Abstract B26: Phase 1b trial of investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with docetaxel, paclitaxel/carboplatin, or gemcitabine in patients (pts) with solid tumors
Authors: Lockhart A. Craig , Bauer Todd M. , Harvey R. Donald , Lee Carrie B. , Aggarwal Charu , Cohen Roger B. , Sedarati Farhad , Wang Ling , Faessel Hélène M. , Dezube Bruce J. , Santillana Sergio , Dowlati Afshin 
Published: May 2016

Abstract
Introduction: Pevonedistat is a first-in-class NAE inhibitor. This open-label, multi-arm, dose-escalation study (NCT01862328) is the first study of pevonedistat plus standard-of-care (SoC) chemotherapy in pts with solid tumors.
Methods: Objectives were to establish the MTD and safety/tolerability of pevonedistat (at &lt;100 mg/m2) with 3 SoC therapies. Pts ≥18 yrs who could benefit from 1 of the SoC therapies received pevonedistat IV on d 1, 3, and 5 every 21 d, with docetaxel 75 mg/m2 IV (Arm 1) or paclitaxel 175 mg/m2 + carboplatin AUC5 (Arm 2) on d 1 (lead-in cohort: pevonedistat 15 mg/m2 + carboplatin AUC6), or pevonedistat + gemcitabine 1000 mg/m2 IV on d 1, 8, and 15 every 28 d (Arm 3). Pts were treated for up to 12 cycles (and could then continue single-agent pevonedistat) or until disease progression/unacceptable toxicity. Pevonedistat dose was escalated from 15 (Arm 1+2; 1 dose level below lowest single-agent dose tested) or 25 mg/m2 (Arm 3) using an adaptive Bayesian continual reassessment method. Once established, ∼6 additional pts were to be treated at each MTD.
Results: As of 3 Jun 2015, 64 pts (median age 60.5 yrs; 47% male) had been enrolled: 22 to Arm 1, 26 to Arm 2 (6 in lead-in cohort), and 10 to Arm 3. Common tumor types were NSCLC (n = 16), breast, head and neck (each n = 6), and ovarian (n = 4) cancers. In Arm 1, MTD was pevonedistat 25 mg/m2 + docetaxel 75 mg/m2; 4 pts had dose-limiting toxicities (DLTs) of G3 AST/ALT elevations during dose escalation (n = 2) and expansion (n = 2), all at 25 mg/m2. In Arm 2, MTD was pevonedistat 20 mg/m2 + paclitaxel 175 mg/m2 + carboplatin AUC5; in the lead-in cohort 1 pt had a DLT of G3 AST/ALT elevation. Due to toxicity carboplatin AUC5 was used for dose escalation, DLTs included G3 febrile neutropenia (n = 1; 15 mg/m2), G3 AST/ALT elevation (n = 2; 20 mg/m2, n = 2; 25mg/m2), and G4 thrombocytopenia (n = 1; 20 mg/m2, C5D8). One DLT of G3 AST elevation occurred during MTD expansion. In Arm 3, MTD was not determined; the combination was deemed intolerable and discontinued. DLTs were G4/5 febrile neutropenia (n = 2) and G3 AST/ALT elevation (n = 1) at 25 mg/m2. Adverse events (AEs) were similar across arms; common drug-related AEs were fatigue (41%), nausea (34%), peripheral neuropathies (PN) (27%), and asymptomatic, reversible AST/ALT elevations (27/25%). 58% had &gt;1 drug-related ≥G3 AE; most frequent were asymptomatic AST/ALT elevations (17/16%) and neutropenias (19%). Pevonedistat PK were unaffected by SoC therapies (n = 22/17/10 pts in Arms 1/2/3). Eleven objective responses were observed (3/22 pts Arm 1, 8/32 pts Arm 2; including pts previously exposed to carboplatin/cisplatin and paclitaxel). One pt with endometrial carcinoma achieved a complete response. Partial responses were observed in head and neck (n = 5), cholangiocarcinoma (n = 2), bladder, NSCLC, sarcoma, and breast cancer (each n = 1). Responses were durable for up to 12 cycles.
Conclusion: Pevonedistat plus docetaxel or paclitaxel/carboplatin appeared well tolerated with MTDs of 25 and 20 mg/m2, respectively, and common drug-related AEs of fatigue, nausea, PN, and AST/ALT elevations. Preliminary data suggest antitumor activity with paclitaxel/carboplatin in pts with heavily pretreated solid tumors, notably endometrial carcinoma, head and neck cancer, cholangiocarcinoma, and NSCLC.
Citation Format: A. Craig Lockhart, Todd M. Bauer, R. Donald Harvey, Carrie B. Lee, Charu Aggarwal, Roger B. Cohen, Farhad Sedarati, Ling Wang, Hélène M. Faessel, Bruce J. Dezube, Sergio Santillana, Afshin Dowlati. Phase 1b trial of investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with docetaxel, paclitaxel/carboplatin, or gemcitabine in patients (pts) with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B26.