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A Genotype-guided Study of Irinotecan Administered in Combination With 5-fluorouracil/Leucovorin (FOLFIRI) and Bevacizumab in Advanced Colorectal Cancer Patients

Primary Purpose

Metastatic Colorectal Cancer

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
FOLFIRI, Avastin, Irinotecan
Sponsored by
University of Chicago
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Histologically or cytologically confirmed diagnosis of metastatic colorectal adenocarcinoma
  2. No prior chemotherapy for metastatic disease
  3. Age ≥18 years
  4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (5. Life expectancy > 3 months
  5. Adequate organ function, including bone marrow (absolute neutrophil count (ANC) ≥l500/μl, haemoglobin ≥ 9g/dL, platelets ≥ 100,000/ μl); hepatic (total bilirubin < 1.6 mg/dl;SGOT and SGPT < 2.5 x upper limit of normal for patients without liver metastases and < 5x upper limit of normal for patients with liver metastases); and renal (serum creatinine ≤ 1.5x upper limit of normal).
  6. Patients who are eligible to be registered in the study, based upon the above criteria, will be genotyped for the UGT1A1*28 polymorphism and stratified into two groups based on the presence of the UGT1A1*1/*1 or UGT1A1*1/*28 genotype.
  7. Patients with the UGT1A1*28/*28 genotype or carriers of the other alleles (TA5 and TA8)will be excluded.
  8. For patients to be evaluable for response (a secondary end point), they must have at least one measurable lesion as defined by RECIST (i.e., lesions that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm using spiral CT scan).
  9. Patients without measurable lesions can be included and will be evaluated only for toxicity.
  10. Signed informed consent and local IRB approval is required.
  11. 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.

Exclusion Criteria:

  1. Prior irinotecan or bevacizumab treatment
  2. Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
  3. Diarrhea greater than grade 1
  4. Bowel obstruction
  5. Documented brain metastases
  6. Serious active infectious disease
  7. Active uncontrolled bleeding or fistulas
  8. Pregnancy
  9. Radiotherapy or major surgery within 4 weeks
  10. 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 disease-free for five years.

Sites / Locations

  • The University of Chicago
  • CRO-National Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

UGT1A1*1/*1

UGT1A1*1/*28

Arm Description

Participants with UGT1A1*/*1 genotype will receive escalating doses of FOLFIRI (folinic acid+fluorouracil+irinotecan) and bevacizumab. The initial dose of irinotecan will be 260 mg/m2 administered as a 120 min intravenous infusion every two weeks. The dosage of irinotecan will be increased to 310, 370, and 420 mg/m2, and further irinotecan doses will be increased by 14%. 5-FU will be administered as a 400 mg/m2 bolus right after the end of the irinotecan infusion, followed by 2,400 mg/m2 over a 46 h continuous infusion plus LV 200 mg/m2 every two weeks. Bevacizumab will be administered at a dose of 5 mg/kg over 15-30 min IV (after an initial 90 min infusion without a reaction) every two weeks. The first dose will be administrated on day 2 (48 hours after the first irinotecan administration), while the second dose on day 14 (the same day as the second irinotecan administration). No dose escalation will be performed for 5-FU, LV or bevacizumab.

Participants with UGT1A1*1/*28 genotype will receive escalating doses of FOLFIRI (folinic acid+fluorouracil+irinotecan) and bevacizumab. The initial dose of irinotecan will be 260 mg/m2 administered as a 120 min intravenous infusion every two weeks. The dosage of irinotecan will be increased to 310, 370, and 420 mg/m2, and further irinotecan doses will be increased by 14%. 5-FU will be administered as a 400 mg/m2 bolus right after the end of the irinotecan infusion, followed by 2,400 mg/m2 over a 46 h continuous infusion plus LV 200 mg/m2 every two weeks. Bevacizumab will be administered at a dose of 5 mg/kg over 15-30 min IV (after an initial 90 min infusion without a reaction) every two weeks. The first dose will be administrated on day 2 (48 hours after the first irinotecan administration), while the second dose on day 14 (the same day as the second irinotecan administration). No dose escalation will be performed for 5-FU, LV or bevacizumab.

