Clinical Trials /

Genotype-Directed Study Of Irinotecan Dosing In FOLFIRI + BevacizumabTreated Metastatic Colorectal Cancer

NCT02138617

Description:

This study involves standard combination chemotherapy treatment for colon cancer, 5-Fluorouracil (5FU), leucovorin and irinotecan (known as FOLFIRI), plus bevacizumab (Avastin). The study is designed to test the FOLFIRI regimen based on certain characteristics of a person's genetic makeup or "genes". Genes are made of DNA and determine not only inherited traits or appearance (hair and eye color, height, body type, etc.) but also play an important role in health and how the body responds to illness and treatments for those illnesses. In this study, the investigators will examine the relationship between a patient's genes (DNA), or "genotype", and how the patient's body breaks down and removes or "metabolizes" the anti-cancer drug irinotecan. Circulating blood level of irinotecan plays an important role in how well this drug works against a patient's cancer as well as the adverse side effects the patient may experience. The current standard dose of irinotecan was determined in clinical trials without knowing individual genotypes and thus does not take into account a patient's ability to metabolize irinotecan. This means that based on one genotype the current standard dose of irinotecan may be correct or based on other genotypes the standard dose could result in lower and possibly less effective blood levels and result in significant under-dosing of irinotecan. Based on genotype the patient will be assigned to one of the following doses of irinotecan: - 180 mg/m2 (standard dose) - 260 mg/m2 - 310 mg/m2 The purpose of this research study is to determine if dosing irinotecan based on genotype is effective and safe for patients with colon cancer. Patient genotype will be determined from a small sample of blood and a laboratory test or "assay" performed at UNC Laboratories. For the purpose of this study, this assay is new and considered to be "investigational". This means that the genotype assay used in this study has not yet been approved by the FDA for determining irinotecan dose levels in patients with colon cancer.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Genotype-Directed Study Of Irinotecan Dosing In FOLFIRI + BevacizumabTreated Metastatic Colorectal Cancer
  • Official Title: Genotype-Directed Phase II Study Of Higher Dose Of Irinotecan In First-Line Metastatic Colorectal Cancer Patients Treated With Folfiri Plus Bevacizumab

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1317
  • NCT ID: NCT02138617

Conditions

  • Colon Cancer

Interventions

DrugSynonymsArms
5-Fluorouracil5-FU, Adrucil*1/*1 Genotype
LeucovorinLV, leucovorin calcium, folinic acid, citrovorum factor*1/*1 Genotype
IrinotecanCamptosar, Novaplus Irinotecan Hydrochloride*1/*1 Genotype
BevacizumabAvastin*1/*1 Genotype

Purpose

This study involves standard combination chemotherapy treatment for colon cancer, 5-Fluorouracil (5FU), leucovorin and irinotecan (known as FOLFIRI), plus bevacizumab (Avastin). The study is designed to test the FOLFIRI regimen based on certain characteristics of a person's genetic makeup or "genes". Genes are made of DNA and determine not only inherited traits or appearance (hair and eye color, height, body type, etc.) but also play an important role in health and how the body responds to illness and treatments for those illnesses. In this study, the investigators will examine the relationship between a patient's genes (DNA), or "genotype", and how the patient's body breaks down and removes or "metabolizes" the anti-cancer drug irinotecan. Circulating blood level of irinotecan plays an important role in how well this drug works against a patient's cancer as well as the adverse side effects the patient may experience. The current standard dose of irinotecan was determined in clinical trials without knowing individual genotypes and thus does not take into account a patient's ability to metabolize irinotecan. This means that based on one genotype the current standard dose of irinotecan may be correct or based on other genotypes the standard dose could result in lower and possibly less effective blood levels and result in significant under-dosing of irinotecan. Based on genotype the patient will be assigned to one of the following doses of irinotecan: - 180 mg/m2 (standard dose) - 260 mg/m2 - 310 mg/m2 The purpose of this research study is to determine if dosing irinotecan based on genotype is effective and safe for patients with colon cancer. Patient genotype will be determined from a small sample of blood and a laboratory test or "assay" performed at UNC Laboratories. For the purpose of this study, this assay is new and considered to be "investigational". This means that the genotype assay used in this study has not yet been approved by the FDA for determining irinotecan dose levels in patients with colon cancer.

Detailed Description

      This phase II multicenter clinical trial will use a genotype-guided dosing strategy for
      irinotecan to prospectively analyze efficacy in 100 metastatic colorectal cancer patients
      (mCRC) receiving FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) plus bevacizumab.
      Irinotecan is detoxified and excreted primarily by glucuronidation in the liver via the
      isoenzyme uridine diphosphate glucuronosyl transferase (UGT1A1). Common variants in UGT1A1
      alter the rate of glucuronidation and thus alter exposure to irinotecan.

      The UGT1A1 *28 allele results in slower irinotecan glucuronidation, and thus greater
      exposure to its active metabolite SN-38. At the standard irinotecan dose used in FOLFIRI
      (180 mg/m2; established prior to our understanding of the importance of genotype in the rate
      of this drug's metabolism), there is a small increased risk of neutropenia in *28
      homozygotes. However, the risk of clinically important consequences of neutropenia, such as
      febrile neutropenia and infection, are not significantly increased. Patients with other
      genotypes have a quite low risk of adverse effects suggesting patients with these low risk
      genotypes may tolerate higher doses of irinotecan in FOLFIRI. This finding was demonstrated
      in a phase I study in which *1/*28 and *1/*1 genotypes were able to tolerate escalating
      doses of irinotecan up to 260 mg/m2 and 310 mg/m2, respectively.

