WO2017172678A1 - Méthodes de traitement du cancer à l'aide de polythérapies comprenant une préparation d'anticorps anti-egfr oligoclonal et de l'irinotécan lipsomal - Google Patents

Méthodes de traitement du cancer à l'aide de polythérapies comprenant une préparation d'anticorps anti-egfr oligoclonal et de l'irinotécan lipsomal Download PDF

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WO2017172678A1
WO2017172678A1 PCT/US2017/024410 US2017024410W WO2017172678A1 WO 2017172678 A1 WO2017172678 A1 WO 2017172678A1 US 2017024410 W US2017024410 W US 2017024410W WO 2017172678 A1 WO2017172678 A1 WO 2017172678A1
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single administration
irinotecan
patient
colorectal cancer
leucovorin
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PCT/US2017/024410
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Jonathan Basil Fitzgerald
Jeffrey D. KEARNS
Helen Lee
Rachel C. NERING
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Merrimack Pharmaceuticals, Inc.
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    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
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    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the specification relates to the treatment of cancer with a combination of an EGFR inhibitor, liposomal irinotecan, leucovorin and 5-fluorouracil, including the treatment of colorectal cancer.
  • CRC Colorectal Cancer
  • Approved agents include 5-FU, irinotecan, oxaliplatin, capecitabine, bevacizumab, aflibercept, cetuximab, panitumumab, regorafenib, and trifluridine / tipiracil hydrochloride.
  • Optimum sequencing and/or combinations of these therapies has not been clearly defined, but aggressive therapy improves overall survival.
  • FOLFOX based chemotherapy is a standard first line option in these patients within the United States.
  • Combination therapies including folinic acid (leucovorin or levoleucovorin), 5- fluorouracil, and irinotecan (FOLFIRI), folinic acid, 5-fluorouracil, innotecan and oxaliplatin (FOLFIRINOX), or a combination of folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) are also used to treat some cancers.
  • Bevacizumab, cetuximab and panitumumab are frequently combined with these regimens depending on patient presentation, biomarker status and physician preference.
  • Irinotecan is 7-ethyl-10-[4-(l-piperidino)-l-piperidino]
  • Irinotecan is a member of the topoisomerase I inhibitor class of drugs and is a semi-synthetic and water soluble analog of the naturally-occurring alkaloid, camptothecin.
  • irinotecan is currently marketed formulated as an aqueous solution as Camptosar ® (irinotecan hydrochloride injection).
  • Topoisomerase I inhibitors such as irinotecan work to anest uncontrolled cell growth by inhibiting the unwinding of DNA and thereby preventing DNA replication.
  • Irinotecan is a prodrug that is converted by nonspecific carboxylesterases into a 100-1000 fold more active metabolite, SN-38.
  • SN-38 is not recognized by P-glycoprotein, a drug transporter that plays an important role in acquired drug resistance by pumping certain drugs out of cells, so irinotecan is likely to be active in tumors resistant to other standard chemotherapies.
  • SN-38 is cleared via glucuronidation, for which major pharmacogenetic variability has been described, and biliary excretion.
  • Irinotecan hydrochloride injection is approved in the United States for treatment of metastatic colon or renal cancer and is also used to treat colorectal, gastric, lung, uterine cervical and ovarian cancers.
  • EGFR signaling is important for the proliferation and survival of many epithelial malignancies affecting humans. Although EGFR-targeting antibodies have been approved for use in human malignancies that appear to be driven by EGFR, there still remains a high unmet need in these tumors, as limited efficacy is attributable to de novo or acquired resistance mechanisms to these targeted therapies.
  • One reason for this state of affairs might stem from observations that EGFR signaling is very robust due to amplification of cell signaling downstream of the receptor, thus making the need for complete inhibition of the pathway imperative for potential success in the clinic.
  • EGFR signaling is further complicated by the presence in tumors of multiple ligands that bind to EGFR with either high or low affinity and result in activation of the pathway downstream of EGFR.
  • Certain anti-EGFR monoclonal antibodies have demonstrated a lack of efficacy in patients with mCRC containing KRAS mutations, based on retrospective analyses. In these trials, patients received standard of care (i.e., BSC or chemotherapy) and were randomized to receive either an anti-EGFR antibody (cetuximab or panitumumab) or no additional therapy. In all studies, investigational tests were used to detect KRAS mutations in codon 12 or 13. The percentage of study populations for which KRAS status was assessed ranged from 23% to 92%. In CRC tumor cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears independent of EGFR regulation.
  • a patient i.e., a human patient
  • liposomal irinotecan e.g., irinotecan sucrose octasulfate salt liposome injection, also referred to as MM-398, nal-IRI, or ONIVYDE
  • 5-FU 5-fluorouracil
  • leucovorin an EGFR inhibitor
  • Compositions adapted for use in such methods are also provided.
  • a combination of the EGFR inhibitor MM- 151, MM-398 liposomal irinotecan, 5-fluorouracil and leucovorin can be used to treat metastatic colorectal cancer (mCRC).
  • irinotecan can be combined with EGFR inhibitors to treat RAS wild type tumors.
  • Nal-IRI also disclosed as MM-398 or ONIVYDE ® ) is a
  • nanoliposomal formulation of irinotecan improves the pharmacokinetics of irinotecan and results in a lower C ma x, longer half-life, and higher levels of irinotecan and SN-38 in tumor tissue compared with standard irinotecan.
  • Nal-IRI is approved by the FDA under the brand name ONIVYDE, in combination with 5-FU and leucovorin in gemcitabine refractory pancreatic adenocarcinoma.
  • nal-IRI + 5-FU + LV as a 2nd line therapy in mCRC
  • cetuximab and irinotecan represent established treatments, in a combination regimen or in combination with 5-FU/leucovorin (comprising the FOLFIRI regimen)
  • the present disclosure provides methods of treating colorectal cancer by administering both MM- 151 (a next-generation EGFR antibody) and ONIVYDE (also called MM-398 or nal-IRI) in combination with 5-FU and leucovorin.
  • a therapeutically effective combination of the anti-EGFR therapy MM-151 can be administered in combination with liposomal irinotecan, 5- fluorouracil and leucovorin for the treatment of patients diagnosed as having colorectal cancer (CRC), including patients diagnosed as having metastatic CRC (mCRC), containing KRAS mutations.
  • CRC colorectal cancer
  • mCRC metastatic CRC
  • the CRC can be mCRC with tumor cells containing RAS mutations.
  • the patient can be diagnosed with mCRC that harbors somatic mutations in exon 2 (codons 12 or 13), exon 3 (codons 59 and 61) and/or exon 4 (codons 117 and 146) of either KRAS or NRAS.
  • the patient can be diagnosed with mCRC that harbors a BRAF mutation.
  • the BRAF mutation could be the BRAF V600E mutation.
  • the BRAF mutation is a somatic mutation in one or more of codons 464, 466, 469, 595, 596, and 601.
  • the patient can be diagnosed with mCRC that harbors an EGFR mutation.
  • the EGFR mutation can be a somatic mutation in one or more codons of exon 12.
  • the patient can be diagnosed with mCRC that harbors a somatic mutation in the region coding for the catalytic subunit of PI3K, PIK3CA.
  • the PIK3CA mutation is mutation in one or more of codons 542, 545, and 1047. a m
  • MM-151 is a combination of three fully human IgGl monoclonal antibodies. MM- 151 antagonizes high-affinity EGFR ligands more effectively than approved inhibitors, including cetuximab and panitumumab, and has been observed to elicit a greater decrease in signal amplification. MM-151 has been evaluated in a phase I study of solid tumors and demonstrated a safety profile that was comparable to other EGFR inhibitors. The
  • R2D recommended phase II dose identified in the MM-151 monotherapy phase I study was 10.5 mg/kg QW and this is the starting dose for MM-151 in this study.
  • MM-151 was combined with nal-IRI in a xenograft experiment with the LoVo colorectal cancer cell line. The data showed that this combination enhances anti-tumor activity as compared to either therapy alone.
  • MM-151 was combined with nal-IRI and 5-FU in a xenograft experiment with the LFM1215 colorectal cancer cell line. The data showed that this combination enhances anti-tumor activity as compared to the combination of cetuximab, irinotecan (at equivalent SN-38 exposure), and 5-FU.
  • a method for treatment (e.g. effective treatment) of colorectal cancer in a patient comprising intravenously administering to a human patient in need thereof a single administration of 6.0, 7.5, 9.0 or 10.5 mg/kg of MM-151 once per week, following an initial priming dose of 225 mg MM-151 in week 1 and a second priming dose of 450 mg of MM-151 in week 2; and a single administration once every two weeks of: a single administration of 70 mg/m 2 irinotecan (free base) encapsulated in a MM-398 irinotecan liposome over 90 minutes, a single administration of 200 mg/m 2 of the (1) form of leucovorin, and a single administration of 2400 mg/m 2 of 5-fluorouracil over 46 hours, to treat the colorectal cancer in the patient.