Outcomes

Primary Outcome Measures

Number of Participants with Adverse Events as a Measure of Safety and Tolerability
To define the Maximum Tolerated Dose (MTD), the Dose Limiting Toxicity (DLT), and the recommended dosage of irinotecan administered in first-line therapy with FOLFIRI plus bevacizumab for patients with metastatic CRC and either the UGT1A1*1/*1 or UGT1A1*1/*28 genotype.

Secondary Outcome Measures

To evaluate the pharmacokinetic profile of irinotecan in combination with bevacizumab.
To evaluate the effect of bevacizumab on the pharmacokinetics of irinotecan.

Full Information

First Posted
August 12, 2010
Last Updated
April 18, 2019
Sponsor
University of Chicago
Collaborators
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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1. Study Identification

Unique Protocol Identification Number
NCT01183494
Brief Title
A Genotype-guided Study of Irinotecan Administered in Combination With 5-fluorouracil/Leucovorin (FOLFIRI) and Bevacizumab in Advanced Colorectal Cancer Patients
Official Title
A Genotype-guided Phase I Study of Irinotecan Administered in Combination With 5-fluorouracil/Leucovorin (FOLFIRI) and Bevacizumab in Advanced Colorectal Cancer Patients
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Completed
Study Start Date
December 12, 2009 (Actual)
Primary Completion Date
June 2, 2017 (Actual)
Study Completion Date
June 2, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Chicago
Collaborators
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is being done to determine the maximum dose of a certain chemotherapy drug (irinotecan) that can be tolerated as part of a combination of drugs. There is a combination of chemotherapy drugs typically used to treat cancer of the colon and rectum: 5-Flurouracil (5-FU), leucovorin, and irinotecan; the combination is known as FOLFIRI. At the present time, the Food and Drug Administration (FDA) has approved this drug combination for the treatment of cancers of the colon and rectum. The FDA has also approved the use of a drug called bevacizumab (or Avastin) in combination with FOLFIRI, and this is considered one of the standards of care for all patients with colon and rectal cancer which has spread. The best dose of irinotecan to use in the combination of FOLFIRI and bevacizumab is not known. Earlier studies have shown that higher doses of irinotecan can be used safely as part of the FOLFIRI combination, but it is unclear whether these same doses will be safe when bevacizumab is added to this combination.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
UGT1A1*1/*1
Arm Type
Experimental
Arm Description
Participants with UGT1A1*/*1 genotype will receive escalating doses of FOLFIRI (folinic acid+fluorouracil+irinotecan) and bevacizumab. The initial dose of irinotecan will be 260 mg/m2 administered as a 120 min intravenous infusion every two weeks. The dosage of irinotecan will be increased to 310, 370, and 420 mg/m2, and further irinotecan doses will be increased by 14%. 5-FU will be administered as a 400 mg/m2 bolus right after the end of the irinotecan infusion, followed by 2,400 mg/m2 over a 46 h continuous infusion plus LV 200 mg/m2 every two weeks. Bevacizumab will be administered at a dose of 5 mg/kg over 15-30 min IV (after an initial 90 min infusion without a reaction) every two weeks. The first dose will be administrated on day 2 (48 hours after the first irinotecan administration), while the second dose on day 14 (the same day as the second irinotecan administration). No dose escalation will be performed for 5-FU, LV or bevacizumab.
Arm Title
UGT1A1*1/*28
Arm Type
Experimental
Arm Description
Participants with UGT1A1*1/*28 genotype will receive escalating doses of FOLFIRI (folinic acid+fluorouracil+irinotecan) and bevacizumab. The initial dose of irinotecan will be 260 mg/m2 administered as a 120 min intravenous infusion every two weeks. The dosage of irinotecan will be increased to 310, 370, and 420 mg/m2, and further irinotecan doses will be increased by 14%. 5-FU will be administered as a 400 mg/m2 bolus right after the end of the irinotecan infusion, followed by 2,400 mg/m2 over a 46 h continuous infusion plus LV 200 mg/m2 every two weeks. Bevacizumab will be administered at a dose of 5 mg/kg over 15-30 min IV (after an initial 90 min infusion without a reaction) every two weeks. The first dose will be administrated on day 2 (48 hours after the first irinotecan administration), while the second dose on day 14 (the same day as the second irinotecan administration). No dose escalation will be performed for 5-FU, LV or bevacizumab.
Intervention Type
Drug
Intervention Name(s)
FOLFIRI, Avastin, Irinotecan
Intervention Description
Patients will be treated with the FOLFIRI regimen plus bevacizumab. Irinotecan will be administered at doses higher than the standard dose in patients with the UGT1A1*1/*1 and UGT1A1*1/*28 genotypes, while the doses of infusional 5-FU/LV and bevacizumab will remain unchanged.
Primary Outcome Measure Information:
Title
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Description
To define the Maximum Tolerated Dose (MTD), the Dose Limiting Toxicity (DLT), and the recommended dosage of irinotecan administered in first-line therapy with FOLFIRI plus bevacizumab for patients with metastatic CRC and either the UGT1A1*1/*1 or UGT1A1*1/*28 genotype.
Time Frame
3 years
Secondary Outcome Measure Information:
Title
To evaluate the pharmacokinetic profile of irinotecan in combination with bevacizumab.
Description
To evaluate the effect of bevacizumab on the pharmacokinetics of irinotecan.
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically or cytologically confirmed diagnosis of metastatic colorectal adenocarcinoma No prior chemotherapy for metastatic disease Age ≥18 years Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (5. Life expectancy > 3 months Adequate organ function, including bone marrow (absolute neutrophil count (ANC) ≥l500/μl, haemoglobin ≥ 9g/dL, platelets ≥ 100,000/ μl); hepatic (total bilirubin < 1.6 mg/dl;SGOT and SGPT < 2.5 x upper limit of normal for patients without liver metastases and < 5x upper limit of normal for patients with liver metastases); and renal (serum creatinine ≤ 1.5x upper limit of normal). Patients who are eligible to be registered in the study, based upon the above criteria, will be genotyped for the UGT1A1*28 polymorphism and stratified into two groups based on the presence of the UGT1A1*1/*1 or UGT1A1*1/*28 genotype. Patients with the UGT1A1*28/*28 genotype or carriers of the other alleles (TA5 and TA8)will be excluded. For patients to be evaluable for response (a secondary end point), they must have at least one measurable lesion as defined by RECIST (i.e., lesions that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm using spiral CT scan). Patients without measurable lesions can be included and will be evaluated only for toxicity. Signed informed consent and local IRB approval is required. 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. Exclusion Criteria: Prior irinotecan or bevacizumab treatment Inflammatory bowel disease (Crohn's disease, ulcerative colitis) Diarrhea greater than grade 1 Bowel obstruction Documented brain metastases Serious active infectious disease Active uncontrolled bleeding or fistulas Pregnancy Radiotherapy or 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 disease-free for five years.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Manish Sharma, MD
Organizational Affiliation
University of Chicago
Official's Role
Principal Investigator
Facility Information:
Facility Name
The University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
CRO-National Cancer Institute
City
Aviano
ZIP/Postal Code
33081
Country
Italy

12. IPD Sharing Statement

Learn more about this trial

A Genotype-guided Study of Irinotecan Administered in Combination With 5-fluorouracil/Leucovorin (FOLFIRI) and Bevacizumab in Advanced Colorectal Cancer Patients

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