Genotype-guided Dosing of mFOLFIRINOX Chemotherapy in Patients With Previously Untreated Advanced Gastrointestinal Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by University of Chicago
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Chicago
ClinicalTrials.gov Identifier:
NCT01643499
First received: July 16, 2012
Last updated: March 20, 2014
Last verified: March 2014
  Purpose

This study is being done to determine the dose of a chemotherapy drug (irinotecan [irinotecan hydrochloride]) that can be tolerated as part of a combination of drugs. There is a combination of chemotherapy drugs often used to treat gastrointestinal cancer, which consists of 5-FU (fluorouracil), leucovorin (leucovorin calcium), irinotecan and oxaliplatin and is known as "FOLFIRINOX". FOLFIRINOX is a current drug therapy combination (or regimen) used for people with advanced pancreatic cancer, although this combination is not Food and Drug Administration (FDA) approved for this indication. FOLFIRINOX was recently shown in a separate clinical trial to increase survival compared to another commonly used drug in pancreatic cancer called gemcitabine. FOLFIRINOX is also a reasonable regimen for those with other advanced cancers of the gastrointestinal tract, including colon cancer, rectal cancer, esophagus cancer, stomach cancer, gall bladder cancer, bile duct cancer, ampullary cancer, and cancers with an unknown primary location. The best dose of irinotecan to use in FOLFIRINOX is not known. This study will analyze one gene (uridine 5'-diphospho [UDP] glucuronosyltransferase 1 family, polypeptide A1 [UGT1A1] gene) of subjects for the presence of an alteration in that gene, which may affect how the body handles irinotecan. Genes help determine some of the investigators individual characteristics, such as eye color, height and skin tone. Genes may also determine why people get certain diseases and how medicines may affect them. The result of the genetic analysis will divide subjects into one of three groups: A, B, or C. Group A (approximately 45% of subjects) will receive the standard dose of irinotecan. Group B (approximately 45% of subjects) will receive a lower dose of irinotecan. Group C (approximately 10% of subjects) will receive an even lower dose of irinotecan


Condition Intervention Phase
Acinar Cell Adenocarcinoma of the Pancreas
Adenocarcinoma of the Gallbladder
Adenocarcinoma of Unknown Primary
Adult Primary Cholangiocellular Carcinoma
Advanced Adult Primary Liver Cancer
Cholangiocarcinoma of the Extrahepatic Bile Duct
Cholangiocarcinoma of the Gallbladder
Diffuse Adenocarcinoma of the Stomach
Duct Cell Adenocarcinoma of the Pancreas
Intestinal Adenocarcinoma of the Stomach
Localized Unresectable Adult Primary Liver Cancer
Metastatic Carcinoma of Unknown Primary
Metastatic Extrahepatic Bile Duct Cancer
Mixed Adenocarcinoma of the Stomach
Mucinous Adenocarcinoma of the Colon
Mucinous Adenocarcinoma of the Rectum
Newly Diagnosed Carcinoma of Unknown Primary
Signet Ring Adenocarcinoma of the Colon
Signet Ring Adenocarcinoma of the Rectum
Stage III Pancreatic Cancer
Stage IIIA Colon Cancer
Stage IIIA Gallbladder Cancer
Stage IIIA Gastric Cancer
Stage IIIA Rectal Cancer
Stage IIIB Colon Cancer
Stage IIIB Gallbladder Cancer
Stage IIIB Gastric Cancer
Stage IIIB Rectal Cancer
Stage IIIC Colon Cancer
Stage IIIC Gastric Cancer
Stage IIIC Rectal Cancer
Stage IV Gastric Cancer
Stage IV Pancreatic Cancer
Stage IVA Colon Cancer
Stage IVA Gallbladder Cancer
Stage IVA Rectal Cancer
Stage IVB Colon Cancer
Stage IVB Gallbladder Cancer
Stage IVB Rectal Cancer
Unresectable Extrahepatic Bile Duct Cancer
Drug: oxaliplatin
Drug: irinotecan hydrochloride
Drug: leucovorin calcium
Drug: fluorouracil
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Genotype-guided Dosing Study of mFOLFIRINOX in Previously Untreated Patients With Advanced Gastrointestinal Malignancies

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • DLT rate in course 1 for each of the two most common genotype groups (*1*1 and *1*28) [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
    To show that the DLT rate is less than 33% with at least 70-80% confidence, which is comparable to the standard 3+3 phase I design with 0 out of 3 or 1 out of 6 patients experiencing a DLT.


