Study to Compare CAPTEM vs FOLFIRI as Second Line Treatment in Advanced, Colorectal Cancer Patients

• Status: Completed
• Trial end date: 2019-07-30
• Target enrollment: 0
• Participant gender: All

Summary

Open-label, randomized, multicenter, Phase II trial designed to estimate the efficacy of CAPTEM versus FOLFIRI as second line treatment in MGMT methylated, RAS mutated advanced CRC patients who have progressed on or after first-line oxaliplatin containing chemotherapy for metastatic disease. MGMT will be assessed centrally at Pathology Department of Fondazione IRCCS Istituto Nazionale dei Tumori prior to enrollment. A minimum of ten 3-micron unstained sections on charged slides of tumor will be required and methylation status will be provided within a maximum of seven days to the Study Centers. Presence of RAS mutation will be assessed at each local participating center. Eligible patients will be randomized in a 1:1 ratio to one of two treatment arms:

• Arm A (experimental arm): CAPTEM

• Arm B (control arm): FOLFIRI Study treatment will be given in cycles repeated every 28 days for Arm A and every 14 days for Arm B. Patients in Arm A will receive capecitabine at the oral dose of 1500 mg/mq/die bid from day 1 to day 14 every 28 days plus temozolomide 150 mg/mq/die bid starting on day 9 to 14 every 28 days. Patients in Arm B will receive FOLFIRI chemotherapy starting Day 1 q2w (every cycle) starting on Day 1 of Cycle 1. FOLFIRI consists of irinotecan (starting dose of 180 mg/m2) on day one only; 5-FU 7 (starting bolus and 22-hour infusional doses of 400 mg/m2 and 600 mg/m2, respectively), and leucovorin (racemic, starting dose of 200 mg/m2 or L-form, starting dose of 100 mg/m2) for two consecutive days. Treatment will continue for up to 6 cycles in Arm A and up to 12 cycles in Arm B or up to disease progression, unacceptable toxicity or informed consent withdrawal. Randomization will be stratified across the treatment arms by the following predefined stratification variables: disease progression within 9 months from the start of first-line oxaliplatin-containing chemotherapy (< vs. ≥9 months); prior bevacizumab in combination with oxaliplatin-based chemotherapy (yes vs. no). Efficacy assessments will be performed every 2 cycles in Arm A and every 4 cycles in Arm B until progression. The study is expected to enrol approximately 82 patients who meet the eligibility criteria.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Treatments: Capecitabine; Fluorouracil; Irinotecan; Leucovorin; Temozolomide

Criteria

Inclusion Criteria:

• Signed Informed Consent Form

• Histologically or cytologically confirmed adenocarcinoma of the colon and/or rectum, with MGMT promoter methylation and RAS mutation.

• Progressive disease on or after a first-line oxaliplatin containing chemotherapy regimen for mCRC with or without bevacizumab or other anti-angiogenic drugs. Patients must have received oxaliplatin-containing chemotherapy for ≥ 3 months. No more than one prior chemotherapy regimen for metastatic disease is allowed. 8

• Disease measurableRECIST v1.1

• Age ≥ 18 years and ≤ 75 years

• Life expectancy ≥ 12 weeks

• ECOG Performance Status of 0 1

• Adequate hematologic and end-organ function, defined by laboratory results obtained within 14 days prior to first administration: ANC ≥ 1500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 9.0 g/dL Albumin ≥ 2.5 g/dL

• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN)

• AST, ALT, and/or alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:

Patients with documented hepatic metastases are eligible with AST, ALT, and/or alkaline phosphatase ≤ 5 × ULN. Patients with documented bone metastases are eligible with alkaline phosphatase ≤ 5 × ULN.

• Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) × (weight in kg) × (0.85 if female) 72 × (serum creatinine in mg/dL)

• INR and aPTT ≤ 1.5 × ULN

• documented agreement (by patient and/or partner) to use an effective means of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) and to continue its use for the duration of the study and for 60 days for female patients or 150 days for male patients with partners of childbearing potential after the last infusion of study treatment.

• Consent to provide mandatory archival tumor tissue for biomarker testing

Exclusion Criteria:

• Prior treatment with irinotecan and temozolomide

• Major surgical procedure within 4 weeks and radiotherapy within 2 weeks prior to Day 1 Cycle 1

• Symptomatic hypercalcemia requiring continued use of bisphosphonate.

• Known clinically significant dihydropyrimidine 9 dehydrogenase deficiency

• Current severe, uncontrolled systemic disease Active infection requiring IV antibiotics

• History of heart failure of any New York Heart Association criteria or serious cardiac arrhythmia requiring treatment (except for atrial fibrillation and paroxysmal supraventricular tachycardia)

• History of myocardial infarction within 6 months prior to Cycle 1, Day 1, or history of unstable angina

• Known clinically significant liver disease,or current alcohol abuse

• History of bleeding diathesis or coagulopathy other than that due to anticoagulation therapy

• Patients receiving oral coumarin-derived anticoagulants

• Active haemoptysis within 30 days prior to Cycle 1, Day 1

• HIV infection

• Untreated/active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible provided they meet all of the following criteria: Measurable disease outside the CNS as defined by RECIST v1.1.Radiotherapy completed ≥ 4 weeks prior to Cycle, 1 Day

• Pregnancy or lactation. Women of childbearing potential (including those who have had a tubal ligation) must have a documented negative serum pregnancy test within 14 days prior to Cycle 1, Day 1.

• Inability to take oral medications.

• Malignancies other than CRC within 3 years prior to randomization, with the exception of adequately treated basal or squamous cell skin cancer and carcinoma in situ of the cervix