TY - JOUR
T1 - A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an oral MEK1/2 inhibitor, in relapsed/refractory multiple myeloma
AU - Holkova, Beata
AU - Zingone, Adriana
AU - Kmieciak, Maciej
AU - Bose, Prithviraj
AU - Badros, Ashraf Z.
AU - Voorhees, Peter M.
AU - Baz, Rachid
AU - Korde, Neha
AU - Lin, Hui Yi
AU - Chen, Jin Qiu
AU - Herrmann, Michelle
AU - Xi, Liqiang
AU - Raffeld, Mark
AU - Zhao, Xiuhua
AU - Wan, Wen
AU - Tombes, Mary Beth
AU - Shrader, Ellen
AU - Weir-Wiggins, Caryn
AU - Sankala, Heidi
AU - Hogan, Kevin T.
AU - Doyle, Austin
AU - Annunziata, Christina M.
AU - Wellons, Martha
AU - Roberts, John D.
AU - Sullivan, Daniel
AU - Landgren, Ola
AU - Grant, Steven
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-15-1076
DO - 10.1158/1078-0432.CCR-15-1076
M3 - Article
C2 - 26446942
AN - SCOPUS:84962292920
SN - 1078-0432
VL - 22
SP - 1067
EP - 1075
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -