TY - JOUR
T1 - Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis
AU - Pemmaraju, Naveen
AU - Carter, Bing Z.
AU - Bose, Prithviraj
AU - Jain, Nitin
AU - Kadia, Tapan M.
AU - Garcia-Manero, Guillermo
AU - Bueso-Ramos, Carlos E.
AU - DiNardo, Courtney D.
AU - Bledsoe, Sharon
AU - Daver, Naval G.
AU - Popat, Uday
AU - Konopleva, Marina Y.
AU - Zhou, Lingsha
AU - Pierce, Sherry
AU - Estrov, Zeev E.
AU - Borthakur, Gautam M.
AU - Ohanian, Maro
AU - Qiao, Wei
AU - Masarova, Lucia
AU - Wang, Xuemei
AU - Yee Mak, Po
AU - Cortes, Jorge
AU - Jabbour, Elias
AU - Verstovsek, Srdan
N1 - Funding Information:
Conflict-of-interest disclosure: N.P. has been a consultant to and received honoraria from Celgene, Stemline, Incyte Novartis, Mus-tangBio, Roche Diagnostics, LFB, and Pacylex and has received research funding and clinical trial support from Stemline, Novartis, Abbvie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, Affymetrix, and the SagerStrong Foundation.
Funding Information:
This study was supported in part by National Institutes of (NIH), National Cancer Institute MD Anderson Cancer
Publisher Copyright:
© 2021 American Society of Hematology. All rights reserved.
PY - 2021/8/24
Y1 - 2021/8/24
N2 - Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-A cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with $2 prior therapies and a median baseline platelet count of 52 3 103/mL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.11). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.
AB - Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-A cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with $2 prior therapies and a median baseline platelet count of 52 3 103/mL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.11). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.
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U2 - 10.1182/bloodadvances.2020003829
DO - 10.1182/bloodadvances.2020003829
M3 - Article
C2 - 34424319
AN - SCOPUS:85113851189
SN - 2473-9529
VL - 5
SP - 3163
EP - 3173
JO - Blood Advances
JF - Blood Advances
IS - 16
ER -