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