4395 - DREAMM 4: A Phase I/II single-arm open-label study to explore safety and clinical activity of belantamab mafodotin (GSK2857916) administered in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM)

Background

In BMA117159, GSK2857916, a humanised (IgG1), afucosylated, anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F, has shown clinical activity (overall response rate [ORR]=60%; mPFS 12 months [95% CI, 3.1–NE]) as monotherapy in heavily pre-treated patients with MM. Pre-clinical data indicate that GSK’916 induces immunogenic cell death that activates dendritic cells and an antigen-specific T-cell response. PD-L1 overexpression may be a mechanism of immune evasion in MM. Pembrolizumab, a selective, humanised IgG4 anti-PD-1 monoclonal antibody that blocks the interaction of PD-1 with PD-L1 and PD-L2, may synergise with immunomodulatory drugs to enhance tumor suppression. T-cell-dependent antitumor response induced by GSK’916 may be augmented by combining with pembrolizumab.

Trial design

DREAMM 4 is a Phase I/II, single-arm, open-label, two-part study to evaluate safety and determine the recommended Phase 2 dose (RP2D) and clinical activity of GSK’916 in combination with pembrolizumab in patients with RRMM previously treated with ≥3 prior lines. Part 1 (dose escalation) will evaluate two doses of GSK’916 with a fixed dose of pembrolizumab in up to 12 participants. Modified Toxicity Probability Interval design will guide GSK’916 dose escalation. Primary objectives of Part 1 are to define safety and tolerability and define the RP2D dose of GSK’916 combined with pembrolizumab. Part 2 (dose expansion) will evaluate clinical activity of the RP2D, confirm safety, and collect pharmacokinetic information for GSK’916 in up to 28 participants. Dose expansion may stop early for futility at interim analysis. An additional stopping rule may stop enrolment early if the observed rate of treatment-related ≥Grade 4 AEs equals or exceeds the specified rate (12%). Part 2 objectives are to assess the ORR and confirm the safety profile of GSK’916 and pembrolizumab. Patients will continue combination treatment for 35 cycles or until progression, intolerance, consent withdrawal or death. Enrolment began in March 2019 and is ongoing.

Clinical trial identification

NCT03848845 (Rel. 19Feb2019).

Editorial acknowledgement

Clare Slater, PhD, of Fishawack Indicia Ltd, UK, funded by GlaxoSmithKline (GSK).

Legal entity responsible for the study

GlaxoSmithKline.

Funding

GlaxoSmithKline and is in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Disclosure

S. Trudel: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: GlaxoSmithKline. A. Nooka: Honoraria (self), Advisory / Consultancy: Emory University Winship Cancer Institute; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Adaptive; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Spectrum; Research grant / Funding (institution): Aduro; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): KITE pharmaceuticals. D. Fecteau: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. M. Talekar: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. R.C. Jewell: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. D. Williams: Full / Part-time employment: GlaxoSmithKline. J. Evans: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. J. Opalinska: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline.