Study of Oral Navitoclax Tablet In Combination With Oral Ruxolitinib Tablet When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis

Study Overview
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Brief Summary
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Myelofibrosis is a type of bone marrow cancer that usually develops slowly and disrupts body's normal production of blood cells. It causes bone marrow scarring, leading to severe anemia that can cause weakness and fatigue. It can also cause a low number of blood-clotting cells called platelets, which increases risk of bleeding. Myelofibrosis often causes an enlarged spleen. The purpose of this study is to see if a combination of navitoclax and ruxolitinib is more effective and safe in assessment of change in spleen volume when compared to ruxolitinib in participants with myelofibrosis. Navitoclax is an investigational drug for the treatment of myelofibrosis. Participants in this study are divided into two groups, called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of myelofibrosis will be enrolled. Around 230 participants will be enrolled in approximately 190 sites worldwide. Participants will receive oral navitoclax tablet with oral ruxolitinib tablet or oral ruxolitinib tablet with oral placebo (no active drug) tablet and treatment may continue untill the participant cannot tolerate the study drug, or benefit is not achieved, or other reasons which qualify for discontinuation of the study drug. There may be a higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, magnetic resonance imaging (MRI) or computed tomography (CT) scan, bone marrow tests, checking for side effects, and completing questionnaires.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Of Navitoclax In Combination With Ruxolitinib Versus Ruxolitinib In Subjects With Myelofibrosis (TRANSFORM-1)

Conditions
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Myelofibrosis (MF)

Intervention / Treatment
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* Drug: Navitoclax
* Drug: Ruxolitinib
* Drug: Placebo for Navitoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of Primary MyeloFibrosis (MF) as defined by World Health Organization (WHO) classification or Secondary MF (post polycythemia vera [PPV] - MF or Post Essential Thrombocytopenia [PET] - MF) . Must be able to complete the MF Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days immediately preceding the date of randomization. -- Must have at least 2 symptoms with a score >=3 or a total score of >=12, as measured by the MFSAF v4.0. Classified as intermediate-2, or high-Risk MF as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+). Has splenomegaly defined as spleen palpation measurement >= 5 centimeters (cm) below costal margin or spleen volume greater than or equal to 450 cubic cm as assessed centrally by magnetic resonance imaging (MRI) or computed tomography (CT) scan. Ineligible for stem cell transplantation at time of study entry due to age, comorbidities, or unfit for unrelated or unmatched donor transplant and other criteria per National Comprehensive Cancer Network guidelines. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Exclusion Criteria: Prior treatment with a Janus Kinase-2 (JAK-2) inhibitor. Prior treatment with a B-cell lymphoma 2 homology 3 (BH3)-mimetic compound or bromodomain and extra-terminal motif (BET) inhibitor or stem cell transplant. Receiving medication that interferes with coagulation or platelet function within 3 days prior to the first dose of study drug or during the study treatment period except for low dose aspirin (up to 100 milligram daily) and low molecular weight heparin (LMWH).

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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Navitoclax + Ruxolitinib<br>Participants will receive Navitoclax in combination with Ruxolitinib | Drug: Navitoclax<br>* Tablet; Oral<br>* Other names: ABT-263;Drug: Ruxolitinib<br>* Tablet; Oral<br>|
| Active Comparator: Placebo for Navitoclax + Ruxolitinib<br>Participants will receive placebo for Navitoclax and Ruxolitinib | Drug: Ruxolitinib<br>* Tablet; Oral<br>Drug: Placebo for Navitoclax<br>* Tablet; Oral<br>|

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 at least 35% at Week 24 (SVR35W24) | Reduction in spleen volume is measured by magnetic resonance imaging (MRI) or computed tomography (CT), per International Working Group (IWG) criteria. | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total Symptom Score (TSS) | Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. | Baseline (Week 0) Up to Week 24 | 
| Percentage of Participants who achieve Spleen Volume Reduction of at least 35% (SVR35) | Reduction in spleen volume is measured by MRI or CT, per IWG criteria. | Baseline (Week 0) Up to Week 96 | 
| Duration of 35% Spleen Volume Reduction (SVR35) | Duration of SVR35 is defined as the time between the date of first response of spleen volume reduction of 35% achievement to the date of the first assessment where the spleen volume is less than 35% reduction from baseline and is at least 25% increase from the nadir (the lowest spleen volume). | Baseline (Week 0) Up to Week 96 | 
| Change In Fatigue | Change in fatigue will be assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue SF 7a. | Baseline (Week 0) Up to Week 24 | 
| Change in Physical Functioning | Change in physical functioning is measured by the physical functioning domain of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 or death. | Baseline (Week 0) Up to Week 24 | 
| Percentage of Participants who achieve Anemia Response | The rate of anemia response will be assessed according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria. | Baseline (Week 0) Up to Week 96 | 
| Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death from any cause. | Up To approximately 8 Years | 
| Leukemia-Free Survival | Leukemia-free survival is defined as the number of days from the date of randomization to the onset date of documented leukemia, disease progression due to leukemia, or death due to leukemia, whichever occurs first. | Up To approximately 8 Years | 
| Percentage of Participants who Achieve Reduction in Grade of Bone Marrow Fibrosis | Change in grade of bone marrow fibrosis will be measured per the European consensus grading system through bone marrow biopsy. | Baseline (Week 0) Up to Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Navitoclax, Ruxolitinib, Cancer, ABT-263, TRANSFORM-1