  • a method for treatment of colorectal cancer in a patient comprising co-administering to the patient an effective amount each of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin, wherein the method comprises at least one cycle of administration, wherein the cycle is a period of 2 weeks, and wherein for each cycle (in any order of administration, unless otherwise indicated):
  • leucovorin administered once every two weeks at a dose of 200 mg/m 2 (/ form, or levo-leucovorin) or 400 mg/m 2 (/ + d racemic form) in combination with the MM-398 irinotecan liposome and the 5-FU.
  • Figure 1 is a graph showing the anti-tumor activity of MM-398 in an orthotopic pancreatic tumor model expressing luciferase (L3.6pl).
  • Figure 2 is a graph showing accumulation of SN-38 in tumors following treatment with free irinotecan or liposomal irinotecan (MM-398).
  • Figure 3 is a graph showing the effect of MM-398 on Carbonic Anhydrase IX Staining in a HT29 Xenograft Model.
  • Figure 4 shows the effect of MM-398 on perfusion of small molecule Hoechst stain.
  • Figure 5 summarizes the pharmacokinetics of MM-398 in q3w (irinotecan, liposome + free drug).
  • Figure 6 summarizes the pharmacokinetics of MM-398 in q3w (SN-38).
  • Figure 7 summarizes the pharmacokinetic parameters of individual MM-151 monoclonal antibodies in patients treated with MM-151 monotherapy.
  • Figure 8A shows the simulated serum concentrations of MM-151 in patients administered with two priming doses of MM-151 followed by 10.5 mg/kg qlw dosing schedule.
  • Figure 8B is a graph showing the effect of weekly MM-151 dose intensity on the probability to experience rash event in patients treated with MM-151. Top: any grade rash; Bottom: grade 3 or higher. Error bars indicate standard errors of the mean.
  • Figure 9 shows the mean plasma concentrations of total irinotecan and SN-38 following the administration of either nal-IRI (100 mg/mg 2 ) based on the amount of irinotecan trihydrate hydrochloride) or irinotecan HC1 (300 mg/m 2 ) in study PEP0206.
  • Figure 10 is a graph showing model predictions of tumor and plasma drug metabolites (CPT- 11 and SN-38) in patients treated with nal-IRI.
  • Figures 11A and 11B show levels of CPT-11 and SN-38, respectively, measured in patient tumor biopsies and plasma samples.
  • Figure 12 is a schematic of a clinical treatment program.
  • Figure 13 is a schematic of a clinical treatment program.
  • Figure 14 is a sequence listing for the P1X antibody component of MM-151.
  • Figure 15 is a sequence listing for the P2X antibody component of MM-151.
  • Figure 16 is a sequence listing for the P3X antibody component of MM-151.
  • Figure 17 is a cartoon schematic that shows the MM-151 oligoclonal design with the three component IgGl antibodies— P1X, P2X, and P3X— bound to the EGFR extracellular domains (marked with Roman numerals I, II, III, and IV).
  • P1X and P3X have binding epitopes on EGFR extracellular domain III while P2X has a binding epitope on EGFR extracellular domain I.
  • Figure 18 is a graph showing the results of a ligand antagonism cell binding assay, demonstrating the EGF ligand blocking ability of P1X (dark gray triangle), P2X (black square) or P3X (light gray circle) alone at low doses as compared to EGF ligand alone (black diamond).
  • Figure 19 is a graph showing the results of a phospho-EGFR (pEGFR) inhibition experiment, demonstrating pEGFR inhibition by single-agent treatment with P1X (dark gray triangle), P2X (black square) or P3X (light gray circle) antibody at the indicated doses.
  • Figure 20 demonstrates improved activity of nal-IRI + MM-151 TC combination compared to the two agents alone in LoVo subcutaneous CRC xenograft model.
  • Figure 21 shows the anti-tumor activity of nal-IRI (5 mg/kg) compared to irinotecan (25 mg/kg) at similar SN-38 tumor exposure in a LIM1215 subcutaneous CRC xenograft model.
  • Figure 22 shows the effects of irinotecan+5-FU+cetuximab and nal-IRI+5-FU+MM-151 TC combinations in LIM1215 subcutaneous CRC xenografts.
  • Doses of 5-FU, cetuximab, and MM-151 TC were kept constant, (Figure 22 A) low doses of nal-IRI (1.25 mg/kg) and irinotecan (6.25 mg/kg) and (Figure 22B) high doses of nal-IRI (5 mg/kg) and irinotecan (25 mg/kg) were utilized for comparison at which tumor SN-38 were comparable at these dose levels.
  • Figure 23 provides the amino acid sequences of the Complementarity Determining Regions (CDRs) of an antibody used in Example 8.
  • Figure 24 is a diagram showing detectable pretreatment somatic mutations within the CRC patient subset.
  • Figure 25 is a summary of the 24 colorectal cancer patients discussed in Example 17 and discloses the treatment regimens each patient received.
  • Figure 26 is a table detailing the patient treatment parameters, the duration of treatment, the best overall response, duration of treatment and mutation status (wild type, "WT” or mutant, "MT") for 24 of 29 patients within the CRC efficacy cohort who were evaluated for RECIST response in the clinical trial described in Example 16
  • the term "subject” or "patient” is a human cancer patient.
  • effective treatment refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder.
  • a beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method.
  • a beneficial effect can also take the form of arresting, slowing, retarding, or stabilizing of a deleterious progression of a marker of a cancer.
  • Effective treatment may refer to alleviation of at least one symptom of a cancer.
  • Such effective treatment may, e.g., reduce patient pain, reduce the size and/or number of lesions, may reduce or prevent metastasis of a cancer tumor, and/or may slow growth of a cancer tumor.
  • an effective amount refers to an amount of an agent that provides the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to delay tumor development.
  • an effective amount is an amount sufficient to prevent or delay tumor recurrence.
  • An effective amount can be administered in one or more administrations.
  • the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and may stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and may stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • “concurrent administration” include simultaneous administration of at least two therapeutic agents to a patient or their sequential administration within a time period during which the first administered therapeutic agent is still present in the patient when the second administered therapeutic agent is administered.
  • the term “monotherapy” refers to administering a single drug to treat a disease or disorder in the absence of co-administration of any other therapeutic agent that is being administered to treat the same disease or disorder.
  • Dosage refers to parameters for administering a drug in defined quantities per unit time (e.g., per hour, per day, per week, per month, etc.) to a patient. Such parameters include, e.g., the size of each dose. Such parameters also include the configuration of each dose, which may be administered as one or more units, e.g., taken at a single administration, e.g., orally (e.g., as one, two, three or more pills, capsules, etc.) or injected (e.g., as a bolus). Dosage sizes may also relate to doses that are administered continuously (e.g., as an intravenous infusion over a period of minutes or hours). Such parameters further include frequency of administration of separate doses, which frequency may change over time.
  • Dose refers to an amount of a drug given in a single administration.
  • cancer refers to a condition characterized by abnormal, unregulated, malignant cell growth.
  • the cancer is colorectal cancer.
  • resistant and refractory refer to tumor cells that survive treatment with a therapeutic agent. Such cells may have responded to a therapeutic agent initially, but subsequently exhibited a reduction of responsiveness during treatment, or did not exhibit an adequate response to the therapeutic agent in that the cells continued to proliferate in the course of treatment with the agent.
  • Nal-IRI can be administered by IV infusion over 90 minutes ( ⁇ 10 minutes) every two weeks at a dose of 70 mg/m 2 (free base), on Days 1 and 15 of each 28-day cycle.
  • the first cycle Day 1 is a fixed day; subsequent doses should be administered on the first day of each cycle +/- 2 days.
  • the appropriate dose of nal-IRI must be diluted in 5% Dextrose Injection solution (D5W) or normal saline to a final volume of 500 mL. Care should be taken not to use in-line filters or any diluents other than D5W or normal saline.
  • Nal-IRI can be administered at a rate of up to 1 mL/sec (30 mg/sec).
  • nal-IRI dose of nal-IRI to be administered will be determined by calculating the patient's body surface area at the beginning of each cycle. A +/- 5% variance in the calculated total dose will be allowed for ease of dose administration. Since nal-IRI vials are single use vials, site staff must not store any unused portion of a vial for future use and they must discard unused portions of the product.
  • All patients can be pre-medicated prior to nal-IRI infusion and 5-FU/LV infusion with standard doses of dexamethasone and a 5-HT3 antagonist, or equivalent other anti-emetics according to standard institutional practices for irinotecan and 5-FU administration.
  • Atropine may be prescribed prophylactically, according to standard institutional practices, for patients who experienced acute cholinergic symptoms in the previous cycles.
  • irinotecan is administered in a stable liposomal formulation as irinotecan sucrose sulfate liposome injection (otherwise termed “irinotecan sucrose octasulfate salt liposome injection” or “irinotecan sucrosofate liposome injection”), the formulation referred to herein as "MM-398” (also known as PEP02, see US 8,147,867).
  • MM-398 may be provided as a sterile, injectable parenteral liquid for intravenous injection. The required amount of MM-398 may be diluted, e.g., in 500mL of 5% dextrose injection USP and infused over a 90 minute period.
  • An MM-398 liposome is a unilamellar lipid bilayer vesicle of approximately 80-140 nm in diameter that encapsulates an aqueous space which contains irinotecan complexed in a gelated or precipitated state as a salt with sucrose octasulfate.
  • the lipid membrane of the liposome is composed of phosphatidylcholine, cholesterol, and a polyethyleneglycol- derivatized phosphatidyl-ethanolamine in the amount of approximately one
  • PEG polyethyleneglycol
  • This stable liposomal formulation of irinotecan has several attributes that may provide an improved therapeutic index.
  • the controlled and sustained release improves activity of this schedule-dependent drug by increasing duration of exposure of tumor tissue to drug, an attribute that allows it to be present in a higher proportion of cells during the S-phase of the cell cycle, when DNA unwinding is required as a preliminary step in the DNA replication process.
  • the long circulating pharmacokinetics and high intravascular drug retention in the liposomes can promote an enhanced permeability and retention (EPR) effect.
  • EPR allows for deposition of the liposomes at sites, such as malignant tumors, where the normal integrity of the vasculature (capillaries in particular) is compromised resulting in leakage out of the capillary lumen of particulates such as liposomes.
  • EPR may thus promote site-specific drug delivery of liposomes to solid tumors.
  • EPR of MM-398 may result in a subsequent depot effect, where liposomes accumulate in tumor associated macrophages (TAMs), which metabolize irinotecan, converting it locally to the substantially more cytotoxic SN-38. This local bioactivation is believed to result in reduced drug exposure at potential sites of toxicity and increased exposure at cancer cells within the tumor.
  • TAMs tumor associated macrophages
  • Nal-IRI comprises irinotecan encapsulated in a nanoliposome drug delivery system (nanoliposomal irinotecan; nal-IRI).
  • the active ingredient of the nal-IRI injection, irinotecan is a member of the topoisomerase I inhibitor class of drugs and is a semi-synthetic and water soluble analog of the naturally-occurring alkaloid, camptothecin.
  • Topoisomerase I inhibitors work to arrest uncontrolled cell growth by preventing the unwinding of DNA and therefore preventing replication.
  • the pharmacology of irinotecan is complex, with extensive metabolic conversions involved in the activation, inactivation, and elimination of the drug.
  • Irinotecan is a pro-drug that is converted by nonspecific carboxylesterases into a 100-1000 fold more active metabolite, SN-38. SN-38 is cleared via glucuronidation, (for which major
  • Drug carrier technologies represent a rational strategy to improve the pharmacokinetics and biodistribution of irinotecan while protecting it from premature metabolism.
  • Nal-IRI employs a novel intraliposomal drug stabilization technology for encapsulation of irinotecan into long-circulating liposome-based nanoparticles with high drug load and high in vivo stability.
  • the stable nanoliposome formulation of irinotecan has several attributes that may provide an improved therapeutic index.
  • the controlled and sustained release should improve activity of this schedule-dependent drug by increasing duration of exposure of tumor tissue to drug, an attribute that allows it to be present in a higher proportion of cells during the more sensitive S-phase of the cell cycle.
  • the improved pharmacokinetics, high intravascular drug retention in the liposomes, and enhanced permeability and retention (EPR) effect may result in site-specific drug delivery to solid tumors.
  • Stromal targeting results from the subsequent depot effect, where liposomes accumulating in tumor associated macrophages (TAMs) release the active drug and convert it locally to the substantially more cytotoxic SN-38.
  • TAMs tumor associated macrophages
  • the preferentially local bioactivation should result in reduced exposure to potential sites of toxicity and increased exposure to neighboring cancer cells within the tumor.
  • the enzyme produced by the UGT1 Al gene, UDP-glucuronosyltransferase 1, is responsible for bilirubin metabolism and also mediates SN-38 glucuronidation, which is the initial step in the predominant metabolic clearance pathway of this active metabolite of irinotecan. Besides its anti -tumor activity, SN-38 is also responsible for the severe toxicity sometimes associated with irinotecan therapy. Therefore, the glucuronidation of SN-38 to the inactive form, SN-38 glucuronide, is an important step in the modulation of irinotecan toxicity.
  • the metabolic transformation of MM-398 to SN-38 includes two critical steps: (1) the release of irinotecan from the liposome and (2) the conversion of free irinotecan to SN-38. While not intending to be limited by theory, it is believed that once irinotecan leaves the liposomes, it is catabolized by the same metabolic pathways as conventional (free) irinotecan. Therefore the genetic polymorphisms in humans predictive for the toxicity and efficacy of irinotecan and those of MM-398 can be considered similar.
  • the deficient genetic polymorphisms may show more association with severe adverse events and/or efficacy.
  • UGT1A1 *28 allele is relatively common in Caucasians (estimates 10%)), the prevalence is varied in other ethnic groups. Furthermore, additional UGT1A1 genotypes are found with higher prevalence for example in Asian populations and these could be important for the metabolism of irinotecan in these populations. For example, the UGT1 Al *6 allele is more prevalent in Asians. This allele is not associated with a ta repeat, but with a Gly71 Arg mutation that reduces enzyme activity. In previous and ongoing studies of MM-398, pharmacogenetic information has been collected on patients being enrolled.
  • 5-FU can be administered at a dose of 2400 mg/m 2 as an IV infusion over 46-48 hours on Days 1 and 15 of each 28-day cycle.
  • 5-FU should be reconstituted per the instructions on the package insert, SmPC or standard institutional guidelines for reconstitution of leucovorin.
  • 5-FU can be administered after leucovorin and last in the treatment regimen. Actual dose of 5-FU and leucovorin to be administered will be determined by calculating the patient's body surface area prior to each cycle. A +/- 5% variance in the calculated total dose will be allowed for ease of dose administration.
  • Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea, anorexia, nausea, emesis and leukopenia are commonly seen with treatment;
  • alopecia and dermatitis in the form of pruritic rash usually appearing on the extremities, may also be seen (see US package insert or SmPC).
  • 5-Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid
  • the deoxyribonucleotide of the drug inhibits thymidylate synthetase, thus inhibiting the formation of thymidylic acid from deoxyuridylic acid, thus interfering in the synthesis of DNA. It also interferes with RNA synthesis.
  • Leucovorin also called folinic acid
  • Leucovorin acts as a biochemical cofactor for 1 -carbon transfer reactions in the synthesis of purines and pyrimidines.
  • Leucovorin does not require the enzyme dihydrofolate reductase (DHFR) for conversion to tetrahydrofolic acid.
  • DHFR dihydrofolate reductase
  • the effects of methotrexate and other DHFR-antagonists are inhibited by leucovorin.
  • Leucovorin can potentiate the cytotoxic effects of fluorinated pyrimidines (i.e., fluorouracil and floxuridine).
  • 5-FU is activated within the cell, it is accompanied by a folate cofactor, and inhibits the enzyme thymidylate synthetase, thus inhibiting pyrimidine synthesis.
  • Leucovorin increases the folate pool, thereby increasing the binding of folate cofactor and active 5-FU with thymidylate synthetase.
  • Leucovorin can be administered at a dose of 400 mg/m 2 of the 1 + d racemic form, as an IV infusion over 30 minutes ( ⁇ 5 minutes), on Days 1 and 15 of each 28-day cycle.
  • Leucovorin should be reconstituted per the instructions on the package insert, SmPC or standard institutional guidelines for reconstitution of leucovorin.
  • Leucovorin should be administered after MM-151 and prior to the 5-FU infusion. Actual dose of 5-FU and leucovorin to be administered will be determined by calculating the patient's body surface area prior to each cycle. A +/- 5% variance in the calculated total dose will be allowed for ease of dose administration.
  • Leucovorin has dextro- and levo-isomers, only the latter one being pharmacologically useful. As such, the bioactive levo-isomer (“levoleucovorin”) has also been approved by the FDA for treatment of cancer. The dosage of levoleucovorin is typically half that of the racemic mixture containing both dextro (d) and levo (/) isomers.
  • MM-151 (preferred EGFR inhibitor)
  • EGFR signaling is important for the proliferation and survival of many epithelial malignancies. Although EGFR targeting antibodies have been approved for use in human malignancies driven by the EGFR pathway, there remains a high unmet need in these tumors, as limited efficacy is attributable to de novo or acquired resistance mechanisms to these targeted therapies.
  • One reason for this state of affairs might stem from observations that EGFR signaling is very robust due to amplification of cell signaling downstream of the receptor, thus making the need for complete inhibition of the pathway imperative for potential success in the clinic.
  • EGFR signaling is further complicated by the presence in tumors of multiple ligands that bind to EGFR with either high or low affinity and result in activation of the pathway downstream of EGFR. Preclinical evidence obtained at Merrimack suggests that EGFR signaling driven by high affinity ligands is not always inhibited by currently approved EGFR antagonists.
