refrigerated (2-8 ° C), and within 6 hours if stored at room temperature (15-30 ° C) Use a dilute solution. MM-398 was administered by intravenous (IV) infusion every two weeks at a dose of 60-100 mg/m ² over 90 minutes. Day 1 of the first cycle is a defined day; subsequent doses are administered +/- 2 days on the first day of each cycle. A suitable dose of MM-398 was diluted to a final volume of about 250 mL in a 5% dextrose injection solution (D5W) prior to administration. Be careful not to use an inline filter or any thinner other than D5W. MM-398 is not mixed with other drugs prior to infusion.

The actual dose of MM-398 to be administered is determined by calculating the surface area of the patient at the beginning of each cycle. The +/- 5% deviation of the calculated total dose makes it easy to dose. The MM-398 vial is a single-use vial and the unused portion of the vial cannot be stored for future use. The 90-minute infusion period can be extended due to acute infusion-related reactions or any other clinical need. If there is no acute infusion reaction during the first cycle, the infusion time can be reduced to 1 hour from the second cycle. Prior to MM-398 infusion with standard doses of dexamethasone and 5-HT3 antagonists or other antiemetics, all patients were pre-operatively administered according to standard procedures for irinotecan administration. Atropine can be prophylactically prescribed to patients experiencing acute choline-induced symptoms in previous cycles.

Free irinotecan

Irinotecan HCl is a well-known product and is commercially available as a sterile aqueous solution, see irinotecan HCl (CAMPTOSAR®) US Package Insert. Irinotecan is administered according to standard procedures. For storage conditions, we should follow the standard procedures for this compound. Other drugs should not be added to the infusion solution. Irinotecan is administered every two weeks by intravenous (IV) infusion over a period of 60 minutes at a dose of 90-150 mg/m ² . Patients are advised to receive premedication with an antiemetic agent according to standard institutional procedures. Prophylactic or therapeutic administration of atropine is considered in patients experiencing choline-induced symptoms.

Drug infusion extravasation

If extravasation of the study drug occurs at the infusion site, the following steps should be followed: 1. Suspend IV. 2. Infiltration is handled according to institutional guidelines for infiltration of non-cause agents.

Research assessment

The medical history includes all relevant prior medical conditions, surgery, or other medical procedures. Physical examination includes careful assessment of all body systems, including the skin; central and peripheral nervous systems; eyes, ears, nose and throat; respiratory and cardiovascular systems; abdomen and limbs. Pay particular attention to areas of possible twinning. Signs of life include weight, resting blood pressure, pulse, breathing rate, and temperature. The Eastern cooperative oncology group Performance Score is obtained by asking patients about their functional capabilities. The 12-lead ECG includes a description of heart rate, rhythm, interval duration, and overall impression. Tumor response was evaluated according to the Real Cancer Response Evaluation Criteria (RECIST) version 1.1, and disease progression was established by computed tomography or MRI. In addition, other radiographic or scintigraphic procedures (such as radionuclide bone scans) are performed to assess the location of the neonatal involvement. The same method of assessment was used throughout the study. The investigators selected target and non-target lesions according to the RECIST v1.1 guidelines (Eisenhauer, E.A., et al. (2009), EJC, 45(2), 228-47). Tracking measurements and response confirmation are based on these guidelines. In the case of discontinuation of study treatment for reasons other than progression of the disease, unless the tumor assessment is performed within 4 weeks in advance, the tumor assessment is completed as quickly as possible relative to the date of termination of the study to ensure that no disease progression is present. And to assess the overall disease state. In such patients, this assessment is conducted no later than the date of the 30-day follow-up visit, and future assessments continue every 8 weeks during the tracking period until the target disease progression or new anti-neoplastic therapy begins.

