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

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ClinicalTrials.gov Identifier: NCT02138617
Recruitment Status : Recruiting
First Posted : May 14, 2014
Last Update Posted : February 22, 2019
Sponsor:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Colon Cancer Drug: 5-Fluorouracil Drug: Leucovorin Drug: Irinotecan Drug: Bevacizumab Phase 2

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)).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Genotype-Directed Phase II Study Of Higher Dose Of Irinotecan In First-Line Metastatic Colorectal Cancer Patients Treated With Folfiri Plus Bevacizumab
Study Start Date : May 2014
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: *1/*1 Genotype
FOLFIRI (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.
Drug: 5-Fluorouracil
400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 .
Other Names:
  • 5-FU
  • Adrucil

Drug: Leucovorin
200-400 mg/m2 IV over 2 hours, Day 1 and Day 15
Other Names:
  • LV
  • leucovorin calcium
  • folinic acid
  • citrovorum factor

Drug: Irinotecan
IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype.
Other Names:
  • Camptosar
  • Novaplus Irinotecan Hydrochloride

Drug: Bevacizumab
Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Other Name: Avastin

Experimental: *1/*28 Genotype
FOLFIRI (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.
Drug: 5-Fluorouracil
400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 .
Other Names:
  • 5-FU
  • Adrucil

Drug: Leucovorin
200-400 mg/m2 IV over 2 hours, Day 1 and Day 15
Other Names:
  • LV
  • leucovorin calcium
  • folinic acid
  • citrovorum factor

Drug: Irinotecan
IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype.
Other Names:
  • Camptosar
  • Novaplus Irinotecan Hydrochloride

Drug: Bevacizumab
Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Other Name: Avastin

Experimental: *28/*28
FOLFIRI (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.
Drug: 5-Fluorouracil
400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 .
Other Names:
  • 5-FU
  • Adrucil

Drug: Leucovorin
200-400 mg/m2 IV over 2 hours, Day 1 and Day 15
Other Names:
  • LV
  • leucovorin calcium
  • folinic acid
  • citrovorum factor

Drug: Irinotecan
IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype.
Other Names:
  • Camptosar
  • Novaplus Irinotecan Hydrochloride

Drug: Bevacizumab
Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Other Name: Avastin




Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: From date of registration until date of first documented progression up to 8 years. ]
    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 :
  1. Number of Participants with adverse events [ Time Frame: From date of registration up to 8 years. ]
    Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.03)

  2. Overall Response [ Time Frame: 5 years ]
    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).

  3. Overall Survival [ Time Frame: 8 years ]
    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



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02138617


Contacts
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Contact: Bob Broomer 919-966-9257 bob_broomer@med.unc.edu

Locations
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United States, Indiana
IU Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Principal Investigator: Bert O'Neil, MD         
IU Arnett Hospital Terminated
Lafayette, Indiana, United States, 47905
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Julie White, RN    919-843-7115    julie_white@med.unc.edu   
Principal Investigator: Hanna Sanoff, MD         
Carolina Healthcare Systems Recruiting
Charlotte, North Carolina, United States, 28204
Principal Investigator: Jai Patel, MD         
Cone Health Cancer Center Recruiting
Greensboro, North Carolina, United States, 27403
Principal Investigator: Gary Sherrill, MD         
Rex Healthcare Recruiting
Raleigh, North Carolina, United States, 27607
Principal Investigator: Jeremiah Boles, MD         
United States, Virginia
Bon Secours Cancer Institute Recruiting
Midlothian, Virginia, United States, 23114
Contact: William J Irvin, Jr., MD    804-893-8717    william_irvin@bshsi.org   
Principal Investigator: William J Irvin, Jr., MD         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
Layout table for investigator information
Principal Investigator: Hanna Sannoff, MD UNC Lineberger Comprehensive Cancer Center

Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02138617     History of Changes
Other Study ID Numbers: LCCC 1317
First Posted: May 14, 2014    Key Record Dates
Last Update Posted: February 22, 2019
Last Verified: February 2019

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Colon Cancer
Irinotecan
FOLFIRI
Genotyping
UGT1A1

Additional relevant MeSH terms:
Layout table for MeSH terms
Colorectal Neoplasms
Colonic Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Irinotecan
Fluorouracil
Leucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents