A pilot clinical trial of p53/p16-independent epigenetic therapy for pancreatic ductal adenocarcinoma (PDA).

Abstract

699 Background: PDA treatment is limited to cytotoxic drugs. A key factor limiting their efficacy is TP53 mutations, omnipresent in PDA, which counter apoptosis-mediated cell kill. We evaluated a novel epigenetic approach using decitabine (Dec) to inhibit DNA methyltransferase 1 (DNMT1) and effect cancer cell cycle exits by epithelial-differentiation, combined with tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA) and thereby permit oral bioavailability and solid-tissue distribution of Dec. Methods: Open-label single-arm, IRB-approved clinical trial at Cleveland Clinic and University Hospitals for patients with metastatic PDA that had progressed on prior chemotherapy, ECOG PS of 0-2. Treatment was oral, weight-based, with Dec 10-20 mg, and THU 500-1000 mg daily, 5 days/week. Primary endpoint was DNMT1 protein levels at 16-week vs baseline biopsies. Results: From Apr to Aug 2017, we enrolled 13 patients. Median age was 65 (range 44-74) years; 7 (54%) males; 11 (85%) Caucasians. Median time from diagnosis was 13 (3.9-53.5) months, with a median of 2 (1-3) prior lines of therapy. Baseline ECOG PS was 0/1 in 12 (92%) patients. All patients started study drugs; median time on treatment was 35 (4-63) days, and on study 72 (25-105) days. The most frequent adverse events attributable to the study drugs were anemia (n=5), and anorexia, dehydration, nausea, fatigue, febrile neutropenia and decreased lymphocyte count, in 3 patients each; no deaths. Eight (62%) patients underwent evaluation scans at 8 weeks, showing stable disease in 1 patient and progression in 7. Common reasons for coming off of study drugs were progression (n=6), physician discretion (n=3), and adverse events (n=2). Overall, 6 patients died; median survival was 3.1 months, and patients did not reach the 16-week biopsy. Shifts in blood counts, a sensitive indicator of Dec systemic activity, were unexpectedly mild, and plasma CDA enzyme activity was increased versus other cancer and normal controls. Conclusions: This first-of-its-kind study demonstrated feasibility and safety of the novel oral epigenetic therapy. Systemically elevated CDA in these patients requires higher doses of THU; a trial accordingly refined is planned. Clinical trial information: NCT02847000.