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ASCO 2014: A phase 1 (Ph1) trial of MK-3475 combined with lenalidomide (Len) and low-dose dexamethasone (Dex) in patients (pts) with relapsed/refractory multiple myeloma (RRMM)

David Siegel, MD
John Theurer Cancer Center
Hackensack, New Jersey, USA

06.13.14

Abstract No: TPS3117

Background: RRMM patients refractory to proteasome inhibitors and immunomodulatory drugs (IMiD) have a very poor outcome. PD-L1 expressed on most MM plasma cells is a potential mechanism of immune evasion. MK-3475 is a potent, highly selective, humanized IgG4/kappa isotype, anti-PD-1 monoclonal antibody designed to block PD-1 interaction with PD-L1 and PD-L2, enhancing lymphocytic activity, tumor regression and immune rejection.

Methods: This is an open-label, Ph1 multicenter, non-randomized dose escalation trial of MK-3475 combined with Len/Low-dose Dex in RRMM patients failing two lines of prior therapy, including bortezomib and an IMiD, using a modified 3+3 design followed by a toxicity probability interval (TPI) for dose confirmation. Cohorts of 3-6 pts per dose level (DL) will be enrolled sequentially at escalating doses of MK-3475 (2, 5, 10 mg/kg) with Len (25mg) / Low-dose Dex (40mg) until a preliminary maximum tolerated dose (MTD) or maximum administered dose (MAD), is identified. Additional pts will be enrolled at the MTD/MAD in combination with Len/Low-dose Dex to confirm dose and evaluate safety and preliminary efficacy. Primary objectives of the trial are to establish a MTD/MAD and determine safety and tolerability of MK-3475 / Len / Dex in pts with RRMM. Secondary objectivesinclude analysis of efficacy (ORR/CR/sCR/TTP/DOR/PFS/OS), and PD-L1 expression and corresponding efficacy. Exploratory objectives are PK of MK-3475 with Len/Dex and the relationship of candidate efficacy/resistance biomarkers and anti-tumor activity. AEs as categorized in the NCI CTCAE v 4 will be summarized by DL for all pts receiving ≥1 dose. After the TPI, the dose-response relationship (% of subjects with ≥1 dose limiting toxicity (DLT) for each DL selected for confirmation), will be estimated by Bayesian pooling of adjacent violators analysis, using all DLT data. The dose-response profile, along with other tolerability data, will determine the recommended Ph2 dose for the combination. Efficacy endpoints (evaluated using established International Working Group response criteria) will be summarized for each DL using descriptive statistics.

Clinical trial information: NCT02036502.  

Author(s): David Samuel DiCapua Siegel, Philippe Moreau, David Avigan, Kenneth Carl Anderson, Donna Ellen Reece, Jesus San Miguel, María-Victoria Mateos, Dianna Wu, Kenneth Emancipator, Marisa Dolled-Filhart, Christine Gause, Holly Brown, Karl Heath, Robert Iannone, Shelonitda Rose, Robert Z. Orlowski; John Theurer Cancer Center, Hackensack, NJ; Hematology Department, University Hospital Hotel-Dieu, Nantes, France; Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Princess Margaret Cancer Centre, Toronto, ON, Canada; Universidad de Navarra, Pamplona, Spain; University Hospital of Salamanca, Salamanca, Spain; Merck & Co., Inc., Whitehouse Station, NJ; The University of Texas MD Anderson Cancer Center, Houston, TX

 


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Myeloma Minute
March 5, 2015


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