A phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer.

Abstract

488 Background: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and both clinical and preclinical studies have shown the ability to restore platinum sensitivity with the reversal of hypermethylation. CIMP is implicated in the pathogenesis of a subset of colorectal cancers termed CIMP-high. Methods: The primary objectives were as follows: phase I—MTD and DLTs; phase II—RECIST response rate. Prior progression on fluoropyrimidine/oxaliplatin-based treatment was required (RECIST criteria progression in 21 pts). The phase II portion was restricted to patients with CIMP-high (≥ 2/6 methylation-specific PCR markers: hMLH1, P16, P14, MINT1, MINT2, and MINT31). Pre-treatment, C1D5, C2D1, C2D5, and at restaging blood samples were collected. Results: 26 pts [M/F 15/11, median age: 66 yrs (range: 34-75), ECOG PS 0/1: 1/25, median number of prior therapies: 4.5] were enrolled from 8/2010 to 12/2012. The phase I portion enrolled 15 pts (12 treated at MTD), of which 3 were CIMP-high. No DLTs were observed with the MTD determined to be azacitidine (75 mg/m2, SQ D1-5), oxaliplatin (110 mg/m2 IV D2), and capecitabine (1500 mg/m2/d, PO divided BID, D1-14) q21 days. The phase II portion enrolled 11 CIMP-high pts and closed due to lack of an objective response. Common grade 3-4 treatment-related toxicities were neutropenia in 10 pts (38%) and diarrhea in 3 pts (12%). Grade 2 fatigue occurred in 14 pts (54%). No responses were seen. Stable disease (SD) occurred in 7 of 15 phase I pts and 10 of 11 phase II pts (p=0.04) with median PFS of 2.5 and 4.5m (p=0.04), respectively. SD >6 months was seen in 2 phase II pts (6.8m and 8.5m). Median OS and median post-study OS were 9.4m and 5.3m, respectively, and were similar between phase I and phase II portions. Post-study therapy was given to 14 patients: 12 progressed, 1 on active treatment, 1 lost to f/u. Conclusions: Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Improved activity from post-study treatment was not seen. Ongoing correlative work evaluating quantitative changes in methylation from circulating free tumor DNA will be presented. Clinical trial information: NCT01193517.