gFOLFOXIRITAX Regimen for the Treatment of Locally Advanced or Metastatic Upper Gastrointestinal Adenocarcinoma, I-FLOAT Study

Status: closed to accrual

This phase I trial uses genotyping to help determine the best dose of irinotecan when given together with fluorouracil, leucovorin, oxaliplatin, and Taxotere (gFOLFOXIRITAX) in treating patients with upper gastrointestinal adenocarcinoma that has spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Chemotherapy drugs, such as irinotecan, fluorouracil, leucovorin, oxaliplatin, and Taxotere, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Inclusion Criteria

Histologically or cytologically confirmed locally advanced or metastatic pancreatic adenocarcinoma, gastroesophageal adenocarcinoma, cholangiocarcinoma, gallbladder adenocarcinoma, ampullary carcinoma, adenocarcinoma of unclear primary (with upper gastrointestinal [GI] primary suspected), or other primary GI malignancy for which the treating physician feels that I-FLOAT is a reasonable therapeutic option
Patients with a history of obstructive jaundice due to the primary tumor must have resolved to < 1.5 X upper limit of normal and a metal biliary stent in place
Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status =< 1
Absolute neutrophil count (ANC) >= 1500/uL
Hemoglobin >= 9 g/dL (transfusion permitted with stability for > 1 week)
Platelets > 100,000/uL
Total bilirubin =< 1.5 mg/dL
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X upper limit of normal
AST and ALT =< 5 X upper limit of normal if hepatic metastases are present
Creatinine =< 1.5 mg/dL
Measurable or non-measurable disease will be allowed
Women of childbearing potential and sexually active males must use an effective contraception method during treatment and for three months after completing treatment
Negative serum or urine B-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of childbearing potential
Patients taking substrates, inhibitors, or inducers of CYP3A4 should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with irinotecan

Exclusion Criteria

Prior radiation therapy for any cancer
Prior chemotherapy for metastatic disease: Recurrence of disease within 6 months of perioperative chemotherapy are eligible if other eligibility criteria are met
Inflammatory bowel disease (Crohn’s disease, ulcerative colitis)
Diarrhea, grade 1 or greater by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version [v.] 5.0). Pancreatic cancer patients with clinical evidence of pancreatic insufficiency must be taking pancreatic enzyme replacement
Neuropathy, grade 2 or greater by NCI-CTCAE, v. 5.0
Documented brain metastases
Serious underlying medical or psychiatric illnesses that would, in the opinion of the treating physician, substantially increase the risk for complications related to treatment
Active uncontrolled bleeding
Pregnancy or breastfeeding
Major surgery within 4 weeks
Previous or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer for which the patient has been previously treated and the lifetime recurrence risk is less than 30%, and meets all other eligibility criteria

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose in the first month of therapy in each of the three main UGT1A1 genotype groups (low, intermediate, and high risk) using genotype-guided dosing of irinotecan as part of the I-FLOAT regimen.

SECONDARY OBJECTIVES:

I. To determine the cumulative dose of each chemotherapy drug (irinotecan, fluorouracil [5-FU], oxaliplatin, docetaxel) administered in each genotype group over a period of 4 months (8 doses).

II. To determine the total duration of therapy, which would be administered perioperatively in future studies for the curative-intent setting.

III. To determine early efficacy (overall responsive rate, progression free survival, and overall survival) in all patients enrolled and treated in the study.

EXPLORATORY OBJECTIVES:

I. To determine the response rates by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) for each different disease (pancreatic cancer, biliary tract including ampullary cancer, gastroesophageal adenocarcinoma, and small bowel adenocarcinoma) treated in the study.

II. To determine the progression free survival and overall survival for each different disease (pancreatic cancer, biliary tract including ampullary cancer, gastroesophageal adenocarcinoma, and small bowel adenocarcinoma) treated in the study.

III. To study additional pharmacogenomic clinical correlates that may inform predisposition to chemotherapy-related toxicity and the potential for future dose adjustment in susceptible populations.

IV. To assess safety and tolerability of I-FLOAT in combination with HER2-targeted therapy, trastuzumab, in patients with HER2+ gastroesophageal disease.

V. To assess the efficacy (overall response rate [ORR], progression free survival [PFS], overall survival [OS]) of I-FLOAT in combination with HER2-targeted therapy, trastuzumab, in patients with HER2+ disease, and by disease type.

OUTLINE: This is dose-escalation study of irinotecan.

Patients receive docetaxel (Taxotere) intravenously (IV) over 1 hour, oxaliplatin IV over 2 hours, leucovorin IV over 2 hours, irinotecan IV over 1.5 hours, and fluorouracil IV over 46 hours on day 1. Patients receive pegfilgrastim subcutaneously (SC) on day 4. Patients with HER2 disease also receive trastuzumab IV over 30-90 minutes on day 1 before chemotherapy. Cycles repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients with locally advanced unresectable disease may discontinue treatment after 8 cycles if consolidative chemoradiation or laparoscopic hyperthermic intraperitoneal chemotherapy with or without surgery (for peritoneal only disease) is being considered thereafter.

After completion of study treatment, patients are followed up for 60 months.

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gFOLFOXIRITAX Regimen for the Treatment of Locally Advanced or Metastatic Upper Gastrointestinal Adenocarcinoma, I-FLOAT Study

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