MOMENTUM Phase 3 Clinical Trial for Patients with Myelofibrosis

 

Building MOMENTUM for Patients with Myelofibrosis

Welcome to the Sierra Oncology MOMENTUM Clinical Trial Website!

The MOMENTUM Clinical Trial for Patients with Myelofibrosis is a randomized, double-blind, Phase 3 trial to evaluate the activity of momelotinib versus danazol in symptomatic, anemic patients with myelofibrosis (MF). The target enrollment for this clinical trial is 180 patients globally.

About the MOMENTUM Clinical Trial for Patients with Myelofibrosis

Evaluating the Investigational Drug Momelotinib

Momelotinib is an orally-bioavailable inhibitor of Janus kinase1 (JAK1), Janus kinase2 (JAK2), and Activin A receptor, type I (ACVR1) with a differentiated therapeutic profile in myelofibrosis. Data from more than 820 clinical trial subjects suggest that momelotinib can markedly improve constitutional symptoms and splenomegaly while also substantially addressing the chronic anemia and transfusion dependency associated with the disease.

 

Momelotinib’s unique ability to alleviate anemia and reduce or eliminate transfusion dependency contrasts with other JAK inhibitors which have high rates of hematological toxicity and can worsen cytopenias. This anemia benefit is achieved through direct inhibition of ACVR1 leading to a decrease in circulating hepcidin. Hepcidin is often markedly elevated in myelofibrosis and contributes to an iron restricted anemia. By lowering hepcidin, a corresponding increase in serum iron occurs with consequent clinically relevant increases in hemoglobin and red blood cells due to increased iron availability for erythropoiesis. Momelotinib has also been shown to stabilize, and in some cases ameliorate, thrombocytopenia.

In addition to this differentiated anemia benefit, momelotinib therapy elicits significant improvements in constitutional symptoms and splenomegaly, by variously decreasing aberrant inflammatory cytokine signaling, mutant hematopoietic stem cell proliferation and RBC sequestration, consistent with potent inhibition of JAK1, JAK2 and the downstream JAK-STAT pathway.

 

In contrast to other JAK inhibitors, very low rates of thrombocytopenia and other hematological toxicities, also allow maximal momelotinib dose intensity to be sustained during chronic therapy, further supporting the compound’s unique potential for benefit in myelofibrosis.

 

For more information on momelotinib, visit: https://www.sierraoncology.com/momelotinib/

MOMENTUM Trial Overview

MOMENTUM P3 Trial: Phase 3 Registration Trial Schema

A Randomized, Double-Blind, Phase 3 Study to Evaluate the Activity of Momelotinib versus Danazol in Symptomatic, Anemic Subjects with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis who were Previously Treated with JAK Inhibitor Therapy

MOMENTUM is a randomized, double-blind, active control trial intended to confirm the differentiated clinical benefits of momelotinib versus danazol in patients who have previously received an approved JAK inhibitor therapy for myelofibrosis, including either ruxolitinib or fedratinib. Patients must be symptomatic with a Myelofibrosis Symptom Assessment Form v4.0 (MFSAF) Total Symptom Score (TSS) of ≥ 10 at screening and be anemic with hemoglobin (Hgb) < 10 g/dL.

For patients with ongoing JAK inhibitor therapy at screening, JAK inhibitor therapy must be tapered over a period of at least 1 week, followed by a 2-week non-treatment washout interval that concludes prior to randomization.

Patients will be randomized 2:1 to orally self-administer blinded treatment, momelotinib plus placebo or danazol plus placebo. Patients randomized to receive momelotinib who complete the randomized treatment period to the end of Week 24 may continue to receive momelotinib in the open-label extended treatment period to the end of Week 204 (a total period of treatment of approximately 4 years).

Patients randomized to receive danazol may cross-over to momelotinib open-label treatment in the following circumstances:

  • at the end of Week 24 if they complete the randomized treatment period; or
  • at the end of Week 24 if they discontinue treatment with danazol but continue trial assessments and do not receive prohibited medications including alternative active anti-myelofibrosis therapy; or
  • at any time during the randomized treatment period if they meet the protocol-defined criteria for radiographically-confirmed symptomatic splenic progression.

