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PHASE 3 RANDOMIZED TRIAL OF MOMELOTINIB VERSUS RUXOLITINIB IN JAK INHIBITOR NAIVE PATIENTS WITH MYELOFIBROSIS: RESULTS OF THE SIMPLIFY-1 STUDY
Author(s): ,
Jason R. Gotlib
Affiliations:
Stanford University Medical Center,Stanford,United States
,
Jean-Jacques Kiladjian
Affiliations:
Saint-Louis Hospital (APHP) and Paris Diderot University,Paris,France
,
John V. Catalano
Affiliations:
Monash University,Melbourne,Australia
,
Timothy Devos
Affiliations:
University Hospitals Leuven,Leuven,Belgium
,
Miklos Egyed
Affiliations:
Kaposi Mor Teaching Hospital,Kaposvar,Hungary
,
Andrzei Hellman
Affiliations:
Medical University of Gdańsk,Gdańsk,Poland
,
Donal P. McLornan
Affiliations:
Guy's and St. Thomas' NHS Foundation Trust,London,United Kingdom
,
Kazuya Shimoda
Affiliations:
University of Miyazaki,Miyazaki,Japan
,
Elliott F. Winton
Affiliations:
Emory University School of Medicine,Atlanta,United States
,
Wei Deng
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Ronald L. Dubowy
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Julia D. Maltzman
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Francisco Cervantes
Affiliations:
Hospital Clinic, University of Barcelona,Barcelona,Spain
Ruben A. Mesa
Affiliations:
Mayo Clinic Cancer Center,Scottsdale,United States
(Abstract release date: 05/18/17) EHA Library. R. Gotlib J. 06/25/17; 182072; S785
Jason R. Gotlib
Jason R. Gotlib
Contributions
Abstract

Abstract: S785

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:15 - 08:30

Location: Hall E

Background
Momelotinib (MMB), an investigational oral JAK inhibitor (JAKi), has been shown in early trials to reduce spleen volume, improve disease associated symptoms and improve red blood cell (RBC) transfusion requirements in patients with myelofibrosis (MF). 

Aims
To test the non-inferiority of MMB vs ruxolitinib (RUX) in splenic volume reduction and symptom amelioration, and superiority in transfusion requirement, in JAKi naïve patients with primary myelofibrosis, and post-polycythemia vera or post-essential thrombocythemia myelofibrosis.

Methods
Eligibility included primary myelofibrosis or post-polycythemia vera/essential thrombocythemia myelofibrosis; International Prognostic Scoring System (IPSS) high risk, intermediate-2 risk, or intermediate-1 risk associated with symptomatic splenomegaly; palpable spleen ≥5cm; platelets ≥50 K/μl; no Grade ≥2 peripheral neuropathy. Informed consent was obtained. Stratification was by transfusion dependency and platelets (<100K, 100K-200K, and >200K/μl). Patients were randomized 1:1 to 24 weeks of MMB 200 mg qd + RUX placebo or RUX 20 mg bid (or modified per label) + MMB placebo, after which all patients could receive open label MMB. Assessments: spleen volume by MRI, and patient reported symptoms using a daily eDiary of modified MPN-SAF Total Symptom Score (TSS). The primary endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline) at 24 weeks. Secondary endpoints, evaluated sequentially at 24 weeks, were rates of TSS response (≥50% reduction from baseline), RBC transfusion independence and RBC transfusion dependence, and rate of RBC transfusion.

Results
175 of 215 (81%) and 201 of 217 (93%) patients randomized to MMB and RUX, respectively, completed the 24 week double blind phase. Efficacy results are shown in the Table below. The most common Grade ≥3 adverse events in the double blind phase with MMB were thrombocytopenia (7%) and anemia (6%), and with RUX were anemia (23%), thrombocytopenia (5%) and neutropenia (5%). Grade ≥3 infections occurred in 7% of MMB and 3% of RUX patients. Treatment emergent peripheral neuropathy occurred in 22 (10%) of MMB (all Grade ≤2) and 10 (5%) of RUX (9 Grade ≤2, 1 Grade 3) patients in the double blind phase, none discontinuing study drug for this problem. Overall, adverse events led to study drug discontinuation in 13% of MMB and 6% of RUX patients in double blind phase.

