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

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

来源：Cancer Chemotherapy and Pharmacology, 2013, 71(5): 1191-1199.

DOI：10.1007/s00280-013-2113-1

• PARP
• DNA repair
• Melanoma
• Chemopotentiation
• Phase II

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. %26lt;br%26gt;Patients with chemotherapy na %26lt; ve measurable metastatic melanoma, performance status a parts per thousand currency sign2 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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2013-5