Combination Chemotherapy With or Without Ganitumab in Treating Patients With Previously Untreated Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, irinotecan hydrochloride, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as ganitumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving more than one drug (combination chemotherapy) is more effective with or without ganitumab in treating patients with pancreatic cancer. PURPOSE: This phase I/II trial is studying the best dose of combination chemotherapy and ganitumab and how well combination chemotherapy with or without ganitumab works in treating patients with previously untreated metastatic pancreatic cancer.

Detailed Description
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OBJECTIVES: Primary To assess the safety and determine the maximally tolerated dose (MTD) of modified FOLFIRINOX (mFOLFIRINOX) and ganitumab in patients with previously untreated, metastatic pancreatic adenocarcinoma. (phase I) To compare overall survival of patients with previously untreated, metastatic pancreatic adenocarcinoma who receive mFOLFIRINOX plus ganitumab versus mFOLFIRINOX plus placebo. (phase II) To assess the convergent validity of each selected PRO-CTCAE item by comparing each item at baseline between patients with ECOG performance status (PS) 0 vs 1. (phase II) Secondary To compare objective response rate, duration of response, and progression-free survival of patients with previously untreated, metastatic pancreatic adenocarcinoma who receive mFOLFIRINOX plus ganitumab versus mFOLFIRINOX plus placebo. To compare treatment-related toxicity in patients with previously untreated, metastatic pancreatic adenocarcinoma who receive mFOLFIRINOX plus ganitumab versus mFOLFIRINOX plus placebo. To assess the responsiveness (sensitivity to change) of Patient-Reported Outcomes (PRO)-CTCAE by comparing change scores within groups of patients as defined by changes in ECOG PS at post-baseline administrations. (phase II) To compare the maximum post-baseline score for each PRO-CTCAE item per patient between arms in the randomized phase II component of the study. (exploratory). OUTLINE: This is a dose-escalation, phase IB study followed by a randomized phase II study. Patients in the phase II study are stratified according to ECOG performance status of 0 versus 1. Phase IB: Patients receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 48 hours beginning on day 2 (mFOLFIRINOX). After cohort 0, subsequent patients also receive ganitumab IV over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients are randomized to 1 of 2 treatment arms: Arm I: Patients receive mFOLFIRINOX as in Phase IB and ganitumab IV over 30-60 minutes on day 1. Arm II: Patients receive mFOLFIRINOX as in Phase IB and placebo IV over 30-60 minutes on day 1. In both arms, treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Patients randomized in the phase II component of the study may complete 16 Patient-Reported Outcomes (PRO)-CTCAE items (measuring 8 symptoms) on paper on day 1 of all odd-numbered courses (i.e., courses 1, 3, 5, etc.). Tumor tissue and blood samples may be collected for correlative studies. After completion of study therapy, patients are followed every 3 months for 3 years.

Official Title
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Phase IB/Randomized Phase II Study of Folfirinox Plus AMG-479 (Ganitumab) or Placebo in Patients With Previously Untreated, Metastatic Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Biological: ganitumab
* Drug: fluorouracil
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium
* Drug: oxaliplatin
* Other: placebo
* Other: questionnaire administration


