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A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis (REFINE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03222609
Recruitment Status : Active, not recruiting
First Posted : July 19, 2017
Last Update Posted : March 3, 2023
Sponsor:
Information provided by (Responsible Party):
AbbVie

Study Description
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Brief Summary:
This is a Phase 2 open-label, multicenter study evaluating tolerability and efficacy of navitoclax alone or when added to ruxolitinib in participants with myelofibrosis.

Condition or disease Intervention/treatment Phase
Myelofibrosis (MF) Drug: Ruxolitinib Drug: Navitoclax Phase 2

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 191 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Open-Label Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Subjects With Myelofibrosis (REFINE)
Actual Study Start Date : October 31, 2017
Actual Primary Completion Date : March 28, 2022
Estimated Study Completion Date : February 2, 2029

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Navitoclax + ruxolitinib
Participants will be administered navitoclax once daily (QD) at various doses and a dose greater than or equal to 10 mg of ruxolitinib twice daily (BID).
 Drug: Ruxolitinib
Tablet; Oral
Other Name: Jakafi

Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263
Experimental: Navitoclax
Participants will be administered various doses of navitoclax once daily (QD)
 Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Participants who achieve Spleen Volume Reduction of greater than or equal to 35% (SVR35) from baseline [ Time Frame: From Baseline (Week 0) through Week 24 ]
    Reduction in spleen volume is measured by magnetic resonance imaging/computerized tomography (MRI/CT).


Secondary Outcome Measures :
  1. Percentage of participants achieving 50% Reduction in Total System Score (TSS) [ Time Frame: From Baseline (Week 0) through Week 24 ]
    TSS is assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0.

  2. Anemia Response [ Time Frame: Every 12 weeks up to approximately 96 weeks ]
    The anemia response will be assessed according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria.

  3. Change in Grade of Bone Marrow Fibrosis [ Time Frame: Through Week 96 ]
    Bone marrow grading is assessed according to the European Consensus Grading System.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants with documented diagnosis of intermediate-2 or high-risk primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis.
  • Participant 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.
  • Eastern Cooperative Oncology Group (ECOG) of 0, 1, or 2.

  • Prior treatment must meet at least one of the following criteria:

    • Prior or current treatment with ruxolitinib and no prior treatment with a Bromodomain and Extra-Terminal motif (BET) proteins inhibitor or another Janus Kinase 2 (JAK-2) inhibitor, and meet all of the following criteria:

      • Ruxolitinib treatment must meet at least one of the following criteria:

        • Ruxolitinib treatment for >=24 weeks with lack of efficacy defined as a lack of spleen response (refractory) or a loss of spleen or symptom response (relapsed)
        • Ruxolitinib treatment for <24 weeks with documented disease progression on spleen measurements while on ruxolitinib as defined in the protocol:
        • Ruxolitinib treatment for >=28 days with intolerance defined as new red blood cell 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.
      • If 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.
      • Participant has at least 2 symptoms each with a score >=3 or a total score of >=12, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days during screening prior to study drug dosing; OR

    • Prior treatment with a JAK-2 inhibitor and meet one of the following criteria:

      • Prior treatment with a JAK-2 inhibitor for at least 12 weeks
      • Prior treatment with a JAK-2 inhibitor for >=28 days complicated by either 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; OR

    • No prior treatment with a JAK-2 or BET inhibitor:

      • Participant 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.
  • Participant has splenomegaly as defined in the protocol.
  • Participant must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol.

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).
  • Participant 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.
  • Prior therapy with a BH3 mimetic compound or stem cell transplantation.
  • Participant has received strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A inhibitors (e.g., fluconazole) within 14 days prior to the administration of the first dose of study drug.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03222609


Locations
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Sponsors and Collaborators
AbbVie
Investigators
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Study Director: ABBVIE INC. AbbVie
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT03222609    
Other Study ID Numbers: M16-109
2017-001398-17 ( EudraCT Number )
First Posted: July 19, 2017    Key Record Dates
Last Update Posted: March 3, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/
URL: https://vivli.org/ourmember/abbvie/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AbbVie:
Post-polycythemia vera MF (PPV-MF)
Post-essential thrombocythemia (PET-MF)
ruxolitinib
navitoclax
splenic volume
Primary Myelofibrosis
 Jakafi
enlarged spleen
splenomegaly
ABT 263
bone marrow fibrosis
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
 Hematologic Diseases
Navitoclax
Antineoplastic Agents