  • MM-151 is a novel mixture of three fully human monoclonal antibody EGFR antagonists designed to optimally inhibit EGFR dependent signaling. MM-151 antibodies have non-overlapping epitopes and can simultaneously engage the same EGFR receptor molecule. Preclinical studies suggest that MM- 151 leads to downregulation of EGFR expression via internalization and degradation of EGFR. Preclinical studies demonstrate that MM-151 is more effective in inhibiting EGFR signaling and proliferation driven by both high and low affinity ligands, compared to currently approved EGFR targeting monoclonal antibodies which inhibit only low-affinity ligand pathway activation.
  • MM-151 leads to antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), with the latter being a unique property of the antibody mixture that is not observed with currently approved EGFR-targeting antibodies.
  • ADCC antibody-dependent cellular cytotoxicity
  • CDC complement-dependent cytotoxicity
  • MM-151 contains three distinct antibodies: P1X, P2X and P3X. All are colorless, liquid solutions that are formulated in 20mM Histidine, 10% sucrose and 0.02% Polysorbate 80, pH 6.0. The molecular weights of the drug P1X, P2X and P3X are 145, 148 and 146 respectively. P1X, P2X and P3X drug substances are combined in a ratio of 1 : 1 :0.5 to form the final MM-151 drug product. Similar to the three drug substances, MM-151 drug product is formulated in 20mM Histidine, 10% sucrose and 0.02% Polysorbate 80, pH 6.0. The final concentration of drug product is 25 mg/ml per 10ml vial.
  • MM-151 P1X is a full EGF ligand antagonist and binds an epitope on domain III of EGFR with subnanomolar affinity (1 lpM) resulting in significant inhibition of pEGFR.
  • MM-151 P1X is a recombinant human IgGl monoclonal antibody. The complete tetrameric structure of the IgGl molecule is composed of two heavy chains (451 amino acids each) and two kappa light chains (214 amino acids each) held together by intra-chain and inter-chain disulfide bonds. The MM-151 P1X amino acid sequence predicts a molecular weight of 145 ko for the intact IgGl, which is within 0.2% of the actual molecular weight as experimentally determined by mass spectroscopy. MM-151 P1X is produced using a recombinant CHO cell system. The heavy and light chain sequences of the P1X antibody are provided in FIG. 14.
  • P2X is also a full EGF ligand antagonist and binds a distinct epitope different from that of P1X located on domain I of EGFR with subnanomolar affinity (70pM) resulting in significant inhibition of pEGFR.
  • MM-151 P2X is a recombinant human IgGl monoclonal antibody. The complete tetrameric structure of the IgGl molecule is composed of two heavy chains (449 amino acids each) and two kappa light chains (220 amino acids each) held together by intra-chain and inter-chain disulfide bonds.
  • the predicted molecular weight of intact glycosylated MM-151 P2X is 148 kD, which is within 0.2% of the actual molecular weight as experimentally determined by mass spectroscopy.
  • MM-151 P2X is produced using a recombinant CHO cell system.
  • the heavy and light chain sequences of the P2X antibody are provided in FIG. 15.
  • P3X is a partial EGF antagonist and binds a third epitope on domain III distinct from those of P1X and P2X.
  • P3X binds EGFR at a lower affinity than P1X and P2X (360pM) resulting in moderate inhibition (20%) of pEGFR.
  • MM-151 P3X is a recombinant human IgGl monoclonal antibody. The complete tetrameric structure of the IgGl molecule is composed of two heavy chains (453 amino acids each) and two kappa light chains (215 amino acids each) held together by intra-chain and inter-chain disulfide bonds.
  • the MM-151 P3X amino acid sequence predicts a molecular weight of 146 kD for the intact IgGl, which is within 0.2% of the actual molecular weight as experimentally determined by mass spectroscopy.
  • MM-151 P3X is produced using a recombinant CHO cell system.
  • the heavy and light chain sequences of the P3X antibody are provided in FIG. 16.
  • the CDR regions of the MM151 antibodies are provided in the table below, and in publication WO2013/006547.
  • the mixture of these three EGFR antagonists is expected to increase the relative potency of MM-151 compared to currently approved antibody based EGFR antagonists by completely blocking EGFR pathway activation in tumor cells through acting on three distinct epitopes of the target receptor.
  • the mixture of the three antibodies inhibited EGF -mediated signaling of both the target receptor, EGFR, and its downstream effector, ERK.
  • EGFR is one of the key growth factor receptors used by tumors cells to proliferate and migrate to distal sites
  • MM-151 has the potential to treat a number of patients with unmet medical needs in oncology.
  • PIX and P2X are fully human anti- EGFR IgGl monoclonal antibodies that bind to three distinct epitopes on the extracellular domain of EGFR.
  • Surface plasma resonance experiments showed that PIX, P2X and P3X can associate simultaneously; that they associate with EGFR domains III, I and II respectively ( Figure 16) and that the order of association does not matter.
  • PIX and P2X have been shown to be potent ligand antagonists, while P3X only partially blocks EGF ligand binding. However, together the mixture acts as potent EGF ligand blockers ( Figure 17).
  • PIX and P2X are potent inhibitors of pEGFR signaling, whereas P3X only partially blocks EGF -induced receptor signaling, ( Figure 19).
  • MM-151 is administered by IV infusion every week.
  • the first two doses of Cycle 1 are priming doses and the dose levels are 225 mg for priming dose 1 and 450 mg for priming dose 2.
  • Subsequent doses of MM-151 are administered according to the dose levels outlined above. MM-151 should not be administered as a bolus or a push.
  • MM-151 is also described in Patent Cooperation Treaty (PCT) patent application PCT/US2012/045235, filed July 2, 2012, and published as WO2013/006547, incorporated herein by reference in its entirety.
  • PCT Patent Cooperation Treaty
  • Liposomal irinotecan is administered intravenously, either alone or in combination with 5-fluorouracil (5-FU) and/or leucovorin.
  • liposomal irinotecan is administered prior to 5-FU and leucovorin.
  • leucovorin is administered prior to 5-FU.
  • liposomal irinotecan is administered intravenously over 90 minutes.
  • 5-FU is administered intravenously over 46 hours.
  • leucovorin is administered intravenously over 30 minutes.
  • the liposomal irinotecan is MM-398.
  • the concentration of MM-398 will be 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial irinotecan in the form of the sucrosofate salt, encapsulated in liposomes for intravenous infusion.
  • Nal-IRI must be stored refrigerated at 2 to 8°C, with protection from light.
  • Nal-IRI is administered by IV infusion over 90 minutes every two weeks at a dose of 70 mg/m 2 (free base).
  • 5-FU is a commercially available product that can be supplied at multiple
  • 5-FU is administered by IV infusion over 46 hours every two weeks at a dose of 2400 mg/m 2 .
  • LV is a commercially available product that can be supplied at multiple concentration levels and vial sizes depending on the source country. It must be stored at room temperature with protection from light. Leucovorin (1 + d racemic form) will be administered by IV infusion over 30 minutes every two weeks at a dose of 400 mg/m 2 .
  • a patient treated using the methods and compositions disclosed herein exhibits evidence of recurrent or persistent colorectal cancer following primary chemotherapy.
  • the patient has had and failed at least one prior platinum based chemotherapy regimen for management of primary or recurrent disease, e.g., a chemotherapy regimen comprising carboplatin, cisplatin, or another organoplatinum compound.
  • a chemotherapy regimen comprising carboplatin, cisplatin, or another organoplatinum compound.
  • the patient has failed prior treatment with gemcitabine or become resistant to gemcitabine.
  • a resistant or refractory tumor is one where the treatment-free interval following completion of a course of therapy for a patient having the tumor is less than 6 months (e.g., owing to recurrence of the cancer) or where there is tumor progression during the course of therapy.
  • Suitable treatment protocols include, for example, those wherein the patient is administered an effective amount of liposomal irinotecan, wherein the treatment comprises at least one cycle, wherein the cycle is a period of 3 weeks, and wherein for each cycle the liposomal irinotecan is administered on day 1 of the cycle at a dose of 120 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride), except if the patient is homozygous for the UGT1A1 *28 allele, wherein liposomal irinotecan is administered on day 1 of cycle 1 at a dose of 80 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride).
  • the dose of liposomal irinotecan administered to the patient homozygous for the UGT1A1 *28 allele is increased after one cycle in increments of 20 mg/m 2 , up to a maximum of 120 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride).
  • the treatment protocol includes administering to the patient an effective amount each of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin, wherein the treatment comprises at least one cycle, wherein the cycle is a period of 2 weeks, and wherein for each cycle: (a) liposomal irinotecan is administered on day 1 of the cycle at a dose of 80 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride), except if the patient is homozygous for the UGT1A1 *28 allele, wherein liposomal irinotecan is administered on day 1 of cycle 1 at a dose of 60 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride); (b) 5-FU is administered at a dose of 2400 mg/m 2 ; and (c) leucovorin is administered at a dose of 200 mg/m 2 (/ form) or 400 mg/m 2 (/ + d racemic form
  • the dose of liposomal irinotecan administered to the patient homozygous for the UGT1A1 *28 allele is increased after one cycle to 80 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride).
  • MM-151 e.g., once weekly
  • MM-398 liposomal irinotecan
  • 5-FU 5-fluorouracil
  • leucovorin e.g., 5-fluorouracil
  • Pathologic complete response absence of invasive cancer in the breast and lymph nodes following primary systemic treatment.
  • CR Complete Response
  • Partial Response At least a 30% decrease in the sum of dimensions of target lesions, taking as reference the baseline sum diameters;
  • SD Stable Disease
  • non-CR/Non-PD denotes a persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
  • Progressive Disease (PD) denotes at least a 20% increase in the sum of dimensions of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of 5 mm. The appearance of one or more new lesions is also considered progression.
  • the patient so treated exhibits pCR, CR, PR, or SD.
  • the patient so treated experiences tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth.
  • unwanted cell proliferation is reduced or inhibited.
  • one or more of the following can occur: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited; recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent.
  • such improvement is measured by a reduction in the quantity and/or size of measurable tumor lesions.
  • Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter is to be recorded) as >10 mm by CT scan (CT scan slice thickness no greater than 5 mm), 10 mm caliper measurement by clinical exam or >20 mm by chest X-ray.
  • CT scan CT scan slice thickness no greater than 5 mm
  • 10 mm caliper measurement by clinical exam >20 mm by chest X-ray.
  • the size of non-target lesions e.g., pathological lymph nodes can also be measured for improvement.
  • lesions can be measured on chest x-rays or CT or MRI films.
  • cytology or histology can be used to evaluate responsiveness to a therapy.
  • the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease can be considered to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease.
  • administration of effective amounts of liposomal irinotecan, 5- FU and leucovorin produce at least one therapeutic effect selected from the group consisting of reduction in size of a breast tumor, reduction in number of metastatic lesions appearing over time, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
  • the improvement of clinical benefit rate is about 20% 20%, 30%, 40%, 50%, 60%, 70%, 80% or more compared to the same combinations of anticancer agents administered without concomitant MM-398 administration.
  • Example 1 Activity of MM-398 in an Orthotopic Pancreas Tumor Model Expressing Luciferase (L3.6pl)
  • MM-398 The anti-tumor activity of MM-398 was assessed in an orthotopic pancreatic cancer model (L3.6pl), a highly hypoxic preclinical tumor model. Approximately 2.5 x 10 "5 L3.6pl pancreatic tumor cells were implanted by direct injection into the pancreas. The
  • MM-398 and free irinotecan were dosed at a dose of 20 mg/kg/dose weekly for three weeks. As shown in Figure 1, MM-398 (liposomal CPT11) had significant anti-tumor activity, as compared to a control (HBS) and free CPT11.
  • MM-398 reduces markers of hypoxia
  • experiments were conducted in a human colon cancer cell (HT-29) model.
  • HT-29 cells were injected subcutaneously into nude mice, on day 13 either PBS control or 1.25, 2.5, 5, 10 or 20 mg/kg MM-398 was injected intravenously.
  • MM-398 was dosed once a week for 4 weeks at the indicated doses.
  • MM-398 reduced markers of hypoxia. Specifically, the graphs in Figure 3 show the percentage of cells that stained with medium (middle third) or high (top third) intensity for CAIX. Representative samples from each group are shown as well as the group average (mean +/- stdev). MM-398 treatment modifies the tumor microenvironment by decreasing the percentage of both medium and high CAIX positive cells in a dose- dependent manner. As hypoxia is a hallmark of resistant and aggressive disease, a reduction in hypoxia is expected to make tumor cells more sensitive to chemotherapies.
  • Example 4 MM-398 Increases Perfusion of Hoechst Stain
  • MM-398 treatment led to increased microvessel density 6 days after treatment as measured by CD31 (platelet endothelial cell adhesion molecule) staining in an HT29 xenograft study.
  • CD31 platelet endothelial cell adhesion molecule
  • a Hoechst 33342 perfusion experiment was conducted. Specifically, a primary pancreatic tumor was grown in NOD-SCID mice and given one dose of MM-398 (20mg/kg). After 24 hours, Hoechst 33342 stain was
  • MM-398 single agent The pharmacokinetic profile of MM-398 single agent was investigated in a phase I clinical study (PEP0201) in patients at 60, 120 or 180mg/m 2 dose levels and in a phase II clinical trial in gastric cancer patients (PEP0206) at 120mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride). Plasma levels of total irinotecan, SN-38 and encapsulated irinotecan were measured in these studies.
  • the peak serum concentrations of total irinotecan ranged from 48-79 ⁇ g/ml for 120mg/m 2 of MM-398 (based on the amount of irinotecan trihydrate hydrochloride), which was approximately 50-fold higher than 125mg/m 2 free irinotecan.
  • the total irinotecan half- life (ti/ 2 ) for MM-398 ranged from 21 to 48 hours, which was approximately 2-3 folds higher than 125mg/m 2 of free irinotecan.
  • total irinotecan exposure at one week ranged from 1200- 3000 ( ⁇ g*h/ml) at a dose of 120 mg/m 2 of MM-398 (based on the amount of irinotecan trihydrate hydrochloride), approximately 50-100 fold higher than 300mg/m 2 of free irinotecan.
  • SN38 Cmax levels at 120mg/m 2 of MM-398 ranged from 9 to 17 ng/ml, which was approximately 50% less than free irinotecan at 125mg/m 2 .
  • a regimen combining fluorouracil, leucovorin, and MM-398 was studied in a phase I trial of solid tumors in 16 subjects, of whom 5 were patients with pancreatic cancer.
  • the objective tumor response rate, duration of response, and disease control rate were efficacy endpoints of the study.
  • the overall disease control rate was 73.3%.
  • Partial response was observed in one gastric cancer patient (at 80mg/m 2 dose level, based on the amount of irinotecan trihydrate hydrochloride) and one breast cancer patient (at 100 mg/m 2 dose level, based on the amount of irinotecan trihydrate hydrochloride), with the duration of response of 142 and 76 days, respectively.
  • the MTD dose 80 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride)
  • the tumor response rate and disease control rate were 16.7%) and 83.3%, respectively.
  • the main DLTs were grade 3 diarrhea, leucopenia, neutropenia and febrile neutropenia.
  • the MTD for MM-398 was 80mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride).
  • MM-398 in combination with 5-FU/LV in advanced solid tumors (PEP0203), a total of 401 episodes of AE were reported from the 16 treated subjects (safety population), of which 74 (18.4%) were of CTC grade 3 or above.
  • 74 (18.4%) were of CTC grade 3 or above.
  • 231 57.6% were considered by the investigators to be treatment-related.
  • Table 2 provides the incidence of treatment-emergent adverse events by maximum CTC grade and by causality (incidence > 20%), as seen in the PEP0203 study.
  • Table 3 provides the incidence of grade 3 or higher treatment-emergent adverse events seen in the 5 pancreatic cancer patients treated in the PEP0203 study.
  • MM-151 has been assessed in one clinical study to date, MM-151-01-01-01.
  • This study was a phase I study that evaluated MM-151 as a monotherapy and in combination with innotecan, at different dosing levels and at dosing frequencies of QW, Q2W and Q3W.
  • the study has completed, and preliminary signs of meaningful clinical benefit and an acceptable safety profile were observed, warranting further evaluation in metastatic CRC. Rationale for MM-151 starting dose
  • the starting dose of 10.5 mg/kg is the QW RP2D that was identified in the phase I study.
  • NAPOLI-l NAPOLI-l
  • nal-IRI single agent nal-IRI
  • irinotecan HCl Camptosar ®
  • administration of nal-IRI 100 mg/m 2 resulted in higher exposure of total irinotecan (Cmax: 13.4 fold, AUCo- ⁇ : 46.2 fold, ti/ 2 : 2.0 fold), and higher SN-38 ti/ 2 (3 fold) and marginally higher AUCo- ⁇ (1.4 fold)
  • SN-38 Cmax was reduced by 5.3 fold ( Figure 4).
  • Figure 9 is a graph showing the mean plasma concentrations of total irinotecan and SN-38 following the administration of either nal-IRI (100mg/m 2 ) (based on the amount of irinotecan trihydrate hydrochloride) or irinotecan HCl (300mg/m 2 ) in Study PEP0206.
  • nal-IRI at a dose of 100 mg/m 2 (blue line) (based on the amount of irinotecan trihydrate hydrochloride) or nal-IRI at a dose of 300 mg/m 2 (red line) (based on the amount of irinotecan trihydrate hydrochloride) every 3 weeks.
  • Total irinotecan (top) and its active metabolite, SN-38 (bottom) were measured during Cycle 1. Error bars indicate 95% confidence interval.
  • Dotted lines indicate lower limit of quantification (LLOQ); total irinotecan measurements consists of two LLOQ values because of two different irinotecan assay was used to measure low and high range of concentrations.
  • irinotecan increases with dose. Additionally, the Cmax of total SN-38 increases
  • nal-IRI extended plasma PK of both CPT-11 and SN-38 compared to treatment with irinotecan HC1.
