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

• ClinicalTrials.gov Identifier: NCT03222609
• Recruitment Status: Active, not recruiting
• First Posted: July 19, 2017
• Last Update Posted: March 3, 2023
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: July 17, 2017
• First Posted Date: July 19, 2017
• Last Update Posted Date: March 3, 2023
• Actual Study Start Date: October 31, 2017
• Actual Primary Completion Date: March 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 5, 2021)

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).

Original Primary Outcome Measures (submitted: July 17, 2017)

Percent Change in Splenic Volume from baseline [ Time Frame: Up to approximately 96 weeks ]

Evaluate the effect of the addition of navitoclax to ruxolitinib on spleen volume as assessed by magnetic resonance imaging (MRI)

Current Secondary Outcome Measures (submitted: June 29, 2020)

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

Original Secondary Outcome Measures (submitted: July 17, 2017)

• Percent Change in Total System Score (TSS) [ Time Frame: Up through Week 24 ]
  TSS is assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0.
• Anemia Response Rate [ Time Frame: Every 12 weeks up to approximately 96 weeks ]
  The rate of anemia response will be assessed according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria
• Change in Degree of Bone Marrow Fibrosis [ Time Frame: Evaluated at Week 12, 24, 48 and 96 ]
  Change in degree of bone marrow fibrosis from baseline as assessed by bone marrow biopsy.
• Overall Response Rate [ Time Frame: Up to approximately 96 weeks ]
  To determine the overall response rate (ORR defined as the sum of rates of complete remission [CR] + partial remission [PR]) associated with the addition of navitoclax to ruxolitinib according to the IWG criteria
• Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Week 1 Day 1 ]
  Maximum Observed Plasma Concentration (Cmax)
• Time to Cmax (peak time, Tmax) [ Time Frame: Week 1 Day 1 ]
  Tmax defined as time to maximum observed plasma concentration.
• Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) [ Time Frame: Week 1 Day 1 ]
  Area under the plasma concentration-time curve from time zero to the last measureable concentration

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis
• 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myelofibrosis (MF)

Intervention

• Drug: Ruxolitinib
  Tablet; Oral
  Other Name: Jakafi
• Drug: Navitoclax
  Tablet; Oral
  Other Name: ABT-263

Study Arms

• 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).
  Interventions:

  • Drug: Ruxolitinib
  • Drug: Navitoclax
• Experimental: Navitoclax
  Participants will be administered various doses of navitoclax once daily (QD)
  Intervention: Drug: Navitoclax

Publications *

• Pemmaraju N, Garcia JS, Potluri J, Harb JG, Sun Y, Jung P, Qin QQ, Tantravahi SK, Verstovsek S, Harrison C. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. Lancet Haematol. 2022 Jun;9(6):e434-e444. doi: 10.1016/S2352-3026(22)00116-8. Epub 2022 May 13.
• Harrison CN, Garcia JS, Somervaille TCP, Foran JM, Verstovsek S, Jamieson C, Mesa R, Ritchie EK, Tantravahi SK, Vachhani P, O'Connell CL, Komrokji RS, Harb J, Hutti JE, Holes L, Masud AA, Nuthalapati S, Potluri J, Pemmaraju N. Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy. J Clin Oncol. 2022 May 20;40(15):1671-1680. doi: 10.1200/JCO.21.02188. Epub 2022 Feb 18.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 5, 2021): 191
• Original Estimated Enrollment (submitted: July 17, 2017): 34
• Estimated Study Completion Date: February 2, 2029
• Actual Primary Completion Date: March 28, 2022 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Bulgaria, Canada, Croatia, France, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Poland, Puerto Rico, Russian Federation, Serbia, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Denmark, New Zealand

Administrative Information

• NCT Number: NCT03222609
• Other Study ID Numbers: M16-109; 2017-001398-17 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: 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/

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: March 2023