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A Pharmacogenetic-Based Phase I Trial of Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in Patients With Advanced Gastrointestinal Cancer

Phase 1
18 Years
Open (Enrolling)
Anal Cancer, Carcinoma of the Appendix, Colorectal Cancer, Esophageal Cancer, Extrahepatic Bile Duct Cancer, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Liver Cancer, Pancreatic Cancer, Small Intestine Cancer

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Trial Information

A Pharmacogenetic-Based Phase I Trial of Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in Patients With Advanced Gastrointestinal Cancer



- To determine the maximum tolerated dose of irinotecan hydrochloride in FOLFIRI for each
respective UGT1A1 TA indel genotype grouping (group 1 [7/7, 7/8, 8/8], group 2 [6/7,
5/7, 5/8 ,6/8], and group 3 [6/6, 5/6, 5/5]).


- Determine the molecular basis of toxicity, other than UGT1A1 variants, in
FOLFIRI-treated cancer patients.

- Determine the pharmacodynamic molecular profiles of cell signaling pathways associated
with the development and severity of early and late specific toxicities in cancer
patients treated with FOLFIRI.

OUTLINE: This is a dose-escalation study of irinotecan hydrochloride. Patients are
stratified according to genotype of UGT1A1 TA indel.

- Group 1 ( TA genotype 7/7, 7/8, 8/8): Patients receive irinotecan hydrochloride IV over
90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV bolus
over 5 minutes followed by IV continuously over 46 hours on days 1-3.

- Group 2 (TA genotype 6/7, 6/7, 5/8, 6/8): Patients receive treatment as in group 1 with
a higher initial dose of irinotecan hydrochloride.

- Group 3 (TA genotype 5/5, 5/6, 6/6): Patients receive treatment as in group 2. In all
groups, treatment repeats every 14 days in the absence of disease progression or
unacceptable toxicity.

Patients undergo blood collection at baseline and periodically during study for
pharmacokinetics, dihydropyridine deaminase enzyme assay, and pathway expression analysis.

After completion of study treatment, patients are followed every 6 weeks for up to 2 years.

Inclusion Criteria


- Biopsy confirmed diagnosis of gastrointestinal cancer

- Advanced, unresectable disease

- Confirmation of UGT1A1 TA indel genotype

- Measurable or evaluable (non-measurable) disease

- Measurable disease is defined as ≥ 1 lesion that can be accurately measured
(longest diameter to be recorded) as ≥ 2.0 cm with conventional techniques or as
≥ 1.0 cm with spiral CT scan

- Clinical lesions will only be considered measurable when they are
superficial (e.g., skin nodules, palpable lymph nodes)

- Lesions on chest x-ray are acceptable as measurable lesions when they are
clearly defined and surrounded by aerated lung

- The following are considered non-measurable disease:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusions

- Lymphangitis cutis/ pulmonis

- Inflammatory breast disease

- Abdominal masses (not followed by CR scan or MRI)

- Cystic lesions

- All other lesions (or sites of disease), including small lesions (longest
diameter < 2.0 cm with conventional techniques or as < 1.0 cm with spiral

- No known central nervous system metastases or carcinomatous meningitis


Inclusion criteria

- Life expectancy ≥ 12 weeks.

- ECOG performance status 0-2

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- SGOT ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN if liver metastases)

- Total Bilirubin ≤ ULN for patients in group 3 and ≤ 2.0 times ULN for patients in
groups 1 and 2

- Hemoglobin ≥ 9.0 g/dL

- Creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception for the duration of study treatment

- Willing to provide blood samples for mandatory translational studies

Exclusion criteria

- Known allergy to irinotecan hydrochloride-related agents (e.g., topotecan),
5-fluorouracil, and/or leucovorin calcium

- Active or uncontrolled infection

- Evidence of serious intercurrent illness (e.g., unstable angina, symptomatic
congestive heart failure, serious uncontrolled cardiac arrhythmia)


- Recovered from all toxicities

- More than 4 weeks since prior major surgery

- More than 2 weeks since completion of prior radiotherapy

- No prior radiotherapy to > 25% of bone marrow

- More than 2 week since prior cytotoxic chemotherapy, biologic therapy, or

- No concurrent sargramostim (GM-CSF)

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of genotype-based dosing of FOLFIRI with or without monoclonal antibody therapy

Safety Issue:


Principal Investigator

Robert McWilliams, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Federal Government

Study ID:




Start Date:

June 2008

Completion Date:

Related Keywords:

  • Anal Cancer
  • Carcinoma of the Appendix
  • Colorectal Cancer
  • Esophageal Cancer
  • Extrahepatic Bile Duct Cancer
  • Gallbladder Cancer
  • Gastric Cancer
  • Gastrointestinal Carcinoid Tumor
  • Gastrointestinal Stromal Tumor
  • Liver Cancer
  • Pancreatic Cancer
  • Small Intestine Cancer
  • stage IIIB anal cancer
  • stage IV anal cancer
  • recurrent anal cancer
  • carcinoma of the appendix
  • stage III colon cancer
  • stage IV colon cancer
  • recurrent colon cancer
  • stage III rectal cancer
  • stage IV rectal cancer
  • recurrent rectal cancer
  • stage III esophageal cancer
  • stage IV esophageal cancer
  • recurrent esophageal cancer
  • recurrent extrahepatic bile duct cancer
  • unresectable extrahepatic bile duct cancer
  • unresectable gallbladder cancer
  • recurrent gallbladder cancer
  • stage III gastric cancer
  • stage IV gastric cancer
  • recurrent gastric cancer
  • metastatic gastrointestinal carcinoid tumor
  • recurrent gastrointestinal carcinoid tumor
  • regional gastrointestinal carcinoid tumor
  • gastrointestinal stromal tumor
  • advanced adult primary liver cancer
  • localized unresectable adult primary liver cancer
  • recurrent adult primary liver cancer
  • stage II pancreatic cancer
  • stage III pancreatic cancer
  • stage IV pancreatic cancer
  • recurrent pancreatic cancer
  • recurrent small intestine cancer
  • small intestine adenocarcinoma
  • small intestine leiomyosarcoma
  • small intestine lymphoma
  • Anus Neoplasms
  • Carcinoid Tumor
  • Carcinoma
  • Colorectal Neoplasms
  • Esophageal Diseases
  • Esophageal Neoplasms
  • Liver Neoplasms
  • Stomach Neoplasms
  • Pancreatic Neoplasms
  • Duodenal Neoplasms
  • Ileal Neoplasms
  • Jejunal Neoplasms
  • Gallbladder Neoplasms
  • Bile Duct Neoplasms
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Gastrointestinal Stromal Tumors
  • Intestinal Neoplasms
  • Colonic Neoplasms



Mayo Clinic Rochester, Minnesota  55905