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

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.

Figure 1

Structure of AG014699, phosphate salt of tricyclic indole PARP-inhibitor with Ki < 5 nM

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.