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Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; ² Department of Medical Oncology and ³ Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; ⁴ Queen's University, Belfast, United Kingdom; ⁵ Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, United Kingdom; ⁶ Pfizer GRD, La Jolla, California; ⁷ Pfizer GRD, Sandwich, United Kingdom; and ⁸ Cancer Research UK Drug Development Office, London, United Kingdom

Requests for reprints: Ruth Plummer, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom. Phone: 44-191-2464414; Fax: 44-191-2454301; E-mail: ruth.plummer{at}ncl.ac.uk.

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.

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