Laboratory procedure

Complete blood counts include white blood cell count (WBC) and hemoglobin, hematocrit, and platelet counts. Serum chemistry includes electrolytes (sodium, potassium, chloride, and bicarbonate), BUN, serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, dehydrogenation of lactate Enzymes, uric acid, total protein, albumin, calcium, magnesium and phosphate. Whole blood and plasma are collected to potentially identify factors that are associated with tumor response and resistance to MM-398. Examples of potential assays include cytokine levels (eg, MCSF1 and IL-6), growth factor markers (eg, IGF1 and EGFR family receptors and ligands), and enzyme levels (eg, MMP9). The UGT1A family polymorphism can also test either or both of the UGT1A1*28 and UGT1A1*6 dual gene states. The tumor marker CEA was analyzed by a local laboratory. The coagulation profile includes partial thromboplastin time and an internationally standardized ratio. Urinalysis includes description of color and clarity; pH; specific gravity; and blood analysis, glucose, ketones, and total protein. If the urine analysis is abnormal, microscopic examination of urine, including WBC, RBC, bacteria, and shedding. Urine or serum pregnancy testing is performed on all women with fertility possibilities. Female patients who are exempt from pregnancy will include those female patients who have undergone bilateral oophorectomy or hysterectomy or menopause (defined as having no menstrual cycle for at least 12 consecutive months). Plasma samples were collected during the first cycle to determine MM-398/Irinotecan, SN-38, and SN-38G (SN-38 glucuronide, a less active metabolite of SN-38, which can be correlated with the UGT1A1 dual gene The level of state change). The SN-38G/SN-38 concentration ratio can be calculated. This ratio can be used to guide the dose adjustment of irinotecan. The PK time points are summarized in the table below. Consider the point in time when the situation exists. Additional analytes that may affect the pharmacokinetics of MM-398, if present, such as lipid-binding proteins, are also measured from such samples for further analysis of elimination rate related problems.

Organizational collection

If clinically appropriate during the first treatment cycle (Day 3), a biopsy (primary tumor or metastatic disease) is performed to isolate the tumor tissue for further analysis of the pharmacodynamics. It is necessary to isolate the tumor material at least three times for further analysis. If the tumor biopsy is not feasible during the first cycle, both the plasma sample and the tumor biopsy can be performed during the second cycle (Day 3). The archived FFPE tumor mass or unstained paraffin section containing tumor tissue prepared at the time of initial diagnosis and at the time of cancer metastasis (if available) was collected from each patient.

Image data collection

CT imaging data was used to evaluate the RECIST v1.1 guidelines. Volume analysis can be performed independently. Image density and CT heterogeneity or other advanced analysis strategies can be assessed as well.

Overall survival / post-study tracking

Overall survival data was collected every 2 months (+/- 1 week) from the date of the 30-day follow-up visit after the patient completed the 30-day follow-up visit. All patients were followed until death or the study was terminated, whichever occurred first.

Adverse event report

Adverse Events Adverse events are any inappropriate medical event in a patient who is administered a medical product and do not necessarily have a causal relationship with the treatment. Adverse events can therefore be any adverse and unintended signs, including being associated with drug use over time, whether or not it is considered an abnormal laboratory finding, symptom or disease associated with the drug. When the efficacy of the study drug is being evaluated, the deterioration of the medical condition is considered an adverse event.

Unexpected Adverse Events Unexpected adverse events are events in which the nature or severity of the incident is inconsistent with applicable product information, such as the Investigator's Brochure.

Major adverse events A major adverse event (SAE) is any adverse medical event at any dose that results in death. Life-threatening (the event that the patient is at risk of death at the time of the event; it does not mean that the event that caused the death if the event becomes more serious). Patients need to be hospitalized or extended for current hospital stay. Lead to persistent or significant disability/inability. For congenital anomalies or birth defects. SAE is also any other important medical event that may not be life-threatening or result in death or hospitalization, but may endanger the patient or may require intervention to prevent one of the other listed results. Examples of such events are intensive treatment of emergency room for allergic bronchospasm; no bloody dyscrasia or convulsions in hospitalization; or drug dependence or drug abuse. The term "serious" is often used to describe the intensity (severity) of an event. The event itself can have a relatively small medical importance (such as a severe headache). This is not the same as "significant", based on patient/event results or operational criteria that are typically associated with events that threaten the life or function of the patient.

