Investigational NEDD8-activating enzyme inhibitor pevonedistat (Pev) plus chemotherapy in patients (Pts) with solid tumors (Phase 1b study): Antitumor activity of pev plus carboplatin (Carbo)/paclitaxel (Pac).

Abstract

2580 Background: This is an open-label, multi-arm, dose-escalation study (NCT01862328) of pev (TAK-924/MLN4924) plus chemotherapy in pts with solid tumors. Safety and preliminary efficacy results have been reported (Lockhart et al, AACR-NCI-EORTC 2015); common adverse events in pts treated with pev + carbo/pac were fatigue (50%), nausea (38%), and G3 elevated AST/ALT (19%). We present previously unreported antitumor activity in pts treated with this combination. Methods: Twenty-six pts received pev IV 15, 20, or 25 mg/m2 on d 1, 3, and 5 with carbo AUC5 + pac 175 mg/m2 on d 1 (lead-in cohort, n = 6: pev 15 mg/m2 + carbo AUC6) every 21 d. The combination appeared tolerable; MTD pev 20 mg/m2 + carbo AUC5 + pac 175 mg/m2. Response was assessed per RECIST v1.1; sparse PK sampling was carried out during C1. ERCC1 expression was assessed by IHC. Results: Nine responses were observed in 32 pts (28%) including those resistant to prior platinum/taxane therapy. Two pts (1 endometrial carcinoma, 1 bladder cancer) achieved a complete response (CR), and remain on study ( > 12 cycles). Seven pts (3 head and neck, 1 cholangiocarcinoma, 1 NSCLC, 1 sarcoma, 1 breast cancer) achieved a partial response (PR). The 9 responders received 4–18 cycles and had a median of 4 (range 1–8) prior therapies, including 4 with prior taxane (best response: 1 CR, 1 PR, 1 stable disease [SD], 1 unknown) and 8 with prior platinum (best response: 1 PR, 6 SD, 1 unknown). The majority had response within 2 cycles. Prolonged SD was seen in 3 pts (1 sarcoma, 1 endometrial cancer, 1 ovarian cancer), all 3 discontinued chemotherapy due to toxicity but continued to benefit from single-agent pev (SD duration 4.9–14.7 mos). Pev PK was unaffected in the presence of carbo/pac. Archival tumor sections from 23/30 pts were evaluable for ERCC1 staining. Conclusions: Pev+ carbo/pac showed broad-based antitumor activity in heavily pre-treated pts with solid tumors. Consistent with preclinical synergy between agents, lengthy treatment durations and improved responses in pts resistant to prior platinum/taxane therapy suggest the potential reversal of resistance by the addition of pev. Clinical trial information: NCT01862328.