Metastatic Colorectal Cancer
Conditions
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.
Interventions
DRUGFOLFIRI, Avastin, Irinotecan
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.
Sponsors
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
University of Chicago
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the pharmacokinetic profile of irinotecan in combination with bevacizumab. | 3 years | To evaluate the effect of bevacizumab on the pharmacokinetics of irinotecan. |
Countries
Italy, United States
Outcome results
None listed