Evaluation of tolerability, safety, and pharmacokinetics of INO-1001 plus temozolomide (TMZ) in patients with unresectable stage III/IV melanoma

Abstract

12015 Background: TMZ, an orally bioavailable cytotoxic agent with the same active metabolite as DTIC, is a commonly used for treatment (Rx) of metastatic melanoma (MM). It causes methylation of the O6 position of guanine. Unrepaired O6-methylguanine pairs with thymine rather than guanine and activates DNA mismatch repair. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein that functions as DNA damage sensor. PARP inhibitors increase TMZ cytotoxicity by causing interruption of the repair process of N-methylpurines generated by TMZ. INO-1001 (INO), an ultrapotent PARP inhibitor has been tested in combination of TMZ and found to be safe and well tolerated. Here we report the initial results of Phase Ib clinical trial. Methods: Patients (pts) with unresectable stage III/IV MM with no prior Rx with TMZ or DTIC were treated with INO given IV q 12 hours for 10 doses at the starting dose of 100mg/dose. The doses of INO are planned to escalate from 100 to 200mg/dose and then to the maximum dose of 400 mg/dose in successive groups of 3–6 pts. TMZ is taken po within 2 hours of the second dose of INO at the dose of 200mg/m 2 /day for 5 days. Blood samples are collected for pharmacokinetics study during cycle 1. The Rx cycles are repeated q 4 weeks and tumor responses are evaluated q 8 weeks. Results: 6 pts with median age 63 (range 55–67) years and median PS Zubrod 1 (range 0–2) have been treated. Initially 3 pts were treated with INO at the dose level of 100mg. One pt with a BSA of 2.76 had grade 4 neutropenia and thrombocytopenia with Rx cycle 1. TMZ dose was not adjusted to her ideal body weight. Subsequently, the dose of TMZ was reduced by 25% and the following 2 cycles were tolerated well. 3 more pts were entered at the dose level 1. To date, a total of 8 cycles of Rx have been completed. All except for the cycle mentioned earlier were tolerated well. 3 pts were evaluated for response, 1 pt had objective tumor regression, 1 had stable disease and 1 had tumor progression. The non-hematologic side effects were mild and are mostly related to TMZ. Conclusions: TMZ-INO combination is fairly well tolerated. A complete report will be presented. No significant financial relationships to disclose.