Phase II dose titration study of regorafenib for patients with unresectable metastatic colorectal cancer who are progressed after standard chemotherapy
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ABSTRACT:
DISEASE(S): Unresectable Metastatic Colorectal Cancer
PROVIDER: 2634263 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:We report the RNA sequencing data from the REPEAT study, in which patients with beyond first-line esophagogastric cancer were treated with regorafenib and paclitaxel. For the RNA sequencing, biopsies from metastatic lesions were obtained on baseline (n=21) and fifteen days following treatment initiation (n=13). PURPOSE: Regorafenib monotherapy, a multikinase-inhibitor of angiogenesis, tumor microenvironment, and oncogenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment, and explore potential biomarkers. METHODS: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on day 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall- (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second/third line systemic treatment. Paclitaxel pharmacokinetics were assessed using D1 and D15 samples. We performed ELISA measurements of galectin-1, RNA sequencing and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. RESULTS: In the dose-escalation cohort (n=14), the MTD of regorafenib was 120 mg. Thirty-four patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ≥3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up 7.8 months). OS (p=0.08) and PFS (p=0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p<0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p<0.01). Enrichment of angiogenesis-related gene expression was observed in short-survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p=0.02) and PFS (p=0.02). CONCLUSION: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.
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Project description:Intervention1: Arm A TAS-102 plus Bevacizumab: Bevacizumab 5 mg per m2 IV over 60 mins q every 15 days subsequent administrations over 30 mins if the initial administration tolerated well
plus Tab TAS 102 35 mg per m2 twice daily on days 1to5 and 8 to 12 PO every 28 days
1 cycle Start of next cycle on D 29
Control Intervention1: Arm B Regorafenib: Tab Regorafenib 80 mg PO OD 3 weeks on 1 week off q 28 days
1 cycle
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Primary outcome(s): To evaluate the difference in overall survival (OS) at 6 months between
TAS102-Bevacizumab combination and Regorafenib.
Timepoint: 53 months
Study Design: Other Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:On-site computer system Blinding and masking:Open Label
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