A Open-Label Study Evaluating Tolerability and Efficacy of Navitoclax alone or in Combination with Ruxolitinib in Subjects with Myelofibrosis (REFINE)

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 174

Inclusion Criteria

- Subjects = 18 years of age
- Subjects with documented diagnosis of Primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis
- Subjects classified as intermediate-2 or high-risk myelofibrosis, as defined by the Dynamic International Prognostic Scoring System (DIPSS)
- Subject must be ineligible or unwilling to undergo stem cell transplantation at time of study entry
- Subject must have either received prior treatment with ruxolitinib OR another JAK-2 inhibitor therapy OR must not have received any prior treatment with JAK-2 inhibitor or BET inhibitor.
- Subject has splenomegaly defined as a spleen palpation measurement >/= 5 cm below costal margin or spleen volume >/= 450 cm3 as assessed by MRT/CT.
- Subject must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol.
- Cohorts 1b and 3 only: Subject has at least 2 symptoms each with a score = 3 or a total score of = 12, as measured by the MFSAF v4.0.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 87
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 87

Exclusion Criteria

- Splenic irradiation within 6 months prior to screening, or prior splenectomy.
- Leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).
- Subject is currently on medications that interfere with coagulation (including warfarin) or platelet function with the exception of low dose aspirin (up to 100 mg) and Low-molecular-weight heparin.
- Prior therapy with a BH3 mimetic compound.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Evaluate the effect of navitoclax alone or in combination with ruxolitinib on spleen volume;Secondary Objective: - To assess the effect of navitoclax alone or in combination with ruxolitinib on total symptom score (TSS) as assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0 diary<br>- To evaluate the effect of navitoclax alone or in combination with ruxolitinib on bone marrow fibrosis<br>- To determine the rate of anemia response associated with navitoclax alone or in combination with ruxolitinib<br>- To describe the safety profile and PK profile observed with navitoclax alone or in combination with ruxolitinib<br>;Primary end point(s): = 35% spleen volume reduction from baseline (SVR35) at Week 24 measured by MRI/CT.;Timepoint(s) of evaluation of this end point: Week 24

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): The secondary endpoints are at least 50% reduction in total symptom score from baseline measured by MFSAF 4.0; anemia response; and change in grade of bone marrow fibrosis.;Timepoint(s) of evaluation of this end point: Week 24

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