P-134 - Safety and efficacy of low-dose decitabine primed chemotherapy in patients with chemoresistant relapsed/refractory gastrointestinal cancers

Abstract

Introduction: Drug resistance often tempers the clinical benefit of chemotherapy in gastrointestinal (GI) cancers. The potential chemosensitization of low-dose decitabine has been evident both preclinically and in previous phase I trials. We assessed the safety and efficacy of low-dose decitabine primed chemotherapy in a phase II trial in patients with chemoresistant relapsed/refractory GI cancers. Methods: Forty-five patients with advanced stage esophageal, gastric or colorectal cancers were enrolled based on documented disease progression within six months of first-line chemotherapy. All patients received decitabine intravenously daily for 5 days, and then readministered the previously, ineffective first-line chemotherapy on day 6 to 7 of a 28-day cycle. This phase II trial evaluated efficacy and adverse events (AEs) continuously per RECIST and CTCAE, respectively. The primary endpoint was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Preliminary plasma microRNAs analyses were performed to identify putative predictive biomarkers. Results: Grade 3 to 4 AEs were reported in 11 (24.4%) of 45 patients. All AEs were controllable and no patient experienced a treatment-related death. The median PFS was 4 months (95% CI, 4.36 to 8.76 months), which compared favorably to the PFS of the pre-resistant unprimed first-line chemotherapy (0 month; 95% CI, 1.71 to 5.62 months). ORR and DCR were 24.4% (95% CI, 11.9 to 36.9) and 82.2% (95% CI, 71 to 93.4), respectively, including 2 patients who achieved durable complete responses. The median OS, 6-month PFS and 1-year OS rates were 11 months, 40% and 42.2%, respectively. The toxicity and objective response rates exhibited were nonsignificantly different between cancer types. Preliminary data of correlative studies of expression patterns of 5 miRNAs are promising as putative predictive markers of response. Conclusion: The safety and efficacy of decitabine primed resensitization to chemotherapy is attractive and promising. These data warrant further large-scale evaluation of chemoresistant relapsed/refractory GI cancers in patients with advanced stage disease.