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A Study Of PF-05212384 plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS and NRAS Wild Type Metastatic Colorectal Cancer

ABSTRACT: Intervention name : Drug: PF-05212384 Drug: Irinotecan Dosage And administration of the intervention : PF-05212384: 30 minute IV infusion of PF-05212384 110 mg on days 2, 9, 16 and 23 of each cycle Irinotecan: 90 minutes IV infusion of irinotecan 180mg/m2 on days 1 and 15 of each cycle Control intervention name : Drug: Cetuximub Drug: irinotecan Dosage And administration of the control intervention : Cetuximab: 120 minute IV infusion of cetuximab 400 mg/m2 on cycle 1 day 1; 60 minute IV infusion of cetuximab 250 mg/m2 on day 8, 15, and 22 of each cycle and on day of each cycle after cycle 1. Irinotecan: 90 minutes IV infusion of irinotecan 180mg/m2 on days 1 and 15 of each cycle Primary outcome(s): PFS Study Design: Open, 2 arm, randomized controlled trial

DISEASE(S): Metastatic Colorectal Cancer

PROVIDER: 2611015 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Study Design: This is a pragmatic study on the management strategy for patients with metastatic colorectal cancer (CRC) who are candidates for CT, independently of any previous adjuvant therapy received. The aim of this study is to define the role of new target molecules in combination with CT in first- and second line treatment. First line study: Eligible patients were randomized to either treatment: Arm A: FOLFIRI or FOLFOX + Bevacizumab, cycle to be repeated every 2 weeks * BEVACIZUMAB: Day 1,1st cycle 5 mg/kg IV infusion of 90 min Day 1, 2nd cycle if well tolerated, 5 mg/kg IV infusion of 60 min Day 1, 3rd cycle and subsequent cycles if well tolerated, 5 mg/kg IV infusion of 30 min after 5-Fluorouracile (FU) bolus * FOLFIRI Day 1: Irinotecan 180 mg/m2 IV infusion 30-90 min Day 1,2: L-Folinic acid 100 mg/m2 IV infusion of 2 hours 5-Fluorouracil 400 mg/m2 as a bolus 5-Fluorouracil 600 mg/m2 continuous IV infusion of 22 hours - FOLFOX Day 1: Oxaliplatin 85 mg/m2 IV infusion of 2hours Day 1,2: L-Folinic acid 100 mg/m2 IV infusion of 2 hours 5-Fluorouracil 400 mg/m2 as a bolus 5-Fluorouracil 600 mg/m2 continuous IV infusion of 22 hours Arm B: FOLFIRI or FOLFOX, cycle to be repeated every 2 weeks If FOLFIRI: FOLFIRI as specified in arm A without Bevacizumab If FOLFOX: FOLFOX as specified in arm A without Bevacizumab Duration of Therapy For both arms, CT was repeated until progressive disease (PD) or unacceptable toxicity occurs. If unacceptable CT-related toxicity occurs in ARM A, in the absence of PD patients stopped CT and continued with only bevacizumab 5 mg/kg as a 30-min infusion every 2 weeks until progression or intolerable toxicity occurred. Second line - it is divided in two different studies (2A and 2B): Study 2A: Patients from arm A and Kras Wild Type were randomized to: * Arm C: FOLFIRI or FOLFOX (the CT schedule not received in 1st line trial, as defined in arm B) * Arm D: FOLFIRI or FOLFOX (the CT schedule not received in 1st line trial, as described in arm B) plus CETUXIMAB CETUXIMAB 1st cycle Day 1 400 mg/m2 infusion of 120 min 2 hrs before CT infusion 1st cycle Day 8 and subsequent cycles 250 mg/m2 infusion of 60 min 1 hr before CT infusion Patients from arm A and Kras Mutant were treated according to arm C. Study 2B: Patients from arm B and Kras Wild Type were randomized to: * Arm E: FOLFIRI or FOLFOX (the CT schedule not received in the 1st line trial, as defined in arm B) plus BEVACIZUMAB * Arm F: FOLFIRI or FOLFOX (the CT schedule not received in the first-line trial, as defined in arm B) plus BEVACIZUMAB and CETUXIMAB; cycle to be repeated every 2 weeks, whilst cetuximab will be administered weekly. * BEVACIZUMAB 2nd day of 1st cycle 5 mg/kg IV infusion of 90 min 2nd day of 2 nd cycle if well tolerated, 5 mg/kg IV infusion of 60 min 2nd day of 3 rd cycle and subsequent cycles if well tolerated, 5 mg/kg IV infusion of 30 min after the end of 5-FU bolus on the 2nd day * CETUXIMAB 1st cycle Day 1 400 mg/m2 infusion of 120 min 2 hr before CT infusion 1st cycle Day 8 and subsequent cycles 250 mg/m2 infusion of 60 min 1 hr before CT infusion If cetuximab will be stopped for any of the reasons specified in this protocol, bevacizumab will be administered as defined in arm A of the 1st line study Patients from arm B and Kras Mutant were treated according to arm E. Objectives of study The primary objective of the 1st line study is to determine whether the addition of bevacizumab to a poly-chemotherapy (polyCT) regimen (FOLFIRI or FOLFOX) improves efficacy in terms of progression-free survival (PFS). The secondary objectives of the 1st line study are to determine the Overall Response Rate (ORR) and the safety profile of the treatments administered. The primary objective of the 2nd line studies is to determine, separately for each study, whether the addition of cetuximab to a polyCT schemes (FOLFOX or FOLFIRI), or to polyCT schemes plus bevacizumab, improves efficacy in terms of PFS.The secondary objectives of the 2nd line studies are to determine the ORR, the overall survival (OS) and the safety profile of the treatments administered.

