Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.

Journal article

PURPOSE: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. EXPERIMENTAL DESIGN: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide x 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. RESULTS: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. CONCLUSIONS: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.

Authors: Plummer, R; Jones, C; Middleton, M; Wilson, R; Evans, J

• Publication status: Published
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
• Volume: 14
• Issue: 23
• Pages: 7917-7923
• Publication date: 2008-12-01
• DOI: 10.1158/1078-0432.ccr-08-1223
• EISSN: 1557-3265
• ISSN: 1078-0432
• Language: English
• Keywords: Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Humans; Dacarbazine; Indoles; DNA Breaks; Adult; Middle Aged; Aged; Cytochrome P-450 CYP2D6; Female; Male; Comet Assay