First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc).

Abstract

3102 Background: MK4827 is an orally active, PARP 1/2 inhibitor with nanomolar potency. It induces selective synthetic lethality in homologous recombination (HR) repair deficient tumors with BRCA1/2 loss and in tumor cell lines with non-BRCA-related HR defects, supporting broad clinical application. A phase I study was undertaken to determine the toxicity and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and preliminary anti-tumor activity. Methods: Patients (p) with advanced solid tumors enriched for BRCA-mutation carriers (BRCA-MC) and non-BRCA HR defects received once daily, escalating doses of MK4827 in cohorts of 3-6 p. Dose escalation was guided by toxicity, PK and PD data. Results: 60 p (M13, F47; median age 56 yr; 21 BRCA-MC) were treated at 10 dose levels from 30mg to 400mg on days 1-21 of a 28 day cycle (C) in C1, followed by continuous dosing. 20 additional p with soc were enrolled at the MTD. Prior systemic treatments were ≤2 (23p), ≥3 (17p), and ≥4 (40p). Overall, DLT was observed in 4p: grade (G) 3 fatigue in 1/6p at 30mg, reversible G3 pneumonitis in 1/6p at 60mg, and reversible G4 thrombocytopenia in 2/6p treated at 400mg. The MTD was established at 300mg. Other MK4827 related G1-2 reversible adverse events included fatigue, anorexia, nausea and myelosuppression. Dose proportional PK was observed with a mean t1/2 of 40 hours (range 37-42 hr). PD studies confirmed PARP inhibition in peripheral blood mononuclear cells at doses of ≥80 mg. Antitumor activity was observed in both sporadic and BRCA-MC cancers. In total, there have been 12p with partial responses (PR) (10 ovarian [7 BRCA-MC; 3 soc], 2 breast, 10/12 BRCA-MC cancers, 4/12 with ongoing treatment), and 8p with stable disease (SD) (4 ovarian [2 BRMC-MC], 2 NSCLC, 2/4 BRCA-MC) ≥120 days. PRs have ranged from 86(+)-483 days and SD from 18(+)-354 days. Conclusions: MK-4827 was well tolerated, had linear PKs, evidence of target modulation, and promising antitumor activity in both BRCA-MC and sporadic cancer. Specific cohort expansions in other nonhereditary tumors enriched for HR defects is ongoing. Updated safety and response data will be provided.