Project description:Interventions: Single arm study to explore the efficacy of cetuximab in combination with Irinotecan based treatment in advanced stage RAS/BRAF wild type right sided colorectal cancer with high AREG/EREG expression. Dosing regimens include either of the following standard of care regimens for the administration of cetuximab in combination with Irinotecan. They will be chosen at physician discretion; 1) Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle until disease progression, unacceptable toxicity or withdrawal of consent. 2)Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle AND Calcium folinate 50mg Intravenous bolus Day 1, Fluorouracil 400mg/m2 Intravenous infusion on Day 1 followed by continuous intravenous infusion Fluorouracil 2400mg/m2 pump over 46 hours until disease progression, unacceptable toxicity or withdrawal of patient consent. Archival tumour tissue from advanced colorectal cancer patients will be tested using an immunohistochemistry assay for Amphiregulin/epiregulin (AREG/EREG)to determine a population of patients who may benefit from this combination of therapy. Participants will be asked to consent to pre- screening of their archival samples for the purpose of AREG/EREG testing. Once consented, testing of archival tissue may take place at any point during the participants first line treatment. There is no time limit for testing results and being considered eligible for the main study. Once AREG/EREG testing results have been received by the site Investigator ,if clinically appropriate the main study participant information and consent form (PICF) will be o Primary outcome(s): To determine progression free survival (PFS) of patients with right-sided, RAS/BRAF wild-type advanced Colorectal Cancer (CRC ) with high AREG/EREG expression (AREG/EREG high) following treatment with cetuximab + irinotecan based treatment in the second or later line setting. Progression Free Survival will be assessed by CT Chest/Abdomen/Pelvis (or MRI for participants unable to receive contrast) at 8 week intervals during the treatment phase, and at End of Treatment or until disease progression.[Disease status will be assessed at the following time points; CT scan with IV contrast (or MRI for participants unable to receive contrast) every 8 weeks during treatment phase, until disease progression or cessation of treatment for other reasons : ie: patient choice, unacceptable toxicity. Disease status will be accessed within 4 weeks of the last dose of treatment. After a patient has progressed on study treatment, no further study specific follow-up assessments will be required. All patients will be followed until death or study completion, to collect details of any further treatment and survival status.] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Other;Type of endpoint: Efficacy

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A Study Of PF-05212384 plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS and NRAS Wild Type Metastatic Colorectal Cancer

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