A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an oral MEK1/2 inhibitor, in relapsed/refractory multiple myeloma

Beata Holkova, Adriana Zingone, Maciej Kmieciak, Prithviraj Bose, Ashraf Z. Badros, Peter M. Voorhees, Rachid Baz, Neha Korde, Hui Yi Lin, Jin Qiu Chen, Michelle Herrmann, Liqiang Xi, Mark Raffeld, Xiuhua Zhao, Wen Wan, Mary Beth Tombes, Ellen Shrader, Caryn Weir-Wiggins, Heidi Sankala, Kevin T. HoganAustin Doyle, Christina M. Annunziata, Martha Wellons, John D. Roberts, Daniel Sullivan, Ola Landgren, Steven Grant

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Purpose: AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma. Experimental Design: AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles. Results: Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138+ cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation. Conclusions: Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population.

Original languageEnglish (US)
Pages (from-to)1067-1075
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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