Phase II study of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma

Abstract

Purpose To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC).MethodsThis single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1–7 and 150 mg/m2 TMZ PO daily on days 1–5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03.ResultsWe enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (n = 2), thrombocytopenia (n = 2), nausea (n = 1), and anemia (n = 1). The median PFS was 1.9 months, and median OS was 13.1 months.ConclusionThe combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit.ClinicalTrials.gov IdentifierNCT01205828.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-015-2852-2) contains supplementary material, which is available to authorized users.

The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids

“…The BER pathway has also been acknowledged as a major contributor to temozolomide resistance in other cancer models, but moreover, its disruption in conjuction with temozolomide has been shown to sensitize cells to treatment 18, 19, 22–27 . Pharmacological inhibiton of BER by the PARP inhibitor ABT-888 has been demonstrated to enhance the antitumor effects of dacarbazine and temozolomide, and have advanced to phase I and II clinical trials for pediatric and adult gliomas, hepatocellular carcinoma, and metastatic melanoma with mixed success 33–42 . To improve carcinoid susceptibility to alkylating agent therapy for such candidate patients, we investigated the ability of the PARP inhibitor ABT-888 to enhance the activity of dacarbazine in carcinoids.…”

“…Since 2007, the National Cancer Institute has evaluated ABT-888 in 88 clinical trials for the treatment of several cancer types including melanoma, gliomas, hepatocellular carcinoma, pulmonary and colorectal cancers. Select trials have combined ABT-888 and temozolomide therapy, and despite offering no clinical suggestion of synergy, have demonstrated excellent tolerability among both pediatric and adult populations 34, 35, 40, 42 . Several studies report modest antitumor activity with some approaching significance, though their general failure to demonstrate favorable drug interaction may be attributed factors like acquired resistance through BER pathway overexpression 41, 42 .…”

“…Select trials have combined ABT-888 and temozolomide therapy, and despite offering no clinical suggestion of synergy, have demonstrated excellent tolerability among both pediatric and adult populations 34, 35, 40, 42 . Several studies report modest antitumor activity with some approaching significance, though their general failure to demonstrate favorable drug interaction may be attributed factors like acquired resistance through BER pathway overexpression 41, 42 . Previous in vitro reports have revealed that enhanced DNA repair mechanisms and homologous recombination capacity in response to ABT-888 and temozolomide therapy may underlie a learned resistance to this regimen 68 .…”

EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma

“…For instance, olaparib, rucaparib, and niraparib are approved for the treatment of ovarian cancer, whereas olaparib was recently approved for the treatment of BRCA-mutated breast cancer. However, there have been few clinical trials of PARPi for HCC, and the outcomes have been disappointing (13). Interestingly, MET has been reported to be overexpressed in HCC (14).…”

MicroRNA‑543 suppresses liver cancer growth and induces apoptosis via the JAK2/STAT3 signaling pathway

“…In China, there are numerous patients with hepatitis, among whom hepatitis B is more common, and hepatitis B is often transferred into hepatitis B-cirrhosis-liver cancer (1). However, the clinical treatment of liver cancer is not ideal, which primarily results from the recurrence and metastasis of hepatocellular carcinoma (HCC) (1,2). Surgery remains the most effective treatment of liver cancer, but surgical resection is aimed only at the visible tumor, and it cannot remove the invisible small tumor foci or micro-metastases.…”