A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma

• Published in: Clinical cancer research 2016-03, Vol.22 (5), p.1067-1075
• Main Authors: Holkova, Beata, Zingone, Adriana, Kmieciak, Maciej, Bose, Prithviraj, Badros, Ashraf Z, Voorhees, Peter M, Baz, Rachid, Korde, Neha, Lin, Hui-Yi, Chen, Jin-Qiu, Herrmann, Michelle, Xi, Liqiang, Raffeld, Mark, Zhao, Xiuhua, Wan, Wen, Tombes, Mary Beth, Shrader, Ellen, Weir-Wiggins, Caryn, Sankala, Heidi, Hogan, Kevin T, Doyle, Austin, Annunziata, Christina M, Wellons, Martha, Roberts, John D, Sullivan, Daniel, Landgren, Ola, Grant, Steven
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - pharmacokinetics; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Proto-Oncogene Proteins p21(ras) - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-1076

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. AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles. 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. Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population.