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed pancreatic ductal adenocarcinoma Metastatic disease to distant sites, as documented by CT scan or MRI Patients with locally advanced disease are NOT eligible At least one site of disease measurable by RECIST 1.1 criteria; defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan No known CNS metastases or carcinomatous meningitis, as determined by physical examination and/or imaging studies No suspected Gilbert syndrome or known homozygosity for the UGT1A1*28 allele (UGT1A1 genotyping is not required for enrollment on this study; however, patients known to be homozygous for the UGT1A1*28 allele are excluded) PATIENT CHARACTERISTICS: ECOG performance status 0 or 1 Neutrophils ≥ 1,500/μL Platelet count ≥ 100,000/μL Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min Total bilirubin ≤ 1.5 x upper limit of normal (ULN) AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN INR ≤ 1.5 Blood glucose level ≤ 160 mg/dL Patients with non-fasting blood glucose > 160 mg/dL must have a fasting blood glucose ≤ 160 mg/dL to be eligible Patients with diabetes mellitus are allowed at the discretion of the treating investigator, if blood sugars are felt to be under appropriate control Not pregnant or nursing Negative serum or urine pregnancy test No malignancy (other than non-melanoma skin cancer or carcinoma in situ of the cervix) diagnosed within the past 3 years or any currently active malignancy A malignancy is considered not active if all anti-cancer therapies were completed > 3 years before enrollment and there is no current evidence of persistent disease No neurosensory or neuromotor toxicity ≥ grade 2 No known allergy to platinum compounds or E. coli-derived products (e.g., filgrastim, humulin, insulin, or L-asparaginase) No colonic or small bowel disorders with uncontrolled symptoms at baseline (for example, > 3 watery or soft stools daily in patients without colostomy or ileostomy) Patients with colostomy or ileostomy can be enrolled at the discretion of the investigator No history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within 6 months of registration No HIV-positive patients with a prior history of AIDS-defining illness No HIV-positive patients with a CD4 count of < 450 cells/mm³ at any point prior to study Anti-retroviral therapy must be discontinued during study treatment No known positivity for chronic infection with B virus (HBV) PRIOR CONCURRENT THERAPY: Prior treatment with chemotherapy or radiotherapy for resected, locally advanced or metastatic pancreatic cancer is NOT allowed No prior treatment with inhibitors of the insulin-like growth factor 1 receptor No prior treatment with radiotherapy to greater than 25% of bone marrow Palliative radiation therapy may NOT be administered while a subject is on the study No major surgery within 4 weeks of the start of study treatment Patients must have recovered from the side effects of any major surgery at the start of study treatment Major surgery is defined as those surgeries that require general anesthesia Insertion of a vascular access device or endobiliary stent is NOT considered major surgery No percutaneous biliary drain (endobiliary stents are allowed) Warfarin for INR goal > 1.5 is prohibited Patients on warfarin with INR goal of ≤ 1.5 are eligible Hormones or other chemotherapeutic agents may NOT be administered except for steroids given for adrenal failure; hormones administered for non-disease-related conditions (e.g., insulin for diabetes); and intermittent use of dexamethasone as an antiemetic or for the prevention or treatment of ganitumab infusion reactions Patients receiving anti-retroviral therapy must discontinue such therapy while receiving study treatment

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
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 48 hours beginning on day 2 (mFOLFIRINOX) and ganitumab IV over 30-60 minutes on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. | Biological: ganitumab<br>* Given IV<br>Drug: fluorouracil<br>* Given IV<br>Drug: irinotecan hydrochloride<br>* Given IV<br>Drug: leucovorin calcium<br>* Given IV<br>Drug: oxaliplatin<br>* Given IV<br>|
| Experimental: Arm II<br>Patients receive mFOLFIRINOX as in arm I and placebo IV over 30-60 minutes on day 1. | Drug: fluorouracil<br>* Given IV<br>Drug: irinotecan hydrochloride<br>* Given IV<br>Drug: leucovorin calcium<br>* Given IV<br>Drug: oxaliplatin<br>* Given IV<br>Other: placebo<br>* Given IV<br>Other: questionnaire administration<br>* Completed on paper<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (phase I) |  |  | 
| Maximum-tolerated dose (phase I) |  |  | 
| Overall survival (phase II) |  |  | 
| Convergent validity of each selected PRO-CTCAE item (phase II) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate and duration of response between the mFOLFIRINOX plus ganitumab and the mFOLFIRINOX plus placebo arms (phase II) |  |  | 
| Progression-free survival (phase II) |  |  | 
| Responsiveness (sensitivity to change) of PRO-CTCAE (phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV pancreatic cancer, duct cell adenocarcinoma of the pancreas