Table
EndpointsMMBRUXp-value
  Spleen response rate, %26.529.00.011a
  TSS response rate, %28.442.20.98a
  Transfusion independence rate, %66.549.3<0.001b
  Transfusion dependence rate, %30.240.10.019b
  Transfusion rate (units/month), median0.00.4<0.001b
aTest for non-inferiority; bTest for superiority, all values nominally significant

Conclusion
In patients with JAKi naive myelofibrosis, 24 weeks of momelotinib is non-inferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment is associated with a reduced transfusion requirement.  NCT01969838

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Janus Kinase inhibitor, Clinical Trial, Myelofibrosis

Abstract: S785

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:15 - 08:30

Location: Hall E

Background
Momelotinib (MMB), an investigational oral JAK inhibitor (JAKi), has been shown in early trials to reduce spleen volume, improve disease associated symptoms and improve red blood cell (RBC) transfusion requirements in patients with myelofibrosis (MF). 

Aims
To test the non-inferiority of MMB vs ruxolitinib (RUX) in splenic volume reduction and symptom amelioration, and superiority in transfusion requirement, in JAKi naïve patients with primary myelofibrosis, and post-polycythemia vera or post-essential thrombocythemia myelofibrosis.

Methods
Eligibility included primary myelofibrosis or post-polycythemia vera/essential thrombocythemia myelofibrosis; International Prognostic Scoring System (IPSS) high risk, intermediate-2 risk, or intermediate-1 risk associated with symptomatic splenomegaly; palpable spleen ≥5cm; platelets ≥50 K/μl; no Grade ≥2 peripheral neuropathy. Informed consent was obtained. Stratification was by transfusion dependency and platelets (<100K, 100K-200K, and >200K/μl). Patients were randomized 1:1 to 24 weeks of MMB 200 mg qd + RUX placebo or RUX 20 mg bid (or modified per label) + MMB placebo, after which all patients could receive open label MMB. Assessments: spleen volume by MRI, and patient reported symptoms using a daily eDiary of modified MPN-SAF Total Symptom Score (TSS). The primary endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline) at 24 weeks. Secondary endpoints, evaluated sequentially at 24 weeks, were rates of TSS response (≥50% reduction from baseline), RBC transfusion independence and RBC transfusion dependence, and rate of RBC transfusion.

Results
175 of 215 (81%) and 201 of 217 (93%) patients randomized to MMB and RUX, respectively, completed the 24 week double blind phase. Efficacy results are shown in the Table below. The most common Grade ≥3 adverse events in the double blind phase with MMB were thrombocytopenia (7%) and anemia (6%), and with RUX were anemia (23%), thrombocytopenia (5%) and neutropenia (5%). Grade ≥3 infections occurred in 7% of MMB and 3% of RUX patients. Treatment emergent peripheral neuropathy occurred in 22 (10%) of MMB (all Grade ≤2) and 10 (5%) of RUX (9 Grade ≤2, 1 Grade 3) patients in the double blind phase, none discontinuing study drug for this problem. Overall, adverse events led to study drug discontinuation in 13% of MMB and 6% of RUX patients in double blind phase.

Table
EndpointsMMBRUXp-value
  Spleen response rate, %26.529.00.011a
  TSS response rate, %28.442.20.98a
  Transfusion independence rate, %66.549.3<0.001b
  Transfusion dependence rate, %30.240.10.019b
  Transfusion rate (units/month), median0.00.4<0.001b
aTest for non-inferiority; bTest for superiority, all values nominally significant

Conclusion
In patients with JAKi naive myelofibrosis, 24 weeks of momelotinib is non-inferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment is associated with a reduced transfusion requirement.  NCT01969838

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Janus Kinase inhibitor, Clinical Trial, Myelofibrosis

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