A-REPEAT (Anti-Epidermal Growth Factor Receptor -EGFR- rechallenge and plasma genotyping of patients with advanced colorectal tumors) is a Greek, investigator-initiated, single arm open-label phase II study of anti-EGFR therapy rechallenge in combination with chemotherapy in patients with advanced colorectal cancer. Patients with a metastatic, histologically proven colorectal carcinoma RAS wild type will be treated with a combination of panitumumab and third-line irinotecan-based or oxaliplatin-based chemotherapy (FOLFOX,FOLFIRI or irinotecan monotherapy).
Few clinical studies have evaluated the role of anti-EGFR therapy rechallenge in metastatic colorectal cancer patients and there is no prospective clinical trial assessing the activity of treatment rechallenge with panitumumab-based therapy after initial progression. This study aims at exploring the concept of evolution and expansion of RAS wild type clones in order to restore sensitivity of the tumor to prior anti-EGFR therapy after a time interval in which a different, non-anti-EGFR second-line therapy is administered. Based on aforementioned data, it is hypothesized that rescue through rechallenge with panitumumab-based third-line therapy combined with chemotherapy could be associated with further response and clinical benefit. A significant component of the proposed prospective trial is exploratory translational: cell free plasma and platelet-based genotyping for genetic mutations in different time points will be undertaken in order to study the genetic composition of the metastatic tumour at initiation of and at progression through, anti-EGFR rechallenge therapy. Primary endpoint will be to evaluate the efficacy, in terms of overall response rate, of the addition of panitumumab rechallenge to standard third-line irinotecan-based or oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer initially treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line chemotherapy not containing anti-EGFR agents. Exploratory endpoints include to identify, in the context of translational research, tumour tissue and blood-based biomarkers with prognostic/predictive significance in patients with metastatic colorectal cancer treated with rechallenge panitumumab in combination with standard third-line irinotecan-based or oxaliplatin-based chemotherapy, who were initially treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line chemotherapy not containing anti-EGFR agent.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
23
6 mg/Kg will be administered intravenous over 1 hour on Day 1 every 2 weeks or 9 mg/Kg every 3 weeks.
Bank Of Cyprus Oncology Centre
Stróvolos, Nicosia, Cyprus
"Attikon" University Hospital
Chaïdári, Athens, Greece
University Hospital of Heraklion
Heraklion, Crete, Greece
Ioannina University Hospital
Ioannina, Ioannina, Greece
Agii Anargiri Cancer Hospital
Athens, Kalyftaki, Nea Kifisia, Greece
Metropolitan Hospital
Athens, Neo Faliro, Greece
University Hospital of Patra
Rio, Patra, Greece
Euromedica General Clinic of Thessaloniki
Thessaloniki, Thessaloniki, Greece
Evaluation of overall response rate of the addition of panitumumab rechallenge to standard third-line therapy
Evaluation of efficacy of overall response rate, of the addition of panitumumab rechallenge to standard third-line irinotecan-based or oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer initially treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line chemotherapy not containing anti-EGFR agents.
Time frame: At baseline, every 8 weeks with a 2-week tumor evaluation window through study completion, an average of 30 months.
Evaluation of overall response rate by RAS status
Overall response rate will be calculated separately for RAS mutant and wild type patients.Overall response rate is defined as the proportion of patients with confirmed complete response or partial response, as the best overall response to treatment, based on Response Evaluation Criteria in Solid Tumors version 1.1 guidelines
Time frame: At baseline, every 8 weeks with a 2-week tumor evaluation window through study completion, an average of 30 months.
Evaluation of Progression Free Survival
Time frame: From study entry to disease progression or death due to any cause assessed up to 30 months
Evaluation of Overall Survival
Time frame: From study entry until date of death due to any cause or last contact assessed up to 30 months
Evaluation of safety of the combination of standard 3rd-line irinotecan-based or oxaliplatin-based chemotherapy with panitumumab rechallenge.
Time frame: Per cycle (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) assessed up to 30 months.
Mutation status of KRAS gene
Time frame: At baseline
Mutation status of NRAS gene
Time frame: At baseline
Next generation sequencing performed on plasma cell-free DNA.
Time frame: At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 12 of KRAS gene mutations
Time frame: At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 61 of KRAS gene mutations
Time frame: At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in exon 15 of BRAF gene mutations
Time frame: At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 12 of NRAS gene mutations
Time frame: At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in Codon 61 of NRAS gene mutations
Time frame: At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
Mutations analysis on platelet-resorbed tumour RNA (with Real-time PCR) in exon 20 of PIK3CA gene mutations
Time frame: At baseline, at cycle 3 or 4 (each cycle is repeated every 2 weeks for FOLFIRI and FOLFOX regimens and every 3 weeks for irinotecan monotherapy) and at progressive disease assessed up to 30 months
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