Genotype-guided Dosing Of MFOLFIRINOX Chemotherapy In Patients With Previously Untreated Advanced Gastrointestinal Malignancies

Study Overview

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

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 ȯOLFIRINOX". 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

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.

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

12-0033
NCI-2012-00585 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2012-07-16	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2020-05-07
First Submitted that Met QC Criteria 2012-07-17	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2020-05-08
First Posted (ACTUAL) 2012-07-18	Results First Posted N/A	Last Verified 2020-05

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
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 ab	DRUG: oxaliplatin Given IV DRUG: irinotecan hydrochloride Given IV DRUG: leucovorin calcium Given IV DRUG: fluorouracil Given IV OTHER: laboratory biomarker analysis Correlative studies

Participant Group/Arm

Intervention/Treatment

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 ab

DRUG: oxaliplatin

Given IV

DRUG: irinotecan hydrochloride

Given IV

DRUG: leucovorin calcium

Given IV

DRUG: fluorouracil

Given IV

OTHER: laboratory biomarker analysis

Correlative studies

Primary Outcome Measures	Measure Description	Time Frame
DLT rate in course 1 for each of the two most common genotype groups (11 and 128)	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.	4 weeks

Secondary Outcome Measures	Measure Description	Time Frame
Response rates (by RECIST 1.1) for patients with each different type of gastrointestinal malignancy		Up to 1 year
Cumulative dose intensity of irinotecan hydrochloride		Up to 1 year

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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.

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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Hedy Kindler, University of Chicago Comprehensive Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

No publications available

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Resources

Patients

Caregivers

Clinical Trial Record