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

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.