Ensayos clínicos

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.
• Subject has a history of an active malignancy other than MF within the past 2 years prior to study entry, with the exception of:
  • Adequately treated in situ carcinoma of the cervix uteri;
  • Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin;
  • Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy.
• Subject has a known positive test for HIV.
  • Note: HIV testing is not required at Screening.
• Subject has known hepatitis B (HBV) or hepatitis C (HCV) requiring treatment. Subjects with an undetectable viral load within 3 months of screening and those with serologic evidence of prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may participate (Hepatitis B or C testing is not required at screening unless it is required per local guidelines or institutional standards).
• History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same class.
• Clinically relevant or significant ECG abnormalities, including ECG with QT interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) > 450 msec (males) or >470 msec (females).
• Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
  • Ongoing systemic infection (viral, bacterial, mycobacterial or fungal);
  • Active SARS-CoV-2 infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test result.
    • Note: SARS CoV-2 diagnostic tests should be applied following local requirements/recommendations. ● Subjects positive for active SARS-CoV-2 infection may rescreen after they meet either criteria a or b indicating SARS-CoV-2 infection has resolved with viral clearance:
  • At least 14 days since first PCR test result have passed in asymptomatic patients; OR
  • At least 14 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms.

Cohorts 1b and 3 only:

• Subject has tested positive for tuberculosis prior to study entry (subjects must have a negative result per local guidelines or have no evidence of latent infection prior to study entry).
• Febrile neutropenia.

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.

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

• Subject has consumed one or more of the following within 3 days prior to the first dose of study drug:
  • Grapefruit or grapefruit products;
  • Seville oranges (including marmalade containing Seville oranges);
  • Star fruit (carambola).
• Female subject who is pregnant, breastfeeding or is considering becoming pregnant or donating eggs during the study or for approximately 30 days after the last dose of study drug. Male subject who is considering fathering a child or donating sperm during the study or for approximately 90 days after the last dose of study drug.
• Subject has history of a cardiovascular, endocrinologic, hepatic, immunologic metabolic, neurologic, psychiatric, pulmonary, renal disease, or any other condition that in the opinion of the investigator would adversely affect his/her participation in this study or interpretation of study results.
• Subject is concurrently participating in another therapeutic clinical trial or subject has previously participated in other AbbVie clinical trials conducted in subjects with myelofibrosis.

Eligibility last updated 1/13/22. Questions regarding updates should be directed to the study team contact.