Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects With Primary Myelofibrosis (MF), Post-polycythemia Vera MF, or Post-essential Thrombocythemia MF (Simplify 2)

• ClinicalTrials.gov Identifier: NCT02101268
• Recruitment Status: Completed
• First Posted: April 2, 2014
• Last Update Posted: April 8, 2020
• Sponsor: Sierra Oncology, Inc.
• Information provided by (Responsible Party): Sierra Oncology, Inc.

Study Description

Brief Summary:

This study is to determine the efficacy of momelotinib (MMB) versus best available therapy (BAT) in anemic or thrombocytopenic adults with primary myelofibrosis (PMF), or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/ET MF) who were treated with ruxolitinib as measured by splenic response rate at Week 24 (SRR24).

Participants will be randomized to receive either MMB or BAT for 24 weeks during the randomized treatment phase, after which they will be eligible to receive MMB in an extended treatment phase for up to an additional 204 weeks. After discontinuation of study medication, assessments will continue for 12 additional weeks, after which participants will be contacted for survival follow-up approximately every 6 months for up to 5 years from the date of enrollment or until study termination. For those subjects planning to continue treatment with MMB following the end of the study, the End of Treatment, 30-day, 12-Week, and survival follow-up visits are not required.

Condition or disease	Intervention/treatment	Phase
Primary Myelofibrosis (PMF); Post-polycythemia Vera (Post-PV); Post-essential Thrombocythemia Myelofibrosis (Post-ET MF)	Drug: Momelotinib; Drug: Best Available Therapy (BAT)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized Study To Evaluate the Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects With Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis Who Were Treated With Ruxolitinib
• Actual Study Start Date: June 19, 2014
• Actual Primary Completion Date: July 28, 2016
• Actual Study Completion Date: April 25, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1: Momelotinib; Participants will receive momelotinib for 24 weeks during the randomized treatment phase, after which they will be eligible to receive momelotinib in an extended treatment phase for up to an additional 204 weeks.	Drug: Momelotinib; Momelotinib tablet administered orally once daily; Other Names: GS-0387; CYT387
Active Comparator: Arm 2: Best Available Therapy (BAT); Participants in the BAT treatment arm will receive treatment at doses and schedules determined by the investigator in accordance with standard of care. Therapy may be changed at any time during the study except during the screening period. After completion of the randomized treatment phase, participants will be eligible to receive momelotinib for the duration of the study during the extended treatment phase for up to 204 weeks.	Drug: Best Available Therapy (BAT); Regimens for BAT may include but are not limited to chemotherapy (eg hydroxyurea), anagrelide, corticosteroid, hematopoietic growth factor, immunomodulating agent, androgen, interferon, and may include no myelofibrosis treatment.

Outcome Measures

Primary Outcome Measures :

1. Splenic response rate at Week 24 [ Time Frame: Week 24 ]
   Splenic response rate at Week 24 is defined as the proportion of participants achieving a ≥ 35% reduction in spleen volume at Week 24 from baseline as measured by MRI or CT.

Secondary Outcome Measures :

1. Response rate in total symptom score at Week 24 [ Time Frame: Week 24 ]
   Total symptom score (TSS) is defined as the proportion of participants who achieve a ≥ 50% reduction in TSS from baseline to Week 24 as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPNSAF TSS) v2.0 diary.
2. Rate of red blood cell (RBC) transfusion through Week 24 [ Time Frame: Baseline to Week 24 ]
   Rate of RBC transfusion is defined as the average number of RBC units per participant per month.
3. RBC transfusion independence rate at Week 24 [ Time Frame: Week 24 ]
   RBC transfusion independence is the proportion of participants who are transfusion independent at Week 24, defined as absence of RBC transfusions and no hemoglobin level below 8 g/dL in the prior 12 weeks.
4. RBC transfusion dependence rate at Week 24 [ Time Frame: Week 24 ]
   RBC transfusion dependence is the proportion of participants who are transfusion dependent at Week 24, defined as at least 4 units of RBC transfusions, or a hemoglobin level below 8 g/dL in the prior 8 weeks.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Palpable splenomegaly at least 5 cm below left costal margin
• Confirmed diagnosis of PMF in accordance, or Post-PV/ET MF

• Currently or previously treated with ruxolitinib for PMF or Post-PV/ET MF for at least 28 days, and characterized by

  • Requirement for RBC transfusion while on ruxolitinib treatment, OR

  • Dose adjustment of ruxolitinib to < 20 mg twice daily at start of or during ruxolitinib treatment AND at least one of the following while on ruxolitinib treatment:

    • ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 thrombocytopenia, OR
    • ≥ CTCAE Grade 3 anemia, OR
    • ≥ CTCAE Grade 3 hematoma (bleed)
• High risk OR intermediate-2 risk as defined by Dynamic International Prognostic Scoring System (DIPSS), OR intermediate-1 risk as defined by DIPSS and associated with symptomatic splenomegaly, and/or hepatomegaly
• If receiving myelofibrosis therapy, must be on a stable dose of the same regimen for at least 2 weeks prior to screen date and through the screening period
• If not receiving myelofibrosis therapy, must remain off therapy for at least 2 weeks prior to screen date and through the screening period

• Acceptable laboratory assessments obtained within 14 days prior to Randomization

  • Absolute neutrophil count (ANC) > 0.75 x 10^9/L in the absence of growth factor in the prior 7 days
  • Peripheral blood blast count < 10%
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x the upper limit of the normal range (ULN) (≤ 5 x ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy that was started within the prior 60 days)
  • Calculated creatinine clearance of ≥ 45 mL/min
  • Direct bilirubin ≤ 2.0 x ULN
• Life expectancy > 24 weeks
• Negative serum pregnancy test for female subjects (unless surgically sterile or greater than two years post-menopausal)
• Males and females of childbearing potential must agree to use protocol-specified method(s) of contraception
• Females who are nursing must agree to discontinue nursing before the first dose of MMB
• Able to understand and willing to sign informed consent form (ICF)

Key Exclusion Criteria:

• Prior splenectomy
• Splenic irradiation within 3 months prior to Randomization
• Use of investigational agent within 28 days prior to Randomization
• Prior treatment with MMB
• Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) within 28 days prior to Randomization
• Uncontrolled inter-current illness, per protocol
• Known positive status for human immunodeficiency virus (HIV)
• Chronic active or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier
• Presence of peripheral neuropathy ≥ CTCAE Grade 2
• Unwilling or unable to undergo a MRI or CT Scan per study protocol requirements

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

United States, California

Los Angeles, California, United States

United States, Florida

Gainesville, Florida, United States

United States, Georgia

Atlanta, Georgia, United States

United States, Kansas

Kansas City, Kansas, United States

United States, Maryland

Baltimore, Maryland, United States

United States, Missouri

Saint Louis, Missouri, United States

United States, New Mexico

Albuquerque, New Mexico, United States

United States, New York

New York, New York, United States

United States, North Carolina

Durham, North Carolina, United States

Winston-Salem, North Carolina, United States

United States, Ohio

Cleveland, Ohio, United States

United States, Pennsylvania

Pittsburgh, Pennsylvania, United States

United States, Texas

Houston, Texas, United States

Canada, Alberta

Edmonton, Alberta, Canada

Canada

Montreal, Canada

Toronto, Canada

France

Lille cedex, France

Marseille, France

Nantes, France

Paris, France

Pierre Benite Cedex, France

Toulouse, France

Villejuif Cedex, France

Germany

Dresden, Germany

Hamburg, Germany

Koln, Germany

Mannheim, Germany

Israel

Ashkelon, Israel

Haifa, Israel

Jerusalem, Israel

Tel-Aviv, Israel

Italy

Bologna, Italy

Firenze, Italy

Genova, Italy

Milano, Italy

Novara, Italy

Roma, Italy

Varese, Italy

Spain

Badalona, Spain

Barcelona, Spain

Madrid, Spain

Salamanca, Spain

Valencia, Spain

Zaragoza, Spain

United Kingdom

Birmingham, England, United Kingdom

Leeds, England, United Kingdom

Leicester, England, United Kingdom

London, England, United Kingdom

Sponsors and Collaborators

Sierra Oncology, Inc.

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, Passamonti F, Winton EF, Dong H, Kawashima J, Maltzman JD, Kiladjian JJ, Verstovsek S. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018 Feb;5(2):e73-e81. doi: 10.1016/S2352-3026(17)30237-5. Epub 2017 Dec 20.

• Responsible Party: Sierra Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT02101268
• Other Study ID Numbers: GS-US-352-1214; 2013-005007-13 ( EudraCT Number )
• First Posted: April 2, 2014
• Last Update Posted: April 8, 2020
• Last Verified: April 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Blood Platelet Disorders; Blood Coagulation Disorders; Hemorrhagic Disorders; N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action