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Clinical Trial
. 2008 Dec 1;14(23):7917-23.
doi: 10.1158/1078-0432.CCR-08-1223.

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

Ruth Plummer  1 , Christopher Jones, Mark Middleton, Richard Wilson, Jeffrey Evans, Anna Olsen, Nicola Curtin, Alan Boddy, Peter McHugh, David Newell, Adrian Harris, Patrick Johnson, Heidi Steinfeldt, Raz Dewji, Diane Wang, Lesley Robson, Hilary Calvert
Affiliations
Clinical Trial

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

Ruth Plummer et al. Clin Cancer Res. .

Abstract

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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Figures

Figure 1
Figure 1
Structure of AG014699, phosphate salt of tricyclic indole PARP-inhibitor with Ki < 5 nM
Figure 2
Figure 2
Pharmacodynamic effects of AG014699. a, b, c Summary of PBL and tumour PARP inhibition measured using PARP activity immunoassay. a and b representative plots from day -7, 1 and 4 of the first treatment cycle from patients treated with 2 mg/m2 (a) and 12 mg/m2 (b) c Summarised data from tumour biopsies taken 5 hours after the first dose of AG014699 at the dose levels indicated. Data expressed as percentage activity compared to pre-treatment biopsy in the same individual d,. DNA damage in peripheral blood mononuclear cells by cohort. Blood was sampled on day 4 of the first treatment cycle before (hashed), 4h after (white) and 24h after (black) temozolomide dosing. Each reading is the mean of up to 6 patients.
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