A Study Evaluating Tolerability and Efficacy of Navitoclax in Combination With Ruxolitinib in Subjects With Myelofibrosis

Overview

About this study

This is a Phase 2, single-arm, open-label, multicenter study evaluating efficacy, safety and tolerability of navitoclax added to ruxolitinib in participants with myelofibrosis.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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 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. 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:

  • ubject 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.
  • 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 × 109/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 INR ≤ 1.5 × ULN.

Exclusion Criteria:

 

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.
  • 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 × 109/L (Cohorts 1a, 1b or 3);
    • Platelet count ≥ 75 × 109/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 INR ≤ 1.5 × ULN.

Key Exclusio.n:

  • 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 (LMWH).
  • Prior therapy with a BH3 mimetic compound.

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.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Jacksonville, Fla.

Mayo Clinic principal investigator

James Foran, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

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CLS-20423882

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