      The central hypothesis of this trial is that increasing the irinotecan dose in *1/*28 and
      *1/*1 genotypes will increase the overall benefit of FOLFIRI for patients with mCRC as these
      two groups are likely under-dosed with the current dosing regimen. Eligible patients will be
      genotyped for UGT1A1 and assigned into 1 of 3 different dosing groups, based on their
      relative rate of metabolism. The primary objective of this trial is to estimate
      progression-free survival (PFS), and secondary objectives include characterization of
      toxicity and objective response rate (OR; complete response (CR) + partial response (PR)).
    

Trial Arms

NameTypeDescriptionInterventions
*1/*1 GenotypeExperimentalFOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days.
  • 5-Fluorouracil
  • Leucovorin
  • Irinotecan
  • Bevacizumab
*1/*28 GenotypeExperimentalFOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days.
  • 5-Fluorouracil
  • Leucovorin
  • Irinotecan
  • Bevacizumab
*28/*28ExperimentalFOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days.
  • 5-Fluorouracil
  • Leucovorin
  • Irinotecan
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

        Subjects must meet all of the inclusion criteria to participate in this study:

          1. IRB-approved informed consent obtained and signed

          2. Age ≥ 18 years

          3. Histological or cytological documentation of adenocarcinoma of the colon or rectum

          4. Measurable or non-measurable (but evaluable) disease as defined via RECIST 1.1

          5. Metastatic disease not amenable to surgical resection with curative intent

          6. No prior chemotherapy for metastatic disease

          7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see section 11.1,
             Appendix A)

          8. Adequate bone marrow, renal and hepatic function, as evidenced by the following:

               -  absolute neutrophil count (ANC) ≥1,500/mm3

               -  platelets ≥100,000/mm3

               -  hemoglobin ≥9.0 g/dL

               -  serum creatinine ≤1.5 x upper limit of normal (ULN)

               -  AST and ALT ≤3x ULN ( ≤5.0 × ULN for patients with liver involvement of their
                  cancer

               -  Bilirubin ≤1.5 X ULN

               -  Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of their cancer)

          9. Willing to undergo UGT1A1 genotyping

         10. Negative pregnancy test (urine or serum), within 7 day prior to Day 1 of FOLFIRI in
             women of childbearing potential

         11. Women of childbearing potential and male subjects must agree to use adequate
             contraception for the duration of study participation. Adequate contraception is
             defined as any medically recommended method (or combination of methods) as per
             standard of care.

        Exclusion Criteria

          1. UGT1A1 genotype other than *1/*1, *1/*28, or *28/*28

          2. Known dihydropyrimidine dehydrogenase (DPD) deficiency

          3. Prior treatment with irinotecan and/or bevacizumab

          4. Unable or unwilling to discontinue (and substitute if necessary) use of prohibited
             drugs for at least 14 days (fruits and juices for at least 7 days) prior to Day 1 of
             FOLFIRI + bevacizumab initiation (see section 11.2, Appendix B, for list of
             prohibited drugs)

          5. Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg
             and/or diastolic blood pressure > 90 mmHg)

          6. Prior history of hypertensive encephalopathy

          7. Active cardiac disease including any of the following:

               -  New York Heart Association (NYHA) Grade II or greater congestive heart failure
                  (see section 11.3, Appendix C)

               -  History of myocardial infarction or unstable angina within 6 months prior to Day
                  1

               -  History of stroke or transient ischemic attack within 6 months prior to Day 1 of
                  FOLFIRI + bevacizumab initiation

          8. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to Day 1 of FOLFIRI +
             bevacizumab initiation

          9. History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month
             prior to Day 1 of FOLFIRI + bevacizumab initiation

         10. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation)

         11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1 of FOLFIRI + bevacizumab initiation or anticipation of need for major
             surgical procedure during the course of the study

         12. Core biopsy or other minor surgical procedure, excluding placement of a vascular
             access device, within 7 days prior to Day 1 of FOLFIRI + bevacizumab initiation

         13. History of abdominal fistula or gastrointestinal perforation within 6 months prior to
             Day 1 of FOLFIRI + bevacizumab initiation

         14. Serious, non-healing wound, active ulcer, or untreated bone fracture

         15. Proteinuria as demonstrated by:

             Urine protein: creatinine (UPC) ratio ≥ 1.0 at screening OR Urine dipstick for
             proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis
             at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of
             protein in 24 hours to be eligible)

         16. Any serious uncontrolled medical disorder that would impair the ability of the
             subject to receive protocol-driven therapy

         17. Other anti-cancer or investigational therapy while patients are on study therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:From date of registration until date of first documented progression up to 8 years.
Safety Issue:
Description:Tumor measurements within 5 days prior to D1 every 2 cycles starting with cycle 3 to include CT/MRI scans of chest, abdomen and pelvis---any additional suspected sites of disease should be evaluated per treating physician discretion.Progression Free Survival is defined as time from day 1 (D1) of treatment to progression or death from any cause.

Secondary Outcome Measures

Measure:Toxicity
Time Frame:From date of registration up to 8 years.
Safety Issue:
Description:Evaluate toxicity profile when irinotecan is dosed according to UGT1A1 genotype. Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.03)
Measure:Overall Response
Time Frame:5 years
Safety Issue:
Description:Estimate Overall Response (OR =Complete Response +Partial Response) in previously untreated mCRC patients receiving FOLFIRI + bevacizumab when irinotecan dose is based on UGT1A1 genotype. OR will be defined per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Measure:Overall Survival
Time Frame:8 years
Safety Issue:
Description:Estimate Overall Survival (OS) in previously untreated mCRC patients receiving FOLFIRI + bevacizumab when irinotecan dose is based on UGT1A1 genotype. OS is defined as the time from D1 of treatment to death from any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • Colon Cancer
  • Irinotecan
  • FOLFIRI
  • Genotyping
  • UGT1A1

Last Updated

March 17, 2017