Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis
Authors: Pemmaraju Naveen , Carter Bing Z , Kantarjian Hagop M. , Cortes Jorge E. , Bose Prithviraj , Kadia Tapan M. , Garcia-Manero Guillermo , Bueso-Ramos Carlos E. , DiNardo Courtney D. , Bledsoe Sharon , Daver Naval G. , Popat Uday , Konopleva Marina Y , Ohanian Maro , Pierce Sherry A. , Zhou Lingsha , Estrov Zeev E. , Borthakur Gautam M. , Mak Po Yee , Jain Nitin , Jabbour Elias , Verstovsek Srdan 
Published: February 2020

Background: Outcomes in patients (pts) with relapsed/refractory (R/R) myelofibrosis (MF) post JAK inhibitor are poor [overall survival (OS) 13-14 months] (Newberry K, Blood 2017; Kuykendall A, Ann Hematol 2018). There are no approved therapies beyond JAK inhibitors for pts with MF. In certain clinical situations, such as severe thrombocytopenia, administration of JAK inhibitors may be difficult or even contraindicated. SMAC mimetics (or IAP antagonists), a novel class of anti-cancer therapeutics, lead to apoptotic cancer cell death through targeting of IAPs. Because these agents are hypothesized to be particularly effective in a TNFα-rich micro-environment, such as in pts with MF, a group known to have markedly increased cytokines including TNFα (Fleischman A Blood 2011; Heaton W, Leukemia 2018; Tefferi A, JCO 2011), we conducted an investigator-initiated phase 2 clinical trial with LCL161 in pts with intermediate to high risk PMF or post-ET/PV MF.
Objectives: Primary: overall response rate (ORR) by IWG-MRT 2013; secondary and exploratory: time to response, response duration, safety, improvement in symptom burden by MPN-SAF TSS, measurement of cIAP1/2, XIAP, and mutational profiling via next-generation sequencing.
Clinical Trial Design: LCL161 is an oral monovalent SMAC mimetic, administered once weekly, starting dose 1500 mg with 2 dose level reductions (DL-1, 1200mg; DL-2, 900 mg) in pts with MF. One cycle was 28 days. Pts age ≥18, PS 0-2, who were not candidates for, intolerant to, or R/R to JAK inhibitors were eligible. After 3 cycles, bone marrow biopsy/response evaluations were performed. There was no minimum platelet count for eligibility, and prior allogeneic stem cell transplant (SCT) was allowed.
Results: The study has completed enrollment. A total of 47 pts were treated with a median age of 72 years [56-85]. The median baseline platelet count was 51 x 109/L [6-1365]. The median baseline spleen size was 12 cm among 28 pts with enlarged spleen at baseline. 70% of the pts had ≥2 prior therapies; 55% had a prior JAK inhibitor, 2 pts had prior SCT. 75% were IPSS high-risk. Driver mutations: 64% JAK2 V167F; 13% CALR; 11% MPL W515L; 5 pts had triple negative MF. Mutation analysis revealed the three most common additional mutations: ASXL1 (23%); TET2 (15%); DNMT3a (11%). ORR was 32% (15/47 pts); 15 pts exhibited a total of 19 objective responses (4 pts met criteria for 2 separate IWG 2013 responses): Clinical improvement (CI) symptoms (n=11); CI anemia (n=6); CI spleen (n=1), cytogenetic response (n=1). At a median follow-up of 21.1 months (mo) [3.9-49.7+], the median number of cycles received was 5 [1-52+], the median time to response was 1.4 mo [0.9-9.1] and median response duration (mo) was 31.5 [3.6-48.8+]. Long-term responders: n=8 for ≥1 year; n=4 for ≥2 years/ongoing. Importantly, median OS is not yet reached on this study (Figure). The most common non-hematologic toxicities (grade 1/2): nausea/vomiting (60%); fatigue syndrome (49%), dizziness/vertigo (32%); non-hematologic Grade 3/4: syncope (n=2); nausea/vomiting (n=1). Hematologic toxicities (grade 3/4): thrombocytopenia n=3 (6%); anemia n=2 (4%). 36% pts had a dose reduction; the most common cause was fatigue (n=10). Overall, 81% pts are now off study [Stable disease/no objective response (n=16); progressive disease (n=9); toxicity (n=5), pt's choice/other (n=6), proceeded to SCT (n=2)].
Correlative analysis: Preliminary analysis demonstrates on-target inhibition of cIAP1 observed in all responding pts analyzed; high levels of XIAP and/or XIAP increases were observed in many pts with resistance/disease progression.
Anemia responders: 6 pts achieved CI anemia (n=4 hemoglobin responses, n=2 achievement of transfusion independence). Among these 6 pts: median time to response (mo): 3.1 [0.9-9.1]; median response duration (mo): 8.4 [5.5-28.6].
Conclusion: In an older group of pts with 70% with ≥2 prior therapies (55% JAK inhibitor-exposed), median baseline platelet count of 51, ASXL1-mutated in 23%, we observed a 32% ORR. The median OS has not yet been reached. Oral SMAC mimetics may represent a possible option for older pts, those who have failed prior JAK inhibitor, and those with thrombocytopenia limiting entry onto other trials. Future directions include combination studies with hypomethylating agents and JAK inhibitors for pts with myeloid malignancies. This clinical trial is registered at ClinicalTrials.gov as NCT02098161.
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Disclosures
Pemmaraju: sagerstrong: Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; novartis: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; incyte: Consultancy, Research Funding; affymetrix: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding. Carter:Amgen: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding. Cortes:Sun Pharma: Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Merck: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding. Bueso-Ramos:Incyte: Consultancy. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Borthakur:Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Strategia Therapeutics: Research Funding; Xbiotech USA: Research Funding; Tetralogic Pharmaceuticals: Research Funding; GSK: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Cantargia AB: Research Funding; AbbVie: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Cyclacel: Research Funding; Polaris: Research Funding; NKarta: Consultancy; Agensys: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

OffLabel Disclosure:
LCL161- not yet FDA approved drug; investigational agent = SMAC mimetic /IAP antagonist