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

Phase 3

Active, not recruiting

• Conditions: Myelofibrosis (MF)
• Interventions: Drug: Navitoclax; Drug: Best Available Therapy (BAT); Drug: Ruxolitinib

• Registration Number: NCT04468984
• Lead Sponsor: AbbVie

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. In Arm C, participants will receive navitoclax. 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 322 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. In Arm C, participants will receive navitoclax tablet by mouth once daily. 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-07-10
• Study First Submitted QC: 2020-07-10
• Study First Posted: 2020-07-13
• Study Start: 2020-08-31
• Primary Completion: 2025-01-29
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-22
• Last Update Posted: 2025-04-24
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 330

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 B-cell lymphoma 2 homology 3 (BH3)-mimetic compound, bromodomain and extra-terminal (BET) inhibitor, phosphoinositide 3- kinase and telomerase inhibitors (e.g., parsaclisib), 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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: Navitoclax + Ruxolitinib	Navitoclax	Participants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily.
Arm A: Navitoclax + Ruxolitinib	Ruxolitinib	Participants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily.
Arm B: Best Available Therapy (BAT)	Best Available Therapy (BAT)	Participants will receive one of the BAT options, per the investigator's discretion.
Arm C: Continued Access for Navitoclax	Navitoclax	Participants will receive navitoclax tablets once daily.

Primary Outcome Measures

Name	Time	Method
Arms A and B: Percentage of Participants who achieve Spleen Volume Reduction of at least 35% at Week 24 (SVR35W24)	At Week 24	Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), per International Working Group (IWG) criteria.

Secondary Outcome Measures

Name	Time	Method
Arms A and B: Percentage of Participants who achieve at least 50% Reduction in Total Symptom Score (TSS)	Baseline (Week 0) Up to Week 24	Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
Arms A and B: Percentage of Participants who achieve Spleen Volume Reduction of at least 35% at any time	Baseline (Week 0) Up to Week 97	Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), per International Working Group (IWG) criteria.
Arms A and B: Percentage of Participants with Reduction in Grade of Bone Marrow Fibrosis	Baseline (Week 0) Up to Week 97	Reduction in grade of bone marrow fibrosis from baseline as measured by the European consensus grading system will be assessed.
Arms A and B: Percentage of Participants with Anemia Response	Baseline (Week 0) Up to Week 97	Anemia response per International Working Group (IWG) criteria will be assessed.
Arms A and B: Percentage of Participants with Overall Survival	Last Visit Up to 5 Years	Overall survival is defined as the time from start of study to the date of death from any cause.
Arms A and B: Percentage of Participants with Leukemia-free Survival	Last Visit Up to 5 Years	Leukemia free survival is the time from start of study to the date of development of leukemia.
Arms A and B: Percentage of Participants with Change in Fatigue	Baseline (Week 0) Up to Week 24	Change in fatigue will be assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a.
Arms A and B: Time to Deterioration of Physical Functioning	Baseline (Week 0) Up to Week 97	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.
Arms A and B: Percentage of Participants with at Least 50% Reduction in TSS	Baseline (Week 0) Up to Week 97	At least 50% reduction in TSS from baseline (at any time) as measured by MFSAF v4.0.

Trial Locations

Locations (229)

Ironwood Cancer & Res Ctr /ID# 222162; 🇺🇸 Chandler, Arizona, United States

Highlands Oncology Group, PA /ID# 221826; 🇺🇸 Springdale, Arkansas, United States

City of Hope /ID# 218996; 🇺🇸 Duarte, California, United States

Providence - St. Jude Medical Center /ID# 271382; 🇺🇸 Fullerton, California, United States

Moores Cancer Center /ID# 271596; 🇺🇸 La Jolla, California, United States

Moores Cancer Center at UC San Diego /ID# 219009; 🇺🇸 La Jolla, California, United States

Long Beach Memorial Medical Ct /ID# 224542; 🇺🇸 Long Beach, California, United States

Icri /Id# 221967; 🇺🇸 Whittier, California, United States

St. Mary's Hospital Regional Cancer Center /ID# 224229; 🇺🇸 Grand Junction, Colorado, United States

Augusta University Georgia Cancer Center /ID# 219051; 🇺🇸 Augusta, Georgia, United States

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