  • a phase I clinical study of nal-IRI monotherapy investigated tumor levels of both CPT-11 and SN-38 following treatment with nal-IRI using post-treatment biopsies. Based on model predictions, SN-38 levels in tumor were expected to be higher than in plasma, suggesting local conversion of CPT-11 to SN-38 in the tumor microenvironment with nal-IRI ( Figure 10).
  • Figures 11 A and 1 IB are graphs showing the clinical evidence for local activation and accumulation of SN-38 in tumor tissue.
  • Figure 10 illustrates the mechanistic tumor PK model of nal-IRI predicted higher SN-38 levels in tumor compared to plasma when 70mg/m 2 (based on the amount of irinotecan free base) nal-IRI is administered.
  • nal-IRI may be indirectly compared with the safety of irinotecan, primarily based on a qualitative comparison of adverse reactions, as reported in the Camptosar US label for irinotecan.
  • the comparison is qualitative, as both irinotecan and nal-IRI have been used in different doses and schedules as monotherapy and combination therapy with other chemotherapeutic agents; therefore, quantitative comparisons are difficult.
  • the most common adverse reactions of irinotecan and nal-IRI are similar and consist mainly of gastrointestinal events and myelosuppression.
  • the common adverse reactions (>30%) observed in clinical studies with irinotecan in combination with other agents are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia.
  • the common adverse reactions (>30%) observed in single agent irinotecan therapy in clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia (Camptosar US label).
  • nal-IRI when used in combination with 5-FU and leucovorin, the most common adverse reactions (>20 %) observed in clinical trials considered to be related are: diarrhea, nausea, vomiting, decreased appetite, neutropenia, fatigue, anemia, stomatitis and pyrexia.
  • the overall safety profile of nal-IRI is presented in detail in the related Investigator Brochure.
  • Table 6 summarizes > Grade 3 safety data from the NAPOLI-1 trial comparing nal-IRI + 5-FU/LV (at a dose of 80 mg/m 2 based on the amount of irinotecan hydrochloride trihydrate, given on an every 2 week schedule), or nal-IRI monotherapy (at a dose of 120 mg/m 2 based on the amount of irinotecan trihydrate hydrochloride given on an every 3 week schedule), with 5-FU/LV alone (given weekly for 4 weeks followed by 2 weeks of rest) in the same population of patients who had received prior gemcitabine therapy.
  • Nal-IRI, 5-FU and LV are all approved drugs and the dose levels used in this study are the approved dose levels for each therapy as defined in the package insert.
  • the doses of nal-IRI, 5-FU and LV will remain constant and the dose of MM-151 will be adjusted until an MTD is identified.
  • Irinotecan is a well-established therapy in the frontline treatment of mCRC, alone or in combination, and can be combined with EGFR inhibitors to treat RAS wild type tumors; Nal-IRI (OnivydeTM) is a nanoliposomal formulation of irinotecan.
  • the nanoliposomal encapsulation improves the pharmacokinetics of irinotecan and results in a lower Cmax, longer half-life, and higher levels of irinotecan and SN-38 in tumor tissue compared with standard irinotecan.
  • Nal-IRI is approved by the FDA in combination with 5-FU and leucovorin in gemcitabine refractory pancreatic adenocarcinoma under the brand name Onivyde.
  • PEPCOL study a non-comparative study evaluating the use of nal-IRI + 5-FU + LV as a 2nd line therapy in mCRC (PEPCOL study)
  • the nal-IRI containing arm met the threshold of early responses and had lower incidence of diarrhea and neutropenia than the FOLFIRI containing arm.
  • Combination treatment of FOLFIRI and an EGFR inhibitor as first line treatment in mCRC are in accordance with National Comprehensive Cancer Network (NCCN) guidelines.
  • NCCN National Comprehensive Cancer Network
  • MM-151 is an EGFR inhibitor that combines three fully human IgGl monoclonal antibodies. MM-151 antagonizes high-affinity EGFR ligands more effectively than another EGFR inhibitor, cetuximab, and has been observed to elicit a ⁇ 65-fold greater decrease in signal amplification. MM-151 has been evaluated in a phase I study of solid tumors and it demonstrated a safety profile that was comparable to other EGFR inhibitors, in monotherapy and in combination with irinotecan.
  • MM-151 was combined with nal-IRI in a LoVo colon xenograft experiment. The data showed that this combination enhances anti-tumor activity by overcoming EGFR insensitivity. This result, combined with the preliminary efficacy data seen in the PEPCOL study, suggests that the combination of MM-151 + nal-IRI + 5-FU + LV may be a viable therapeutic option in mCRC.
  • nal-IRI+5-FU+LV regimen was studied in the NAPOLI-1 trial and the most common adverse reactions (>20 %) observed in clinical trials considered to be related are: diarrhea, nausea, vomiting, decreased appetite, neutropenia, fatigue, anemia, stomatitis and pyrexia.
  • the following example employs a bin 1 antibody, "ca” which comprises the CDR regions of the Heavy and Light Chains in Figure 23.
  • This antibody is described in the patent entitled “Antibodies Against Epidermal Growth Factor Receptor (EGFR) and Uses Thereof, U.S. Patent No. 9,044,460 as antibody “ca 34", which is herein incorporated by reference.
  • EGFR Epidermal Growth Factor Receptor
  • U.S. Patent No. 9,044,460 as antibody "ca 34"
  • In vivo studies of MM-151 alone and in combination with irinotecan were also performed in a colorectal cancer patient-derived xenograft (ST094). This study utilizes the MM-151 preclinical tool compound ("MM-151 TC”) in which the antibody ca was substituted for antibody PIX.
  • PIX but not ca cross reacts with (binds to) mouse EGFR as well as binding to human EGFR, and the binding of PIX to the mouse antigen depletes the amount of this antibody in the mouse circulation, altering exposure of the human tumor to the antibody.
  • Results obtained with ca are predictive of results that would be obtained in human patients with PIX, except that the antibody trio comprising PIX would be expected to be more active than the trio comprising ca in its stead.
  • MM-151 and to a greater extent, the MM-151/irinotecan combination decreased tumor growth relative to the PBS control.
  • Figure 12 is a scheme of a human clinical trial.
  • the study can have two parts, a dose finding phase to determine the MTD and an expansion cohort after the MTD is identified.
  • the dose levels to be used in this study are summarized in Table 7.
  • Table 7 Dose levels of MM-151, nal-IRI, 5-FU, and LV (irinotecan dose based on amount of irinotecan free base):
  • MM-151 is given at fixed doses of 225 mg and 450 mg on Weeks 1 and 2 respectively.
  • Nal-IRI, 5-FU and Leucovorin are all administered in Week 1 of the Priming Phase at their normal doses listed in the table 7 above. 2 Dose levels -1, -2, and -3 will be used if there is toxicity observed in Method 1 that limits further enrollment. 3 1 + d racemic form of LV will be used
  • the first two doses of MM-151 are administered during a two week priming phase.
  • the first priming dose is given as a fixed dose of 225 mg in week 1 and the second priming dose is given as a fixed dose of 450 mg in week 2.
  • Subsequent dose levels are given as weight based dose levels defined per cohort.
  • nal-IRI 80 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride) was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866.
  • the published expression of the 80 mg/m 2 (based on the amount of irinotecan trihydrate hydrochloride) dose based on irinotecan hydrochloride trihydrate is equivalent to a 69.3 mg/m 2 dose based on irinotecan free base. This was rounded to 70 mg/m 2 to minimize any potential dosing errors.
  • ONIVYDE irinotecan liposome injection
  • topoisomerase inhibitor formulated with irinotecan hydrochloride trihydrate into a liposomal dispersion, for intravenous use.
  • ONIVYDE indicated for the treatment of metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.
  • ONIVYDE is an irinotecan liposome having a pH of about 7.25.
  • the ONIVYDE product contains irinotecan sucrosofate encapsulated in a liposome, obtained from an irinotecan hydrochloride trihydrate starting material.
  • the chemical name of irinotecan is
  • irinotecan tnhydrate hydrochloride starting material used to prepare the irinotecan liposomes, or based on the amount of irinotecan in the liposome.
  • an ONIVYDE dose of 80 mg based on the amount of irinotecan hydrochloride trihydrate starting material actually contains about 0.866x(80mg) of irinotecan in the final product (i.e., a dose of 80 mg/m 2 of ONIVYDE based on the weight of irinotecan hydrochloride starting material is equivalent to about 70 mg/m 2 of irinotecan in the final product).
  • ONIVYDE is a sterile, white to slightly yellow opaque isotonic liposomal dispersion.
  • Each 10 mL single-dose vial contains 43 mg irinotecan free base at a
  • the liposome is a unilamellar lipid bilayer vesicle
  • the vesicle is composed of l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) 6.81 mg/mL, cholesterol 2.22 mg/mL, and methoxy-terminated polyethylene glycol (MW 2000)- distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) 0.12 mg/mL.
