Safety and Efficacy of Mitazalimab in Combination With Chemotherapy in Pancreatic Cancer Patients

Study Overview
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Brief Summary
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Phase 1b/2 study to assess the safety and efficacy of mitazalimab in combination with chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma.

Detailed Description
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OPTIMIZE-1 is a phase 1b/2, open-label, multi-center study assessing the clinical efficacy of mitazalimab in combination with chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma. The efficacy of intravenously administered mitazalimab in combination with the standard of care chemotherapy mFOLFIRINOX will be evaluated in patients with metastatic pancreatic ductal adenocarcinoma. Two dose levels of mitazalimab, 450 ug/kg and 900 ug/kg, are planned to be evaluated together with mFOLFIRINOX for determination of recommended phase 2 dose (RP2D) of mitazalimab in combination with mFOLFIRINOX before entering a dose expansion part with RP2D obtained. The expansion part will evaluate the clinical efficacy of mitazalimab in combination with mFOLFIRINOX assessing objective response rate (ORR), primary endpoint, as well as Progression-free survival (PFS) and Overall survival (OS). The dose expansion part includes a Simon´s two-stage design with an interim analysis for stop for futility or efficacy based on ORR.

Official Title
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An Open-label Phase 1b/2 Study Assessing the Safety and Efficacy of Mitazalimab in Combination With Chemotherapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Conditions
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Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Biological: CD40 agonist mitazalimab in combination with chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed consent Is ≥18 years of age at the time of signing the informed consent form (ICF) Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Has a diagnosis of previously untreated metastatic pancreatic ductal adenocarcinoma (histologically documented) Has measurable disease per RECIST v. 1.1 Has not received previous chemotherapy for pancreatic ductal adenocarcinoma Has not received prior abdominal radiotherapy (except for palliative radiotherapy to non-target lesions) Has a life expectancy of ≥ 3 months Has acceptable hematologic laboratory values defined as: Neutrophils ≥ 1.5 x 109/L without growth factor stimulation within 3 weeks prior to the blood test Platelets ≥100 x 109/L Hemoglobin ≥6.2 mmol/L ( 100 g/L) (may be after transfusion) Has acceptable clinical chemistry laboratory values defined as: Bilirubin ≤1.5 x ULN (biliary drainage is permitted) AST ≤3 x ULN (irrespective of hepatic metastases) ALT ≤3 x ULN (irrespective of hepatic metastases) Creatinine ≤1.5 x ULN or glomerular filtration rate (GFR) of ≥45 mL/min INR ≤1.5 x ULN Albumin ≥28 g/L For women of childbearing potential1: Has a negative highly sensitive serum (β-human chorionic gonadotropin [β-hCG]) pregnancy test at screening Is willing to use highly effective contraception methods during study treatment and for at least six months thereafter Fertile men must practice effective contraceptive methods (i.e. surgical sterilization, or a condom used with a spermicide) during study treatment and for at least six months thereafter Is willing to comply with all study procedures Exclusion Criteria: Has other types of non-ductal tumor of the pancreas, including endocrine tumors or acinar cell adenocarcinoma, cyst adenocarcinoma and ampullary carcinoma Has other current cancer or history of cancer in the prior 3 years before signing the ICF other than in situ cervical cancer, or basal cell or squamous cell carcinoma treated with local excision only Has known CNS metastases or carcinomatous meningitis Has contraindication to any constituent of study treatment (mitazalimab and applicable chemotherapy) Has a history of chronic diarrhea, inflammatory disease of the colon or rectum, or unresolved partial or complete intestinal obstruction Has a history of myocardial infarction within 12 months of the first administration of mitazalimab, uncontrolled angina pectoris, unstable cardiac arrhythmias, or congestive heart failure of New York Heart Association class II or greater Has QTc >450 msec Has uncontrolled intercurrent illness, including active infection Has a known history of HIV, hepatitis B or active hepatitis C infection Is a female patient who is pregnant or nursing Has received attenuated vaccine within 28 days before the first dose of study treatment Any condition that, in the opinion of the Investigator, would place the patient at increased risk or preclude the patient's compliance with the study Participates in another investigational drug or device study with any intervention within the previous 4 weeks prior to first dose of mitazalimab Has received prior treatment with irinotecan or platinum-containing chemotherapy Has pre-existing peripheral neuropathy greater than grade 1 Has known Gilbert's disease Has known genotype UGT1A1 * 28 / * 28 Has known fructose intolerance (malabsorption) Has complete dihydropyrimidine dehydrogenase (DPD) deficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenously administered mitazalimab given in combination with chemotherapy<br>Mitazalimab, a human monoclonal antibody targeting CD40, administered intravenously every 14 days, in combination with standard of care chemotherapy modified FOLFIRINOX. | Biological: CD40 agonist mitazalimab in combination with chemotherapy<br>* Mitazalimab administered intravenously every 14 days in combination with standard of care chemotherapy modified FOLFIRINOX.<br>* Other names: ADC-1013, JNJ-64457107;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) (Part 1: Phase 1b Dose escalation) | Number of patients experiencing DLTs | From first dose to end of dose limiting toxicity period (Day 1-21) | 
| Objective response rate (ORR) (Part 2: Phase 2 Dose expansion) | Proportion of patients achieving complete response or partial response at any time during the study | From first dose to 28-56 days after end of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Type, frequency and severity of Adverse Events | Number of patients experiencing AEs. Number of events summarized by SOC and preferred term. | From informed consent signed to 28-56 days after end of of study treatment | 
| Anti-drug-antibody (ADA) titer in serum (tolerability) | Immunogenicity of mitazalimab | From first dose until 28-56 days after end of study treatment | 
| Cmax of mitazalimab (pharmacokinetics) | Cmax derived from mitazalimab serum concentrations | From first dose until 28-56 days after end of study treatment | 
| Tmax of mitazalimab (pharmacokinetics) | Tmax derived from mitazalimab serum concentrations | From first dose until 28-56 days after end of study treatment | 
| AUC(0-T) of mitazalimab (pharmacokinetics) | AUC(0-T) derived from mitazalimab serum concentrations | From first dose until 28-56 days after end of study treatment | 
| Anti-tumor Activity per RECIST 1.1 guideline (efficacy) | Best overall response, duration of response, Duration of stable disease, disease control rate, Time to next anti-cancer therapy will be assessed | From first dose until 28-56 days after end of study treatment | 
| Progression free survival (efficacy) | Number of days from first dose of mitazalimab to progressive disease or death. | From first dose and up to 2 years after end of study treatment | 
| Overall survival (efficacy) | Number of days from first dose of mitazalimab until death | From first dose and up to 2 years after end of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mitazalimab, modified FOLFIRINOX, Pancreatic ductal adenocarcinoma, PDAC, Pancreatic Cancer, Chemotherapy, combination, 5-Fluorouracil, Oxaliplatin, Leucovorin, Irinotecan