Phase II trial of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma (HCC).

Abstract

240 Background: The combination of the imidazotetrazine derivative temozolomide (TMZ) and poly(ADP-ribose) polymerase inhibitor veliparib (ABT-888) has shown in vivo activity against a variety of tumor types through the alkylating effects of TMZ and DNA repair inhibition by ABT-888. To date, no studies have examined the combination of TMZ and ABT-888 in treating advanced HCC refractory to sorafenib. Methods: This is a single arm Phase II trial. Eligible HCC patients have Child Pugh A/B cirrhosis and have failed prior treatment with sorafenib either through intolerance or disease progression. All patients have received ABT-888 40 mg daily on days 1-7 and Temozolomide 150 mg/m2 daily on days 1-5 in 28 day cycles for a maximum of 6 cycles. Tumor response is analyzed every 2 cycles using RECIST criteria. The primary endpoint is time to disease progression. The trial is being conducted using a modified Simon’s two-stage design optimal design as implemented by Hanfelt, et al. Results: The trial is currently in Simon Stage 1 with 16 patients recruited: 9 patients have stopped the study due to disease progression, 3 patients are still on protocol, and 4 patients stopped the study for reasons other than disease progression. 7 patients had disease progression at two months, 1 patient had cancer progression at 4 months, and 1 patient had disease progression at 16 months. Median time to progression in these 9 patients was 56 days (range 42-486 days). The four patients that stopped the study prematurely were for the following reasons: hiccups/dehydration, Mallory-Weiss tear secondary to refractory nausea, intraperitoneal bleeding from exophytic HCC lesion, and development of hepatorenal syndrome in a paracentesis-dependent patient. The most common grade 3 toxicities in this cohort so far have been nausea/vomiting (in 2 subjects), and anemia/thrombocytopenia (in 2 subjects). Defects in DNA repair pathways are being tested from the liver biopsy in the patient who had response to TMZ and ABT-888 for 16 months. Conclusions: The combination of TMZ and ABT-888 is fairly tolerated in patients with advanced HCC. So far, the treatment did not show activities in majority of patients with advanced HCC. Clinical trial information: NCT01205828.