RT Journal Article
SR Electronic
T1 Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 7917
OP 7923
DO 10.1158/1078-0432.CCR-08-1223
VO 14
IS 23
A1 Plummer, Ruth
A1 Jones, Christopher
A1 Middleton, Mark
A1 Wilson, Richard
A1 Evans, Jeffrey
A1 Olsen, Anna
A1 Curtin, Nicola
A1 Boddy, Alan
A1 McHugh, Peter
A1 Newell, David
A1 Harris, Adrian
A1 Johnson, Patrick
A1 Steinfeldt, Heidi
A1 Dewji, Raz
A1 Wang, Diane
A1 Robson, Lesley
A1 Calvert, Hilary
YR 2008
UL http://clincancerres.aacrjournals.org/content/14/23/7917.abstract
AB 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 × 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.