Secondary Outcome Measures:
  • Response rates (by RECIST 1.1) for patients with each different type of gastrointestinal malignancy [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Cumulative dose intensity of irinotecan hydrochloride [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 45
Study Start Date: March 2012
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (mFOLFIRINOX)
Patients receive oxaliplatin IV over 2 hours on, irinotecan hydrochloride IV over 1.5 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46 hours on days 1 and 15. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicity (DLT) rate in cycle #1 in each of two UGT1A1 genotype groups (*1*1, *1*28) using genotype-guided dosing of irinotecan as part of the modified (m) FOLFIRINOX regimen.

SECONDARY OBJECTIVES:

I. To determine the cumulative dose intensity of irinotecan achieved in each genotype group.

II. To determine the response rates by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) for each different disease (pancreatic cancer, biliary cancers, gastric cancer, colorectal cancer, adenocarcinoma of unknown primary) treated in the study.

OUTLINE:

Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV over 1.5 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46 hours on days 1 and 15. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed locally advanced or metastatic pancreatic adenocarcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, cholangiocarcinoma, gall bladder adenocarcinoma, ampullary carcinoma, adenocarcinoma of unclear primary (with a gastrointestinal primary suspected), or other primary gastrointestinal malignancy for which the treating physician feels that mFOLFIRINOX is a reasonable therapeutic option.
  • Amendment (January 2014): only subjects with the following histologies will be eligible

Cohort # 1 (pancreatic cohort): locally advanced or metastatic pancreatic adenocarcinoma (19 subjects evaluable for the primary endpoint after the amendment)

Cohort #2 (biliary tract cohort): locally advanced or metastatic cholangiocarcinoma, gall bladder adenocarcinoma, or ampullary carcinoma (19 subjects evaluable for the primary endpoint after the amendment). Patients with adenocarcinoma of unclear primary that are most likely of biliary tract origin (in the opinion of the treating physician) will also be allowed on this cohort.

  • Patients with a history of obstructive jaundice due to the primary tumor must have a metal biliary stent in place,
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1,
  • Life expectancy > 3 months,
  • Absolute neutrophil count (ANC) >= l500/ul,
  • Hemoglobin >= 9g/dL,
  • Platelets >= 100,000/ ul,
  • Total bilirubin < 1.5 x upper limit of normal,
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) < 2.5 x upper limit of normal for patients without liver metastases OR SGOT and SGPT < 5 x upper limit of normal for patients with liver metastases,
  • Creatinine =< 1.5 x upper limit of normal,
  • Measurable or non-measurable disease will be allowed,
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, up until 30 days after final study treatment; should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately,
  • Patients taking substrates, inhibitors, or inducers of Cytochrome P450 3A4 (CYP3A4) should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with irinotecan
  • Signed informed consent.

Exclusion Criteria:

  • Prior chemotherapy or radiation therapy for any cancer,
  • 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, v. 4.0); pancreatic cancer patients with clinical evidence of pancreatic insufficiency must be taking pancreatic enzyme replacement,
  • Neuropathy, grade 2 or greater by NCI-CTCAE, v. 4.0,
  • 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%,
  • Patients with any polymorphism in UGT1A1 other than *1 or *28.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01643499

Locations
United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637-1470
Contact: Hedy L. Kindler    773-702-0360    hkindler@medicine.bsd.uchicago.edu   
Principal Investigator: Hedy L. Kindler         
Evanston CCOP-NorthShore University HealthSystem Not yet recruiting
Evanston, Illinois, United States, 60201
Contact: Robert De Marsh    847-570-1381    rmarsh@northshore.org   
Principal Investigator: Robert De Marsh         
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: Hedy Kindler University of Chicago Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT01643499     History of Changes
Other Study ID Numbers: 12-0033, NCI-2012-00585
Study First Received: July 16, 2012
Last Updated: March 20, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Gallbladder Neoplasms
Adenocarcinoma
Carcinoma
Colonic Neoplasms
Rectal Neoplasms
Adenocarcinoma, Mucinous
Cystadenocarcinoma
Liver Neoplasms
Stomach Neoplasms
Pancreatic Neoplasms
Bile Duct Neoplasms
Carcinoma, Acinar Cell
Cholangiocarcinoma
Neoplasms, Unknown Primary
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplasms, Cystic, Mucinous, and Serous
Liver Diseases
Stomach Diseases

ClinicalTrials.gov processed this record on July 24, 2014