Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet to Assess Change in Spleen Volume in Adult Participants With Relapsed/Refractory Myelofibrosis

Study Overview
=================
Brief Summary
-----------------
Myelofibrosis (MF) is a rare blood cancer, notable for scarring of the bone marrow (the spongy tissue inside bones) and the spleen becoming larger. The purpose of this study is to assess safety and change in spleen volume when navitoclax is given in combination with ruxolitinib, compared to best available therapy, for adult participants with MF. Navitoclax is an investigational drug (not yet approved) being developed for the treatment of MF. Participants in this study will be randomly selected (like picking numbers out of a hat) to be in 1 of 2 treatment arms. Neither participants nor the study doctor will be able to pick which treatment arm a participants enters. In Arm A, participants will receive navitoclax in combination with ruxolitinib. In Arm B, participants will receive the best available therapy (BAT) for MF. Adult participants with a diagnosis of MF that came back or did not get better after earlier treatment will be enrolled. Approximately 330 participants will be enrolled in approximately 210 sites across the world. In Arm A, participants will receive navitoclax tablet by mouth once daily with by mouth ruxolitinib tablet twice daily. In Arm B, participants will receive the BAT available to the investigator. Participants will receive the study drug until they experience no benefit (determined by the investigator), participants cannot tolerate the study drugs, or participants withdraw consent. The approximate treatment duration is about 3 years. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

Official Title
-----------------
A Randomized, Open-Label, Phase 3 Study Evaluating Efficacy and Safety of Navitoclax in Combination With Ruxolitinib Versus Best Available Therapy in Subjects With Relapsed/Refractory Myelofibrosis (TRANSFORM-2)

Conditions
-----------------
Myelofibrosis (MF)

Intervention / Treatment
-----------------
* Drug: Navitoclax
* Drug: Ruxolitinib
* Drug: Best Available Therapy (BAT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must complete the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of the 7 days immediately prior to the date of randomization and must agree to collect MFSAF data daily by ePRO device during the study collection window. -- Has at least 2 symptoms each with an average score >= 3 or an average total score of >= 12, as measured by the MFSAF v4.0. Documented diagnosis of primary myelofibrosis (MF) as defined by the World Health Organization (WHO) classification, post polycythemia vera (PPV)-MF, or post essential thrombocytopenia (PET)-MF, characterized by bone marrow fibrosis grades 2 or 3. Classified as intermediate-2 or high-risk MF, as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+). Must currently be on treatment or have received prior treatment with a single Janus Kinase 2 (JAK2) inhibitor, ruxolitinib, and meet one of the following criteria (in addition to the minimum splenomegaly and symptom burden also required for eligibility): Treatment with ruxolitinib for >= 24 weeks that was stopped due to lack of spleen response (refractory), or loss of spleen response or symptom control after a previous response (relapsed), or was continued despite relapsed/refractory status. Treatment with ruxolitinib for < 24 weeks with documented disease progression while on therapy as defined by any of the following: Appearance of new splenomegaly that is palpable to at least 5 cm below the left costal margin (LCM) in participants with no evidence of splenomegaly prior to the initiation of ruxolitinib. A >= 100% increase in the palpable distance below the LCM in participants with measurable spleen distance 5 to 10 centimeters (cm) prior to the initiation of ruxolitinib. A >= 50% increase in the palpable distance below the LCM in participants with measurable spleen distance > 10 cm prior to the initiation of ruxolitinib. A spleen volume increase of >= 25% (as assessed by Magnetic Resonance Imaging [MRI] or Computed Tomography [CT] scan) in participants with a spleen volume assessment prior to the initiation of ruxolitinib. Prior treatment with ruxolitinib of at least 10 mg twice daily (BID) for >= 28 days with intolerance defined as new RBC 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. Note: Participant must not require a ruxolitinib dose less than 10 mg BID (20 mg daily) due to prior history of ruxolitinibrelated ≥ Grade 3 toxicity. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Splenomegaly defined as palpable spleen measurement >= 5 cm below left costal margin or spleen volume >= 450 cm3 as assessed centrally by MRI or CT scan. Baseline platelet count >= 100 × 10^9/L. Exclusion Criteria: Received prior treatment with a BH3-mimetic compound, bromodomain and extra-terminal (BET) inhibitor, or prior use of > 1 JAK2 inhibitor or stem cell transplant. Eligible for stem cell transplantation at the time of study entry. 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 mg daily) and low molecular weight heparin (LMWH). Receiving anticancer therapy for an active malignancy or MF including chemotherapy, radiation therapy, hormonal therapy such that at least 5 half-lives of that medication is completed at least 7 days prior to the first dose of study drug or within 30 days prior to first dose of study drug, whichever is shorter, and during the study treatment period (other than any overlapping therapy as part of the selected BAT).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Navitoclax + Ruxolitinib<br>Participants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily. | Drug: Navitoclax<br>* Tablet; Oral<br>* Other names: ABT-263;Drug: Ruxolitinib<br>* Tablet; Oral<br>|
| Active Comparator: Arm B: Best Available Therapy (BAT)<br>Participants will receive one of the BAT options, per the investigator's discretion. | Drug: Best Available Therapy (BAT)<br>* Tablet/Capsule; Oral or Solution for Subcutaneous Injection<br>|

What is the study measuring?
-----------------
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 |
| --- | --- | --- |
| Percentage of Participants who achieve at least 50% Reduction 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% at any time | Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), per International Working Group (IWG) criteria. | Baseline (Week 0) Up to Week 97 | 
| Percentage of Participants with Reduction in Grade of Bone Marrow Fibrosis | Reduction in grade of bone marrow fibrosis from baseline as measured by the European consensus grading system will be assessed. | Baseline (Week 0) Up to Week 97 | 
| Percentage of Participants with Anemia Response | Anemia response per International Working Group (IWG) criteria will be assessed. | Baseline (Week 0) Up to Week 97 | 
| Percentage of Participants with Overall Survival | Overall survival is defined as the time from start of study to the date of death from any cause. | Last Visit Up to 5 Years | 
| Percentage of Participants with Leukemia-free Survival | Leukemia free survival is the time from start of study to the date of development of leukemia. | Last Visit Up to 5 Years | 
| Percentage of Participants with Change in Fatigue | Change in fatigue will be assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a. | Baseline (Week 0) Up to Week 24 | 
| Time to Deterioration of Physical Functioning | Time to deterioration of 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 97 | 
| Percentage of Participants with at Least 50% Reduction in TSS | At least 50% reduction in TSS from baseline (at any time) as measured by MFSAF v4.0. | Baseline (Week 0) Up to Week 97 | 

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