Patients randomized to receive danazol who are receiving clinical benefit at the end of Week 24 may instead choose to continue open-label danazol therapy up to Week 48.

Trial Objectives

Primary:

To determine the efficacy of momelotinib versus danazol assessed by improvement in MFSAF TSS in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who were previously treated with an approved JAK inhibitor therapy, including either ruxolitinib or fedratinib.

 

Key Secondary:

To compare the effect of momelotinib versus danazol on transfusion independent (TI) status at Week 24.

 

To compare the splenic response rate (SRR) for patients treated with momelotinib versus danazol.

 

In addition, the trial will investigate a number of other secondary and exploratory endpoints, including the duration of symptomatic improvement, the effect of momelotinib treatment on other measures of transfusion burden and patient reported outcome metrics.

Selected Key Eligibility Criteria

Patient Inclusion Criteria

1. Age ≥ 18 years.

2. Confirmed diagnosis of primary myelofibrosis in accordance with the World Health Organization (WHO) 2016 criteria, or post-polycythemia vera/ post-essential thrombocythemia myelofibrosis in accordance with the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT criteria).

3. Symptomatic, defined as a MFSAF TSS of ≥ 10 units assessed by a single MFSAF v4.0 assessment at a Screening visit.

4. Anemic, defined as a Hgb < 10 g/dL in screening/baseline period.

5. Previously treated with an approved JAK inhibitor for primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis for ≥ 90 days, or ≥ 28 days if JAK inhibitor therapy is complicated by RBC transfusion requirement of ≥ 4 units in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma.

6. Baseline splenomegaly, defined as having a palpable spleen at ≥ 5 cm, below the left costal margin, or with volume ≥ 450 cm3 on imaging (ultrasound, MRI or CT are acceptable), assessed during Screening at any point prior to Randomization.

7. High risk, intermediate-2, or intermediate-1 risk myelofibrosis as defined by DIPSS, or DIPSS-plus.

8. No allogeneic stem cell transplant planned.

9. Acceptable laboratory assessments:

ANC ≥ 0.75 × 109/L
PLT ≥ 25 × 109/L
Peripheral blast count < 10%
AST/SGOT and ALT/SGPT ≤ 3 × ULN (≤ 5 × 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 (CCr)

≥ 30 mL/min

Calculated according to Cockcroft-Gault:

CCr = {((140 – age) × weight) / (72 × SCr)} × 0.85 (if female)

CCr (creatinine clearance) = mL/minute

Age = years

Weight = kg

SCr (serum creatinine) = mg/dL

Direct bilirubin ≤ 2.0 × ULN

ANC = absolute neutrophil count, ALT/SGPT = alanine aminotransferase/ serum glutamic-pyruvic transaminase, AST/SGOT = alanine aminotransferase/ glutamic-oxaloacetic transaminase, PLT = platelet count.

Patient Exclusion Criteria

Patients may be excluded if they have received the following treatments within the time periods noted:

a) Prior momelotinib treatment at any time.

b) JAK inhibitor therapy within 2 weeks prior to randomization.

c) Active anti-myelofibrosis therapy within 2 weeks prior to randomization.

d) Potent Cytochrome P450 3A4 (CYP3A4) inducers within 1 week prior to randomization.

e) Investigational agent within 4 weeks prior to randomization.

f) Erythropoiesis stimulating agent (ESA) within 4 weeks prior to randomization

g) Danazol within 3 months prior to randomization

h) Splenic irradiation within 3 months prior to randomization

i) Current treatment with simvastatin, atorvastatin, lovastatin or rosuvastatin

For additional information, visit ClinicalTrials.gov

Chief Investigator

Dr. Srdan Verstovsek

Chief, Section for Myeloproliferative Neoplasms,
Department of Leukemia, Division of Cancer Medicine


The University of Texas MD Anderson Cancer Center, Houston

If you are interested in learning more about the MOMENTUM Clinical Trial for Patients with Myelofibrosis and determining if your patients may be eligible, please complete the following form and you will be contacted by a MOMENTUM Trial representative.

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