  • DSPC l,2-distearoyl-sn-glycero-3-phosphocholine
  • MPEG-2000-DSPE methoxy-terminated polyethylene glycol
  • Each mL also contains 2-[4-(2-hydroxy ethyl) piperazin-l-yl]ethanesulfonic acid (HEPES) as a buffer 4.05 mg/mL and sodium chloride as an isotonicity reagent 8.42 mg/mL.
  • HEPES 2-[4-(2-hydroxy ethyl) piperazin-l-yl]ethanesulfonic acid
  • sodium chloride as an isotonicity reagent 8.42 mg/mL.
  • Each vial of ONIVYDE contains 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial.
  • the unit dosage form can be an intravenous formulation having a total volume of about 500 mL.
  • ONIVYDE is prepared for administering by diluting the isotonic liposomal dispersion from the vial as follows: withdraw the calculated volume of ONIVYDE from the vial.
  • ONIVYDE is diluted in 500mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix diluted solution by gentle inversion; protect diluted solution from light and administer diluted solution within 4 hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2°C to 8°C (36°F to 46°F)].
  • ONIVYDE irinotecan liposome injection
  • 5- fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas that has progressed following gemcitabine-based therapy.
  • ONIVYDE prior to leucovorin and fluorouracil.
  • the recommended dose of ONIVYDE is 70 mg/m 2 irinotecan (free base) administered by intravenous infusion over 90 minutes every 2 weeks.
  • the recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1 *28 allele is 50 mg/m 2 irinotecan administered by intravenous infusion over 90 minutes.
  • the dose of ONIVYDE can be increased to 70 mg/m 2 as tolerated in subsequent cycles.
  • ONIVYDE is infused as a diluted solution intravenously over 90 minutes.
  • Example 11 Activity of MM-151 in combination with Nal-IRI in LoVo CRC xenograft model
  • MM-151 TC MM-151 preclinical tool compound; refer to Example 8
  • nal-IRI was studied in a subcutaneous CRC xenograft model (LoVo).
  • MM-151 TC was utilized for cross-reactivity with murine EGFR, and was administered intraperitoneally (IP) at 1 cycle/week comprised of a loading dose (mAb2E5+P2X+P3X) on C1D1, maintenance doses (mAb2E5+P2X+P3X) on Dl of subsequent cycles, and P2X maintenance doses on D3 and D5 every cycle.
  • IP intraperitoneally
  • Nal-IRI is administered intravenously via tail vein injection weekly.
  • LoVo tumor-bearing mice were randomized for efficacy study at Day 16 post-inoculation.
  • a combination of nal-IRI + MM-151 has improved activity compared to the two agents alone.
  • Table 9 illustrates response analysis based on RECIST-like criteria (modified for preclinical tumor volume analyses) on Day 30 post-inoculation. Individual tumors with -30 to -95%, -30 to 30%, and 30% change in volume were classified as partial response (PR), stable disease (SD), and progressive disease (PD), respectively.
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • nal-IRI + MM-151 resulted in 62.5% PR and 37.5% SD with no PD
  • MM-151 and nal-IRI monotherapies resulted in 100% and 75% PD, respectively.
  • Example 12 Activity of Nal-IRI is superior to free irinotecan in a KRAS/NRAS/BRAF wild type LIM1215 CRC xenograft at a 5-fold lower dose
  • Figure 21 demonstrates the anti-tumor activity of nal-IRI at 5 mg/kg compared to free irinotecan at 25 mg/kg.
  • the doses were chosen due to similar SN-38 (active metabolite of irinotecan) exposure in the tumors based on previously published data [Kalra (2014) Cancer Research, 74(23):7003-13].
  • SN-38 active metabolite of irinotecan
  • Example 13 Activity of nal-IRI + 5-FU + MM-151 TC vs. irinotecan + 5-FU + cetuximab
  • the combination of free irinotecan + 5-FU/LV + cetuximab is one of the standard of care (SOC) regimens for treating metastatic CRC.
  • SOC standard of care
  • Two dose levels of nal-IRI and irinotecan were chosen for combining with constant doses of 5-FU and MM-151 TC or cetuximab.
  • Low dose combinations include Nal-IRI (1.25 mg/kg, IV) + 5-FU (50 mg/kg, IP) + MM-151 TC (3 mg/kg, IP) and irinotecan (6.25 mg/kg, IV) + 5-FU (50 mg/kg, IP) + cetuximab (3 mg/kg, IP).
  • “High dose” combinations include Nal-IRI (5 mg/kg, IV) + 5-FU (50 mg/kg, IP) + MM-151 TC (3 mg/kg, IP) and irinotecan (25 mg/kg, IV) + 5-FU (50 mg/kg, IP) + cetuximab (3 mg/kg, IP).
  • the comparative treatment groups were chosen such that the irinotecan and nal-IRI treatments have similar SN-38 tumor exposure.
  • the dose levels of nal-IRI and IRI were below clinical dose, in which the clinical translated dose for nal-IRI (80 mg/m 2 hydrochloride trihydrate q2w for patients) is 13 mg/kg qlw in mouse, and for irinotecan (180 mg/m 2 q2w, based on the amount of irinotecan trihydrate hydrochloride) is 30 mg/kg qlw in mouse.
  • the dose levels of MM-151 TC and cetuximab were chosen such that the exposure levels in the blood are nearly equivalent in both the first week (with the loading dose) and the subsequent weeks (with the maintenance doses). Exposure was calculated as the area under the concentration curve (AUC) of cetuximab versus the sum total of the AUC of the three antibodies in the MM-151 TC mixture.
  • Figures 22 A and B illustrate the anti -tumor activities of low and high dose combinations, respectively.
  • nal-IRI + 5-FU + MM-151 TC are superior to the SOC irinotecan + 5-FU + cetuximab.
  • Table 10 shows that high dose nal-IRI + 5-FU + MM-151 TC treatment results in 3 CR and 6 PR, while both dose levels of irinotecan + 5-FU + cetuximab did not have any CR.
  • CR tumor volume ⁇ -95%
  • PR between -95% to -30%
  • SD -30% to 30%
  • PD tumor volume > 30%.
  • Example 14 Initiation of Phase 1 Study of MM-151 in Combination with the
  • This phase I clinical study examines oligoclonal EGFR (epidermal growth factor receptor) inhibitor, MM-151, in combination with ONIVYDE® (irinotecan liposome injection) plus fluorouracil (5-FU) and leucovorin in patients with RAS wild-type metastatic colorectal cancer.
  • ONIVYDE® irinotecan liposome injection
  • fluorouracil 5-FU
  • MM- 151 a novel antibody mixture of three human antibodies designed to target EGFR which promotes tumor growth, and ONIVYDE, also known as MM-398 or "nal-IRI,” plus 5-FU and leucovorin as first or second-line treatment in patients with RAS wild-type metastatic colorectal cancer.
  • ONIVYDE also known as MM-398 or "nal-IRI”
  • 5-FU and leucovorin as first or second-line treatment in patients with RAS wild-type metastatic colorectal cancer.
  • MM-151 has shown superior inhibition of the EGFR pathway compared to FDA approved EGFR inhibitors. It is expected that superior topoisom erase- 1 inhibition plus superior EGFR inhibition will lead to improved efficacy in metastatic colorectal cancer.
  • the trial will determine the side effect profile of MM-151 in combination with ONIVYDE plus 5-FU and leucovorin and recommended dose for subsequent trials with this combination.
  • Eligible patients for the study must have metastatic disease, have had no prior exposure to irinotecan or an EGFR inhibitor, and have received no more than one prior line of treatment for metastatic disease.
  • Example 15 Evaluation of MM-151 + Nal-IRI + 5-FU + Leucovorin in RAS/RAF Wild- type Metastatic Colorectal Cancer
  • phase I/II An open label, non-randomized phase I/II study can evaluate the combination of MM-151 + nal-IRI + 5-FU + Leucovorin in RAS/RAF wild-type Metastatic Colorectal Cancer.
  • a modified toxicity probability interval approach mTPI
  • MTD maximum tolerated dose
  • Phase I Approximately 8-12 patients will be enrolled to determine the maximum tolerated dose, safety and tolerability of MM-151 + nal-IRI + 5-FU + LV in patients with mCRC that are RAS wildtype.
  • Phase II Approximately 20-30 patients will be enrolled at the maximum tolerated dose of MM-151 in combination with nal-IRI + 5-FU + LV to characterize initial efficacy in conjunction with levels of irinotecan and SN-38 measured in tissue.
  • ANC 1,500/ ⁇ 1 (unsupported by growth factors) o Platelet count > 100,000/ ⁇ 1 o Hemoglobin > 9 g/dL o
  • abnormalities including prolonged QTc interval (> 450 msecs); abnormal findings on interpretation of ECG are acceptable if principle investigator confirms it is not clinically significant.
  • Clinically significant gastrointestinal disorder including hepatic disorders, occlusion, diarrhea > grade 1, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, or partial bowel obstruction
  • Results A total of 1 1 1 patients were enrolled (87 patients on monotherapy). A summary of the patient demographics are set forth in Table 12. Specific population demographics for patients with HNSCC, NSCLC, or CRC are set forth in Tables 13, 14, and 15, respectively.
