Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma

Abstract

Purpose: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma.

Experimental design: Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles.

Results: Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease.

Conclusions: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.

Conflict of interest statement

Disclosures of conflicts of interest:

JJS: Consulting or Advisory Role. FORMA Therapeutics; Array BioPharma; Novartis; Celgene; Onyx; Takeda; Research Funding: Array Biopharma; Novartis; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd; Onyx; Celgene.

AJJ: Consultancy and honoraria: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Celgene, Centocor Ortho Biotech, Exelixis, Bristol-Myers Squibb, Onyx Pharmaceuticals; honoraria: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Celgene, Centocor Ortho Biotech, Exelixis, and Bristol-Myers Squibb; advisory committee member: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Centocor Ortho Biotech, Exelixis, Bristol-Myers Squibb, Celgene, Onyx Pharmaceuticals.

OAO: Research funding: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Celgene, TG Therapeutics, Spectrum, Acetylon. Scientific advisory boards: Mundipharma, Novartis; TG Therapeutics.

RZO: Research funding: Bristol-Myers Squibb, Celgene Corporation, Millennium Pharmaceuticals, Inc., Onyx Pharmaceuticals, Resverlogix. Honoraria: Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Genentech, Millennium Pharmaceuticals, Inc., Onyx Pharmaceuticals. Membership of advisory boards: Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Genentech, Merck, Millennium Pharmaceuticals, Inc., Onyx Pharmaceuticals.

RDH: Consulting or Advisory Role: BMS; Amgen; Research Funding: Eisai; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd; Onyx; Novartis; Celgene; Sanofi; AstraZeneca; Calithera Biosciences; Acetylon Pharmaceuticals; AVEO; Agensys; Merck; Genzyme; ImClone Systems; Synta; Abbott Biotherapeutics

MRS: Research funding: AbbVIE, Celgene Corporation, Janssen, Millennium Pharmaceuticals, Inc., Seattle Genetics. Membership of advisory boards: Spectrum Pharmaceuticals, Inc.

DL: no conflicts of interest to disclose.

CD: Stock or Other Ownership: Gilead Sciences; Consulting or Advisory Role: Seattle Genetics; Janssen Oncology; Idera Pharmaceuticals; Celgene; Immunogen; Speakers’ Bureau: Seattle Genetics; Gilead Sciences; Research Funding: Seattle Genetics; Genentech; Gilead Sciences; Janssen Oncology; Molecular Templates; Incyte.

KK: no conflicts of interest to disclose.

ZH, AJB, GM, HF, ST, and BJD: employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd

SL: Consultancy: Millennium Pharmaceuticals, Inc., Celgene, Novartis, Bristol-Myers Squibb, Onyx Pharmaceuticals, Merck.

©2015 American Association for Cancer Research.

Figures

Fig 1

Treatment duration with pevonedistat, by dose level and tumor type. MM and lymphoma patients received a median of 3 (range 1–9) and 3 (range 1–14) cycles, respectively. Fourteen patients (7 in each schedule) received ≥5 treatment cycles.

Fig 2

Mean pevonedistat plasma concentration–time profiles on (A) days 1 and 9 of schedule A, and (B) days 1 and 4 (or, alternatively, day 11) of schedule B. Mean plasma concentration–time profiles of pevonedistat exhibited a biphasic disposition phase, characterized by an initial rapid decline at the end of the infusion, followed by a slower phase with plasma concentrations remaining quantifiable up to 24 hours (schedule A) or 48 hours (schedule B) post-infusion at all doses.

Fig 3

Pevonedistat treatment increased CDT-1 and NRF-2 levels compared to baseline. (A) Fold-change from baseline in CDT-1 expression in skin biopsies obtained 3–6 hours after the second dose of pevonedistat in cycle 1 (day 2 on schedule A, day 4 on schedule B). (B) Representative immunohistochemistry images of skin biopsy sections stained for CDT-1 and NRF-2 taken at baseline and on cycle 1, day 2 from a patient enrolled in the 83 mg/m2 dose level on schedule A. Arrows and blue/purple staining indicate CDT-1 or NRF-2 positive staining.