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

Phase 1

Completed

• Conditions: Metastatic Colorectal Cancer
• Interventions: Drug: FOLFIRI, Avastin, Irinotecan

• Registration Number: NCT01183494
• Lead Sponsor: University of Chicago

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.

Detailed Description

Not available

Basic Information
|
Recruitment & Eligibility
|
Study & Design
|
Trial Locations

Study Timeline

• Study Start: 2009-12-12
• Study First Submitted: 2010-08-12
• Study First Submitted QC: 2010-08-16
• Study First Posted: 2010-08-17
• Primary Completion: 2017-06-02
• Study Completion: 2017-06-02
• Status Verified: 2019-04
• Last Update Submitted: 2019-04-18
• Last Update Posted: 2019-04-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 17

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.

Read More

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.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
UGT1A1*1/*28	FOLFIRI, Avastin, Irinotecan	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.
UGT1A1*1/*1	FOLFIRI, Avastin, Irinotecan	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	3 years	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

Name	Time	Method
To evaluate the pharmacokinetic profile of irinotecan in combination with bevacizumab.	3 years	To evaluate the effect of bevacizumab on the pharmacokinetics of irinotecan.

Trial Locations

Locations (2)

CRO-National Cancer Institute; 🇮🇹 Aviano, Italy

The University of Chicago; 🇺🇸 Chicago, Illinois, United States