Recording Adverse Events Adverse events are reported on the date the patient provides informed consent to participate in the study. Information about the occurrence of adverse events is based on open interviews with patients, physical examinations, and review of laboratory results. All adverse events, whether significant or not, are recorded on the adverse events page of the source and case report forms (except as mentioned below). All new events, as well as events whose intensity or frequency deteriorated relative to baseline, were recorded, which occurred after the first 30 days of administration of the study drug followed by the last dose of study drug. If possible, track down adverse events until they resolve. Adverse events in progress at the time of treatment discontinuation were tracked via a 30-day follow-up assessment. However, new adverse events regarding MM-398 and/or irinotecan must be reported at any time the investigator perceives the event, even if the event is more than 30 days after the last dose of study drug. An adverse event is recorded only if the laboratory, vital signs, or ECG abnormalities are medically relevant: symptomatic, require corrective treatment, result in suspension, and/or meet severity criteria.

Describe the information reported in each adverse event including:

● Medical diagnosis of the event (if the medical diagnosis cannot be determined, a description of each symptom or symptom characterizing the event is recorded)

● Event start date

● Event fade date

● Determination of whether the event is significant or not

●Operation: None; change of study drug administration (eg, temporary discontinuation of dosing); need for drug therapy; need for non-drug therapy; need hospitalization or extended hospitalization (complete major adverse events page); perform diagnostic procedures; patient discontinuation study (Complete the final interview part of the case report form)

●Results: dissipated without sequelae; with sequelae subsided; event subsided; event in progress; patient dying (immediately notify the sponsor and complete the major adverse event page and final visit section of the case report form)

Reporting Serious Adverse Events Any SAE that occurred during the screening period will only be reported if it is in the letter regarding the agreed procedure. Report all fatal or life-threatening adverse events or adverse events of particular concern. Within 24 hours of the event, the Significant Adverse Event Form will be faxed to the appropriate contact, regardless of whether all information about the incident is known or not. If the complete information is unknown, additional tracking is required. The SAE form includes source files for all checks, diagnostic procedures, etc. that have completed the event.

In the case of an accidental or intentional overdose of any study drug, the overdose should be reported immediately (within 1 working day) using the AE and SAE forms, even if there is no symptoms or does not meet the severity criteria. Excessive dose will be defined as 133% of the planned dose.

Determining the severity and relevance of adverse events Each adverse event is graded according to NCI CTCAE Version 4.0 (June 14, 2010 v.4.03 reference document), available at http://evs.nci.nih.gov/ftp1/CTCAE /About.html found. For events not listed in CTCAE, the severity is expressed as mild, moderate, severe or life-threatening or fatal, which corresponds to levels 1, 2, 3, 4 and 5 on NCI CTCAE, respectively, with the following definition: light degree: do not lead to disability or inability to subside, and in the absence of intervention events, moderate: no events leading to disability or incapacity, but it needs the intervention; severe: events leading to temporary disability or incapacity and require the intervention; threatening Life : The event at which the patient is at risk of death at the time of the event; fatal : an event that causes the patient to die.

If an adverse event takes some form of use of the study drug, the investigator will attempt to determine. This relationship is described as follows: It is unlikely that the event is clearly attributable to reasons other than the use of the study drug, such as the pre-existing conditions recorded, the effects of concomitant medication, new conditions, and the pathophysiology and research based on the condition. The pharmacology of the drug will be less likely to be related to the use of the study drug; it may be that the event follows a reasonable chronological sequence from the time the drug is administered, and the event follows a known pattern of response to the study drug, but the event can be interrupted by The medical condition is based on the pathophysiology of the condition and the pharmacology of the study drug, and it is unlikely that the use of the study drug, or the event may be an accompanying drug effect; it is likely that the event is self-administered from the study drug reasonable time following the order, and events follow on study drug known response pattern, and the event could not reasonably be interpreted by intercurrent medical conditions, medical condition or event that is unlikely to be associated with the effects of medication; exact: the event The study drug is administered in a reasonable chronological order, the event follows a known response pattern to the study drug and is based on The study drug pharmacology, events obviously effect of the drug on research; Unknown: Based on the available evidence, a causal relationship can not be blamed.

Statistical considerations

General Statistical Considerations The primary objective of this dose escalation study was to assess the safety and tolerability of MM-398 in combination with free irinotecan, and to determine this for further study when administered to patients with unresectable advanced cancer. The recommended dose (RD) for the combination. Use descriptive statistics for safety, efficacy, and pharmacokinetic parameters. The categorical variables are summarized by frequency distribution (number and percentage of patients) and continuous variables are summarized by descriptive statistics (mean, standard deviation, median, minimum, maximum). All data are summarized by the MM-398/Irinotecan Dosage Group. The study population used for safety and efficacy analysis was defined as participating in the study of all patients receiving at least a partial infusion of MM-398. Replace the patient who left the study prior to receiving the study medication or who withdrew during the first cycle for reasons unrelated to drug toxicity.

Sample size determination

Approximately 5 dosing groups were evaluated. In this scenario, the minimum number of patients treated was 18 (5 group members x 3 + 3 patients) and the maximum number of patients treated was 30 (5 group members x 6 patients). The exact number of patients depends on the observed safety profile, which determines the number of patients per dose level and the number of dose increments required to meet the MTD. Increasing to the next dose group depends on the background toxicity rate (ie, the probability of DLT at a given dose). The proposed dose escalation program provides at least a 90% chance of dose escalation to The dose associated with the 10% DLT probability continues. Table 5 shows the increasing probability of group to group with multiple toxicity rates.

Treatment Assignment and Concealment This is a dose escalation, open label study. Therefore, no randomization or privacy procedures have been performed. Patients in the sequential cohort were treated with each dose of the above described dose escalation protocol.

Statistical Analysis As the patient enters, treats, withdraws, and evaluates efficacy and safety, the patient's treatment is presented by the center and overall according to the dose group containing MM-398. Demographic characteristics of patients were outlined using descriptive statistics from the MM-398 dose group. The tumor response was assessed according to RECIST v1.1. The overall response rate (CR+PR) and the percentage of patients with individual categories of response (ie, CR, PR, SD, and PD) by achieving these criteria were estimated by a possible and overall dose group. The percentage of patients who achieved the clinical benefit of the response (CR+PR+SD), the median duration of response, and the median progression-free survival were shown according to the dose group and overall. The response rate for each treatment group was presented using a binomial distribution using the corresponding 95% CI calculated. Progression free survival and overall survival were estimated using the Kaplan and Meier method.

Analysis of Safety and Adverse Events All patients receiving any of the study medications are included in the final overview and list of safety data. All safety analyses were performed by dose level, treatment cycle, and week, as appropriate. The summary table presents the number of patients with the observed treatment-induced adverse events and the corresponding percentage of the dose group. The denominator used to calculate the percentage of morbidity consisted of patients who received at least one dose of MM-398 in the cohort. Within each summary table, AEs are classified by the MedDRA body system and preferred terms. The additional subcategories are based on the intensity of the event (according to the severity of the CTCAE v4.0 classification) and the relationship with the study drug. The analysis focused on AEs classified as dose-limiting. Death and SAE were tabulated on a per patient basis. The frequency of adverse events is also outlined by body systems and organs. Laboratory data is presented by dose groups and visits. If possible, abnormal laboratory values are assessed according to NCI CTCAE v4.0.

Other Analytical Pharmacokinetic parameters were derived from blood PK samples and analyzed using descriptive statistics, including median, mean, and 95% confidence intervals for parameters estimated by dose level. All PK parameters include _Cmax , _Tmax , AUC (area under concentration curve), elimination rate, volume of distribution under steady state (Vd _ss ), and ultimate elimination half-life. Estimation of pharmacokinetic parameters was performed using standard non-compartmental methods. The Spearman pairwise correlation is calculated between the following measurements: tumor-associated macrophage levels. The tumor is irinotecan. Tumor SN-38 and SN38G levels. Graphs and regressions are used to explore potential relationships in related measurements. In addition, the relationship between pharmacodynamic markers and efficacy responses was evaluated in an exploratory manner. Analysis of pharmacodynamic markers includes all patients with available data.

