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PURPOSE: poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma. METHODS: Patients with chemotherapy naïve measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. RESULTS: Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. CONCLUSIONS: This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.

Original publication

DOI

10.1007/s00280-013-2113-1

Type

Journal article

Journal

Cancer Chemother Pharmacol

Publication Date

05/2013

Volume

71

Pages

1191 - 1199

Keywords

Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Dacarbazine, Disease-Free Survival, Drug Synergism, Female, Humans, Indoles, Male, Melanoma, Middle Aged, Poly(ADP-ribose) Polymerase Inhibitors, Skin Neoplasms, Survival Rate, Temozolomide, Treatment Outcome, Young Adult