A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation
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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/m2 and oral temozolomide 200 mg/m2 on days 1–5 every 28 days in patients with advanced metastatic melanoma.
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.
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.
This study showed that temozolomide (150–200 mg/m2/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.
KeywordsPARP DNA repair Melanoma Chemopotentiation Phase II
We would like to thank all our patients and their families for participating in this research, and the research nurses and data managers at the clinical sites for their help and support. This clinical trial was sponsored and funded by Pfizer GRD. Staff working on this project at the 6 UK academic institutions are all supported by Cancer Research UK and the UK Departments of Health through the Experimental Cancer Medicine Centre initiative.
Conflict of interest
Calvert, Plummer, Lorigan, Steven, Middleton, Curtin, Wilson and Scott received research costs to support conduct of the study from Pfizer GRD. Wang, Dewji, Gallo and Abbattista are employees of Pfizer GRD. Calvert, Curtin and Plummer are named as inventors on patents pertaining to PF-01367338.
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