Clinical Trials

Inclusion Criteria:

• Subjects ≥ 18 years of age
• Subjects with documented diagnosis of Primary MF, PPV-MF or PET-MF as defined by the World Health Organization classification.
• Subjects classified as intermediate-2 or high-risk MF, as defined by the Dynamic International Prognostic Scoring System (DIPSS).
• Subject 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.
• ECOG 0, 1, or 2.

Cohort 1a only:

• Subject must have received ruxolitinib therapy for at least 12 weeks and be currently on a stable dose of ≥ 10 mg twice daily of ruxolitinib for ≥ 8 weeks prior to the 1st dose of navitoclax.
• Note: Subjects with ruxolitinib dose reductions within 8 weeks prior to study enrollment may be considered on a stable dose if stable at that decreased dose of ruxolitinib for ≥ 2 weeks prior to the 1st dose of navitoclax. If the dose reduction was due to thrombocytopenia, the platelets must be confirmed to be stable by a repeat laboratory test.

Cohort 1b only:

• Subject must have received treatment with ruxolitinib and meet at least one of the following criteria:
  • Prior or current treatment with ruxolitinib for ≥ 24 weeks with lack of efficacy defined as a lack of spleen response (refractory) or a loss of spleen or symptom response (relapsed);
  • Prior or current treatment with ruxolitinib for < 24 weeks with documented disease progression while on ruxolitinib 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 subjects with no evidence of splenomegaly prior to the initiation of ruxolitinib;
    • A ≥ 100% increase in the palpable distance below the LCM in subjects with measurable spleen distance 5 to 10 cm prior to the initiation of ruxolitinib;
    • A ≥ 50% increase in the palpable distance below the LCM in subjects with measurable spleen distance > 10 cm prior to the initiation of ruxolitinib;
    • A spleen volume increase of ≥ 25% (as assessed by MRI or CT scan) in subjects with a spleen volume assessment prior to the initiation of ruxolitinib.
  • Prior or current treatment with ruxolitinib 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.

Cohort 1b only:

• Subjects that are 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.
• Note: Subjects with ruxolitinib dose reductions within 4 weeks prior to study enrollment are considered to be on a stable dose if dose of ruxolitinib if the dose is unchanged for ≥ 2 weeks prior to Day 1of navitoclax.
  • Note: Subjects with ruxolitinib dose reductions within 4 weeks prior to study enrollment are considered to be on a stable dose if dose of ruxolitinib if the dose is unchanged for ≥ 2 weeks prior to Day 1of navitoclax. The current dose must be ≥ 10 mg twice daily. If the dose reduction was due to thrombocytopenia, platelet counts must be confirmed to be stable by a repeat laboratory test.

Cohort 1b only:

• Subject must not have received treatment with a BET inhibitor or an alternate JAK-2 inhibitor other than ruxolitinib.

Cohort 2 only:

• Subject must have received prior treatment with JAK-2 inhibitor therapy and meet one of the following criteria:
  • Prior treatment with JAK-2 inhibitor for at least 12 weeks;
  • Prior treatment with JAK-2 inhibitor for ≥ 28 days complicated by any of the following:
    • 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.

Cohort 3 only:

• Subject must not have received prior treatment with a JAK-2 or BET inhibitor.
• Subject has splenomegaly defined as spleen palpation measurement ≥ 5 cm below costal margin or spleen volume ≥ 450 cm3 as assessed by MRI/CT.

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, on at least 4 out of 7 days during screening, prior to study drug dosing.
• Subject must meet the following laboratory parameters per local laboratory reference range at Screening:
  • Adequate bone marrow reserves; in the absence of growth factors, thrombopoietic factors, or platelet transfusions for at least 14 days:
    • Platelet count ≥ 100 × 10^9/L (Cohorts 1a, 1b or 3);
    • Platelet count ≥ 75 × 10^9/L (Cohort 2);
    • ANC ≥ 1 × 10^9/L.
• Renal function: calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula.
• Hepatic function and enzymes:
  • AST and ALT ≤ 3.0 × the upper normal limit (ULN);
  • Total Bilirubin ≤ 1.5 × ULN (exception: subjects with Gilbert's Syndrome may have a Bilirubin > 1.5 × ULN).
• Coagulation:
  • aPTT and prothrombin time (PT) or INR ≤ 1.5 × ULN.

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).
• Subject 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 (LMWH).
• Prior therapy with a BH3 mimetic compound or stem cell transplantation.

Cohort 1b Drug-Drug Interaction (DDI) sub-study subjects only:

• Subject has received strong or moderate CYP3A inhibitors (e.g., ketoconazole, clarithromycin and fluconazole) within 14 days prior to the administration of the first dose of study drug.

Eligibility last updated 10/21/21. Questions regarding updates should be directed to the study team contact.