Abstract
Background: There is no standard therapy for patients (pts) with intermediate (Int)-2 or high risk myelofibrosis (MF) who have failed or are intolerant to Janus kinase (JAK) inhibitors such as ruxolitinib. Second mitochondria-derived activator of caspases (SMAC) mimetics, or inhibitors of apoptosis (IAP) antagonists, lead to increased apoptotic cancer cell death, especially in high TNFα-expressing tumor models. An emerging concept in myeloproliferative neoplasm (MPN) tumor pathobiology is the finding of significantly increased levels of TNFαin pts with MF(Fleischman AG et al, Blood 2011).
Objectives: Primary objective: to determine efficacy (IWG-MRT, 2013) of LCL161 as monotherapy for pts with MF. Secondary objectives: to determine safety, durability of response, and changes in symptom burden [Myeloproliferative Neoplasm (MPN)-Total Symptom Score]. Exploratory objectives: to assess JAK2V617F and CALR allele burden; 28-gene panel for molecular mutations via next generation sequencing; and markers of IAP pathway degradation.
Methods: We conducted an investigator-initiated, single-center, phase II study of LCL161 for pts with MF in a Simon's Optimal two-stage design. Pts age ≥18, PS=0-2, Int to high risk MF, who were intolerant to, ineligible for, or relapsed/refractory to JAK inhibitors were eligible. There was no threshold requirement for spleen size or platelet (plt) count, and pts with prior allogeneic stem cell transplant (SCT) were eligible. LCL161, an oral (po) drug, was given at starting dose 1500mg po once weekly. Each cycle=28 days. After 3 cycles, bone marrow exam and objective response assessments were performed.
Results: From January 2015 to July 2016, 21 pts have been enrolled. Baseline characteristics: Median Age: 72 years [56-81], 86% with primary MF. Baseline laboratory values: Hb 9 g/dL (6.3-12); WBC 5.3 K/uL [1.1-38]; platelets 45 K/uL [6-1365]. JAK2V617F mutations were present in 14(67%), CALR mutations in 3(14%), and MPLW515L mutation in 1(5%) pt. Additionally, the most common other molecular mutations were: TET2(n=4); DNMT3A(n=3); RAS(n=1); EZH2(n=1). 17 (81%) had ≥2 prior therapies. Most common prior therapy was a JAK inhibitor (67%). 2 pts had prior SCT. By IPSS, 14 (67%) were high risk MF; 6(28%) were Int-2. Median number of cycles received=3[1-19], median treatment duration=2.8 months (mos)[0.2-16.7]. 19 pts are alive, with median follow-up of 7 mos[0.2-17.7]. Among 21 pts, 5 have been recently enrolled and have not yet reached 12-week evaluation period; among 16 evaluable pts, 6 pts had 9 objective responses (3 pts achieved 2 separate IWG-MRT 2013 response categories): Clinical improvement (CI) (anemia) in 2 pts; CI (Symptom) in 5 pts; CI (Spleen) in 1 pt; Cytogenetic remission in 1 pt. Grade 3/4 non-hematologic adverse events: syncope, n=2. No pts had cytokine release syndrome. Most common grade 1/2 non-hematologic toxicities: fatigue (n=10), nausea (n=10), dizziness/vertigo (n=9). Dose reductions: 7 pts: 6 pts to dose -1 level (1200 mg po once weekly) and 1 pt to dose -2 (900mg po once weekly); importantly, the most common reason was due to grade 2 fatigue (n=6). 10 pts are now off study [n=5 no response; n=3 toxicity; n=1 transformation to AML; n=1 patient on study proceeded to SCT]. Preliminary, ongoing correlative studies demonstrate on-target inhibition (by Western blot) of CIAP1 in eight pts: strong (n=4) or moderate (n=4); among the 6 clinically responding pts, 4 of 4 of these pts with viable/available samples for analysis demonstrated strong on-target CIAP1 inhibition.
Conclusions: In this study, in a cohort of older pts with MF, 67% IPSS high risk, with median plt count of 45 at study entry, in whom 81% had received ≥2 prior therapies, we have observed objective responses in 38% (6/16 evaluable for response). LCL161 has a convenient (po, weekly) dosing schedule, represents a novel target for pts with MPNs, and is able to be administered to pts who have failed or intolerant/ineligible for JAK inhibitor therapy. Notably, grade 2 fatigue was commonly observed, and represents the most common reason for dose reduction and study discontinuation. Based on early responses observed, this study has met criteria for the pre-planned analysis for efficacy (Simon Stage 1) and therefore is able to proceed to Simon Stage 2. This clinical trial is registered at www.clinicaltrials.gov/ct2/show/NCT02098161.
Disclosures
Carter: PRISM Pharma/Eisai: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Bose:Novartis: Research Funding. Verstovsek:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; Lilly Oncology: Research Funding.
Novel Therapies in Myeloproliferative Neoplasms: Beyond JAK Inhibitor Monotherapy