Endnote

Although the present invention has been described in connection with the specific embodiments thereof, it is understood that the invention is capable of Such deviations from the present invention that occur within the scope of the present invention are known or exemplified in the present invention and are applicable to the basic features set forth above. Each and every US, international or The disclosure of his patents or patent applications or publications is hereby incorporated by reference in its entirety herein.

Claims (62)

A method of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of an anticancer drug, wherein the therapeutically effective amount is by co-administering to the patient a) the first amount of a sustained release injectable dosage form The drug and b) the second amount of the drug is administered as an immediate release injectable dosage form. A sustained release injectable dosage form for use in a first amount for administration with a second amount of the pharmaceutical combination in an immediate release injectable dosage form, wherein the first amount plus the second amount Equal to the therapeutically effective amount of the drug. The method of claim 1 or the sustained release of the injectable dosage form of claim 2, wherein the co-administration is produced in comparison with the first amount and the second amount administered to the matched patient in a combined form An improved therapeutic index, an improved pharmacokinetic profile, or a therapeutic synergy wherein the combined amount is in the sustained release injectable dosage form. The method of claim 1 or the sustained release of the injectable dosage form according to claim 2, wherein the sustained release and immediate release dosage forms are both contained in a single formulation, and thereby injected together, and wherein the second amount is At least 10% of the first amount. The method of claim 1 or the sustained release of the injectable dosage form according to claim 2, wherein the sustained release and immediate release dosage form of the drug is contained in a separate formulation, and mixed and simultaneously injected together, or separately Injection, the separate injections are performed simultaneously or sequentially. The method of claim 5, wherein the sequential submissions do not overlap, and thereby the period of simultaneous administration is not included. A method of treating cancer in a patient, the method comprising co-administering to the patient a liposomal irinotecan and free irinotecan, wherein the co-administration is performed in at least one cycle, wherein the cycle is 2 weeks Period of time, and wherein for each cycle: (a) liposome irinotecan is administered once at a dose of 60 or 80 mg/m ² ; and (b) free irinotecan is administered once at a dose of 90 or 120 mg/m ² . The method of claim 7, wherein the cancer is an unresectable cancer. The method of claim 7 or 8, wherein the cancer is colorectal cancer. The method of any one of claims 7 to 9, further comprising co-administering methotrexate and 5-fluorouracil to the patient once in each cycle. The method of claim 10, wherein for each cycle: (c) formazan tetrahydrofolate is administered at a dose of 400 mg/m ² ; (d) 5-fluorouracil is administered at a dose of 2400 mg/m ² . The method of any one of claims 7 to 11, further comprising administering to the patient bevacizumab. The method of claim 12, wherein the bevacizumab is administered once per cycle at a dose of 5 mg/kg or 10 mg/kg by infusion. The method of any one of claims 7 to 13, wherein the cancer is metastatic colorectal cancer. The method of any one of claims 12 to 14, wherein bevacizumab is administered intravenously over 30 to 90 minutes. The method of any one of claims 10 to 15, wherein the 5-fluorouracil is administered intravenously over a period of 46 hours. The method of any one of claims 10 to 16, wherein the formazan tetrahydrofolate is administered intravenously over 2 hours. A method of treating unresectable advanced colorectal cancer in a patient, the method comprising co-administering to the patient a liposomal irinotecan and free irinotecan, wherein the method comprises at least one cycle, wherein The period is a period of 2 weeks, and each of the cycles is once: (a) the liposome irinotecan is administered at a dose of 60 or 80 mg/m ² ; (b) the free irinotecan is 90 or 120 mg/m ² The dose is administered. The method of claim 18, wherein the method further comprises co-administering to the patient a each of formazan tetrahydrofolate and 5-fluorouracil, wherein each cycle is once: (c) formazan tetrahydrofolate at 400 mg/m A dose of ² was administered; (d) 5-fluorouracil was administered at a dose of 2400 mg/m ² . The method of claim 19, wherein the method further comprises co-administering bevacizumab to the patient, wherein each cycle is performed once: (e) bevacizumab is administered at a dose of 5 mg/kg. The method of any one of the preceding claims, wherein the liposome irinotecan is administered intravenously over 90 minutes, and the free irinotecan is administered intravenously over 60 minutes, as appropriate, in each cycle The free irinotecan was administered prior to the liposome irinotecan. The method of any one of claims 7 to 21, wherein the free irinotecan and the liposome irinotecan are administered prior to the 5-fluorouracil in each cycle. The method of any one of claims 7 to 22, wherein the formazan tetrahydrofolic acid is administered prior to administration of the 5-fluorouracil in each cycle. The method of any one of claims 7 to 23, wherein the liposomal irinotecan and the free irinotecan are administered prior to the formazan tetrahydrofolate and the 5-fluorouracil in each cycle. The method according to any one of the preceding claims, wherein, in each cycle, the liposome irinotecan is an irinotecan sulpholipid liposome injection (irinotecan liposome injection MM-398). A formulation of liposomal irinotecan for co-administered with free irinotecan, bevacizumab, formamidinetetrahydrofolate and 5-fluorouracil in at least one cycle, wherein the period is 2 weeks And wherein, in each cycle: (a) the liposome irinotecan is administered at a dose of 60 or 80 mg/m ² ; (b) the free irinotecan is administered at a dose of 90 or 120 mg/m ² ; c) formazan tetrahydrofolate was administered at a dose of 400 mg/m ² ; (d) 5-fluorouracil was administered at a dose of 2400 mg/m ² ; and (e) bevacizumab was administered at a dose of 5 mg/kg. A formulation of liposomal irinotecan for co-administered with free irinotecan in at least one cycle, wherein the period is a period of 2 weeks, and wherein, in each cycle: (a) liposome Irinotecan is administered at a dose of 60 or 80 mg/m ² ; (b) free irinotecan is administered at a dose of 90 or 120 mg/m ² . The formulation of claim 19 or 20, wherein the liposome irinotecan is administered intravenously over 60 minutes or 90 minutes. The formulation of any one of claims 26 to 28, wherein the free irinotecan is administered intravenously over 60 minutes. The formulation of any one of claims 26 or 28 to 30, wherein the bevacizumab is administered intravenously over 30 to 90 minutes. The formulation of any one of claims 26 or 28 to 30, wherein the 5-fluorouracil is administered intravenously over a period of 46 hours. The formulation of any one of claims 26 or 28 to 31, wherein the formazan tetrahydrofolate is administered intravenously over 2 hours. The formulation of any one of claims 26 to 31, wherein the irinotecan liposome formulation is irinotecan sulpholipid liposome injection (MM-398). A kit for treating cancer in a human patient, the kit comprising a first container containing a second container and a third container and, optionally, instructions, the second container comprising a dose of liposomal irinotecan, The third container contains a dose of free irinotecan, and the instructions require that the liposome irinotecan and the free irinotecan be co-administered to a cancer patient. The method, medicament or formulation of any one of claims 1 to 2 or 4 to 34, wherein the co-administration results in an improved therapeutic index, or improved pharmacokinetics, or therapeutic synergy. A method of improving the pharmacokinetic profile of a drug treatment comprising enteral or parenteral for one or more days, or one week, or two weeks, or three weeks, or one month or more The dose-separated dose is administered in an unencapsulated form, and the same drug is co-administered in a liposomal encapsulated injectable form at the same interval, such that the pharmacokinetic profile is improved, because The drug achieves a therapeutic level at the site of action faster than when administered only in the encapsulated form, and maintains a longer therapeutic level at the site of action than when administered only at the same interval in the unencapsulated form . The method of claim 36, wherein the unencapsulated drug and the liposomal encapsulated drug are administered sequentially or simultaneously. The method of claim 37, wherein the drug is an anticancer drug selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor, a taxane, a vinca alkaloid, a platinum salt, An alkylating agent or antimetabolite. The method of claim 38, wherein the topoisomerase I inhibitor is irinotecan, SN-38 or topotecan, and the topoisomerase II inhibitor is anthracycline (anthracycline) ), teniposide or etoposide, the taxane is paclitaxel, docetaxel, cabazitaxel or tesetaxel The vinca alkaloid is vincristine, vinblastine or vinorelbine, and the platinum salt is oxaliplatin, cisplatin or carboplatin, the alkylating agent Bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, ifosfamide, lovastatin Lomustine, mechlorethamine, melphalan (melphalan), streptozocin, thiotepa or uramustine, and the antimetabolite is 5-FU, capecitabine, cytarabine ( Cytarabine), gemcitabine, methotrexate, pemetrexed or tegafur. The method of claim 39, wherein the anthracycline is doxorubicin, daunorubicin, bleomycin, dactinomycin, epirubicin ( Epirubicin), idarubicin, mitomycin or mitoxantrone. The method of any one of claims 36 to 40, wherein the interval is two weeks. The method of any one of claims 36 to 41, wherein the co-administering the drug in an unencapsulated form and the same drug in a liposome encapsulated form produces an improved therapeutic index, or improved pharmacokinetics, Or therapeutic synergy. A method of treating cancer in a patient, the method comprising co-administering at least one cycle with 1) a chemotherapeutic agent as a sustained release dosage form and 2) the same chemotherapeutic agent as an immediate release dosage form, wherein the co-administration of the two dosage forms Provide an improved therapeutic index, or improved pharmacokinetics, or therapeutic synergy. The method of claim 43, wherein the two dosage forms are each contained within a single formulation and are thereby injected together. The method of claim 43, wherein the two dosage forms of the chemotherapeutic agent are contained in separate formulations, and are mixed and injected simultaneously, or separately, and the separate injections are performed simultaneously or sequentially. The method of claim 45, wherein the sequential voting does not overlap, and thereby does not include a time period of simultaneous administration. The method of any one of claims 39 to 46, wherein the chemotherapeutic agent is an alkylating agent, an antimetabolite, an anti-microtubule agent, a topoisomerase inhibitor or a cytotoxic antibiotic Prime. The method of claim 47, wherein the alkylating agent is nitrogen mustard gas, nitrosourea, tetrazine, aziridine, organoplatinum, procarbazine or hexamethylmelamine. The method of claim 47, wherein the antimetabolite is an antifolate, a fluoropyrimidine, a deoxynucleoside analog or a thiopurine. The method of claim 47, wherein the anti-microtubule agent is a taxane, a vinca alkaloid or a vinca alkaloid derivative. The method of claim 47, wherein the topoisomerase inhibitor is a camptothecin topoisomerase I inhibitor or a topoisomerase II inhibitor. The method of claim 54, wherein the camptothecin topoisomerase I inhibitor is topotecan or irinotecan. The method of claim 52, wherein the camptothecin topoisomerase I inhibitor is irinotecan, and the sustained release dosage form is in the form of a liposome, a hyaluronate or a PEGylated form, and the immediate release dosage form is It is in the form of irinotecan hydrochloride solution or an analogue or derivative thereof. The method of claim 53, wherein the sustained release dosage form is a liposome irinotecan thioglycolate, and for each cycle of co-administration: (a) the liposome irinotecan sulphanate is at 60 and 100 mg/m A dose range between ² is administered; and (b) the irinotecan hydrochloride is administered at a dose ranging between 90 and 180 mg/m ² . The method of claim 54, comprising at least a second period, wherein the intervals of the periods are two weeks. The method of claim 54, further comprising co-administering each of an effective amount of formazan tetrahydrofolate (aldehyde folate) and 5-fluorouracil. The method of claim 47, further comprising co-administering each of an effective amount of methotrexate and 5-fluorouracil. The method of claim 57, wherein the formazan tetrahydrofolate is administered at a dose of 400 mg/m ² in a co-administered cycle, and the 5-fluorouracil is administered at a dose of 2400 mg/m ² . The method of any one of claims 36 to 58 further comprising co-administering to the patient an effective amount of an anti-angiogenic agent. The method of claim 59, wherein the anti-angiogenic agent is bevacizumab. The method of claim 60, wherein the bevacizumab is administered at a dose of 5 mg/kg every 2 weeks or 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. The method of claim 38, wherein the topoisomerase I inhibitor is irinotecan, and the liposomal encapsulated irinotecan is irinotecan sulpholipid liposome injection (MM-398).