A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis

Study Overview
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Brief Summary
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This is a Phase 2 open-label, multicenter study evaluating tolerability and efficacy of navitoclax alone or when added to ruxolitinib in participants with myelofibrosis.

Official Title
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A Phase 2 Open-Label Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Subjects With Myelofibrosis (REFINE)

Conditions
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Myelofibrosis (MF)

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Navitoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with documented diagnosis of intermediate-2 or high-risk primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis. Participant must be ineligible due to age, comorbidities, or unfit for unrelated or unmatched donor transplantation or unwilling to undergo stem cell transplantation at time of study entry. Eastern Cooperative Oncology Group (ECOG) of 0, 1, or 2. Prior treatment must meet at least one of the following criteria: Prior or current treatment with ruxolitinib and no prior treatment with a Bromodomain and Extra-Terminal motif (BET) proteins inhibitor or another Janus Kinase 2 (JAK-2) inhibitor, and meet all of the following criteria: Ruxolitinib treatment must meet at least one of the following criteria: Ruxolitinib treatment for >=24 weeks with lack of efficacy defined as a lack of spleen response (refractory) or a loss of spleen or symptom response (relapsed) Ruxolitinib treatment for <24 weeks with documented disease progression on spleen measurements while on ruxolitinib as defined in the protocol: Ruxolitinib treatment for >=28 days with intolerance defined as new red blood cell transfusion requirement (at least 2 units/month for 2 months) while receiving a total daily ruxolitinib dose of >=30 mg but unable to reduce dose further due to lack of efficacy. If receiving ruxolitinib at the time of screening, must currently be on a stable dose >=10 mg twice daily of ruxolitinib for >=4 weeks prior to the 1st dose of navitoclax. Participant has at least 2 symptoms each with a score >=3 or a total score of >=12, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days during screening prior to study drug dosing; OR Prior treatment with a JAK-2 inhibitor and meet one of the following criteria: Prior treatment with a JAK-2 inhibitor for at least 12 weeks Prior treatment with a JAK-2 inhibitor for >=28 days complicated by either development of red blood cell transfusion requirement (at least 2 units/month for 2 months) OR Grade >= 3 adverse events of thrombocytopenia, anemia, hematoma and/or hemorrhage while on JAK-2 inhibitor treatment; OR No prior treatment with a JAK-2 or BET inhibitor: Participant has at least 2 symptoms each with a score >=3 or a total score of >= 12, as measured by the MFSAF v4.0 on at least 4 out of 7 days during screening prior to study drug dosing. Participant has splenomegaly as defined in the protocol. Participant must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol. Exclusion Criteria: Splenic irradiation within 6 months prior to screening, or prior splenectomy. Leukemic transformation (> 10% blasts in peripheral blood or bone marrow aspirate/biopsy). Participant is currently on medications that interfere with coagulation (including warfarin) or platelet function within 3 days prior to the first dose of study drug or during the study treatment period with the exception of low dose aspirin (up to 100 mg/day) and low-molecular-weight heparin. Prior therapy with a BH3 mimetic compound or stem cell transplantation. Participant has received strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A inhibitors (e.g., fluconazole) within 14 days prior to the administration of the first dose of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Navitoclax + ruxolitinib<br>Participants will be administered navitoclax once daily (QD) at various doses and a dose greater than or equal to 10 mg of ruxolitinib twice daily (BID). | Drug: Ruxolitinib<br>* Tablet; Oral<br>* Other names: Jakafi;Drug: Navitoclax<br>* Tablet; Oral<br>* Other names: ABT-263;|
| Experimental: Navitoclax<br>Participants will be administered various doses of navitoclax once daily (QD) | Drug: Navitoclax<br>* Tablet; Oral<br>* Other names: ABT-263;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who achieve Spleen Volume Reduction of greater than or equal to 35% (SVR35) from baseline | Reduction in spleen volume is measured by magnetic resonance imaging/computerized tomography (MRI/CT). | From Baseline (Week 0) through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants achieving 50% Reduction in Total System Score (TSS) | TSS is assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0. | From Baseline (Week 0) through Week 24 | 
| Anemia Response | The anemia response will be assessed according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria. | Every 12 weeks up to approximately 96 weeks | 
| Change in Grade of Bone Marrow Fibrosis | Bone marrow grading is assessed according to the European Consensus Grading System. | Through Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-polycythemia vera MF (PPV-MF), Post-essential thrombocythemia (PET-MF), ruxolitinib, navitoclax, splenic volume, Primary Myelofibrosis, Jakafi, enlarged spleen, splenomegaly, ABT 263, bone marrow fibrosis