  • Table 12 Patient demographics
  • tissue and blood samples were collected from treated patients and used in exploratory biomarker analyses. While samples were requested from all patients identified in Table 12, samples were only collected from a subset of these patients. For those patients from whom samples were obtained, blood and tissue samples were assessed for genomic alterations using next-generation sequencing assays from GuardantHealth (Guardant360) and OmniSeq (OmniSeq Comprehensive; OmniSeq PGM), respectively.
  • the Guardant360 and OmniSeq Comprehensive assays identify somatic mutations, copy number variations, and indels/fusions in oncology-focused gene panels.
  • Table 18 summarizes of the collected samples for biomarker analysis, from patients having EGFR-related indications (i.e., patients for whose condition anti-EGFR antibodies are an approved therapy).
  • Figure 25 is a table listing the cancer type, treatment schedule, duration of treatment and mutation status (wild type, "WT” or mutant, "MT") for 26 patients from whom we collected both pre- and post-treatment serum samples from the clinical trial described in Example 16.
  • the table in Figure 25 indicates the measured maximum change in solid tumor size as measured by RECIST 1.1 ("Maximum Percent Change") compared to the solid tumor size measured prior to treatment.
  • the data in Figure 25 demonstrates a low frequency of acquired KRAS/NRAS/BRAF mutations following MM-151 treatment (i.e., 1 of 5 CRC patients and 2 of 19 in all indications that were assessed as WT for all measured KRAS, NRAS and BRAF prior to treatment).
  • Figure 26 is a table detailing the patient treatment parameters, the duration of treatment, the best overall response, duration of treatment and mutation status (wild type, "WT” or mutant, "MT") for 24 of 29 patients within the CRC efficacy cohort who were evaluated for RECIST response in the clinical trial described in Example 16.
  • the Table in Figure 26 also includes patient treatment parameters listing the treatment type (MM-151 monotherapy or combination of MM-151 and irinotecan), whether the first two weekly doses of MM-151 were priming doses (225 mg and 450 mg fixed dose, respectively), dose of MM- 151 administered (after the priming doses, if applicable), MM-151 dose frequency (every week or every two weeks), and (if applicable) the irinotecan dose and dose frequency.
  • 13 patients had a reduction in target lesions and 7 progressed at first scan, including 2 wild type (WT in KRAS, NRAS, BRAF, PIK3CA, EGFR Exon 12), 3 NRAS mutants, 1 co-occurring PIK3C A mutation, and 1 BRAF mutation.
  • Two patients were noted as progressive having progressive disease (PD) on first scan but had ⁇ 20% increase in target lesions, one patient had a new non-target lesion noted, and one patient was a clinical progression (not RECIST). Of the 15 remaining patients that did not progress outright, 7 patients were WT, 4 KRAS mutant, 3 BRAF mutant, 2 NRAS mutant, and 2 EGFR ECD mutant (including co-occurring).

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Abstract

L'invention concerne des méthodes de traitement du cancer colorectal (y compris le cancer colorectal de type sauvage RAS) chez un patient par administration d'irinotécan liposomal (MM -398) en combinaison avec des anticorps anti-EGFR tels que MM -151. L'irinotécan liposomal (MM -398) peut être co-administré avec du 5-fluorouracile et du leucovorin.
PCT/US2017/024410 2016-03-30 2017-03-28 Méthodes de traitement du cancer à l'aide de polythérapies comprenant une préparation d'anticorps anti-egfr oligoclonal et de l'irinotécan lipsomal WO2017172678A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018083470A1 (fr) * 2016-11-02 2018-05-11 Ipsen Biopharm Ltd. Traitement du cancer gastrique au moyen de polythérapies comprenant de l'oxaliplatine, du 5-fluoruracile (et de la leucovorine) et de l'irinotécan sous forme liposomale
WO2019140266A1 (fr) * 2018-01-12 2019-07-18 Prolynx Llc Protocole pour réduire au minimum la toxicité d'associations posologiques et agent d'imagerie pour vérification
US10980795B2 (en) 2012-06-13 2021-04-20 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan
US11318131B2 (en) 2015-05-18 2022-05-03 Ipsen Biopharm Ltd. Nanoliposomal irinotecan for use in treating small cell lung cancer
US11344552B2 (en) 2015-08-21 2022-05-31 Ipsen Biopharm Ltd. Methods for treating metastatic pancreatic cancer using combination therapies comprising liposomal irinotecan and oxaliplatin
US11369597B2 (en) 2012-06-13 2022-06-28 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies
CN115054700A (zh) * 2022-04-29 2022-09-16 潍坊医学院 一种共载盐酸伊立替康和卡培他滨的靶向脂质体及其制备方法和应用
WO2023059600A1 (fr) * 2021-10-05 2023-04-13 Mirati Therapeutics, Inc. Combinaisons d'inhibiteurs de kras g12d avec de l'irinotécan et méthodes de traitement associés
US11844795B2 (en) 2015-08-20 2023-12-19 Ipsen Biopharm Ltd. Combination therapy for cancer treatment
WO2024144401A1 (fr) * 2022-12-28 2024-07-04 Merus N.V. Traitement du cancer avec une combinaison d'un anticorps qui se lie à l'egfr et de médicaments cytotoxiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015175827A1 (fr) * 2014-05-14 2015-11-19 Merrimack Pharmaceuticals, Inc. Dosage et administration d'agents thérapeutiques anti-egfr
US20160074382A1 (en) * 2012-06-13 2016-03-17 Merrimack Pharmaceuticals, Inc. Methods for Treating Pancreatic Cancer Using Combination Therapies Comprising Liposomal Irinotecan

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160074382A1 (en) * 2012-06-13 2016-03-17 Merrimack Pharmaceuticals, Inc. Methods for Treating Pancreatic Cancer Using Combination Therapies Comprising Liposomal Irinotecan
WO2015175827A1 (fr) * 2014-05-14 2015-11-19 Merrimack Pharmaceuticals, Inc. Dosage et administration d'agents thérapeutiques anti-egfr

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ARENA S. ET AL.: "MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations", SCI. TRANSL. MED ., vol. 8, no. Issue 324ra14, 3 February 2016 (2016-02-03), pages 1 - 10, XP055286470 *
CUTSEM E.V. ET AL.: "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer", THE N.ENG.J.MED, vol. 360, no. 14, 2009, pages 1408 - 1417, XP055013583 *
FUCHS CH. ET AL.: "Irinotecan in the treatment of colorectal cancer", CAN. TREAT. REV., vol. 32, 2006, pages 491 - 503, XP005674591 *
HARALDSDOTTIR S. ET AL.: "Integrating anti-EGFR therapies in metastatic colorectal cance r", J GASTROINTEST.ONCOL., vol. 4, no. 3, 2013, pages 285 - 298, XP055424420 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10980795B2 (en) 2012-06-13 2021-04-20 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan
US11369597B2 (en) 2012-06-13 2022-06-28 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies
US11318131B2 (en) 2015-05-18 2022-05-03 Ipsen Biopharm Ltd. Nanoliposomal irinotecan for use in treating small cell lung cancer
US11844795B2 (en) 2015-08-20 2023-12-19 Ipsen Biopharm Ltd. Combination therapy for cancer treatment
US11344552B2 (en) 2015-08-21 2022-05-31 Ipsen Biopharm Ltd. Methods for treating metastatic pancreatic cancer using combination therapies comprising liposomal irinotecan and oxaliplatin
WO2018083470A1 (fr) * 2016-11-02 2018-05-11 Ipsen Biopharm Ltd. Traitement du cancer gastrique au moyen de polythérapies comprenant de l'oxaliplatine, du 5-fluoruracile (et de la leucovorine) et de l'irinotécan sous forme liposomale
US11071726B2 (en) 2016-11-02 2021-07-27 Ipsen Biopharm Ltd. Treating gastric cancer using combination therapies comprising liposomal irinotecan, oxaliplatin, 5-fluorouracil (and leucovorin)
WO2019140266A1 (fr) * 2018-01-12 2019-07-18 Prolynx Llc Protocole pour réduire au minimum la toxicité d'associations posologiques et agent d'imagerie pour vérification
US11730836B2 (en) 2018-01-12 2023-08-22 Prolynx Llc Synergistic cancer treatment
WO2023059600A1 (fr) * 2021-10-05 2023-04-13 Mirati Therapeutics, Inc. Combinaisons d'inhibiteurs de kras g12d avec de l'irinotécan et méthodes de traitement associés
CN115054700A (zh) * 2022-04-29 2022-09-16 潍坊医学院 一种共载盐酸伊立替康和卡培他滨的靶向脂质体及其制备方法和应用
WO2024144401A1 (fr) * 2022-12-28 2024-07-04 Merus N.V. Traitement du cancer avec une combinaison d'un anticorps qui se lie à l'egfr et de médicaments cytotoxiques

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