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.
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 language | English |
|---|---|
| Pages (from-to) | 1191-1199 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 71 |
| Issue number | 5 |
| Early online date | 20 Feb 2013 |
| DOIs | |
| Publication status | Published - May 2013 |