A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation

Ruth Plummer, Paul Lorigan, Neil Steven, Lucy Scott, Mark R Middleton, Richard H Wilson, Evan Mulligan, Nicola Curtin, Diane Wang, Raz Dewji, Antonello Abbattista, Jorge Gallo, Hilary Calvert

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Abstract

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/m2 and oral temozolomide 200 mg/m2 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/m2/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.
Original languageEnglish
Pages (from-to)1191-1199
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number5
Early online date20 Feb 2013
DOIs
Publication statusPublished - May 2013

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    Plummer, R., Lorigan, P., Steven, N., Scott, L., Middleton, M. R., Wilson, R. H., Mulligan, E., Curtin, N., Wang, D., Dewji, R., Abbattista, A., Gallo, J., & Calvert, H. (2013). A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemotherapy and Pharmacology, 71(5), 1191-1199. https://doi.org/10.1007/s00280-013-2113-1