Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet to Assess Change in Spleen Volume in Adult Participants With Relapsed/Refractory Myelofibrosis (TRANSFORM-2)

• ClinicalTrials.gov Identifier: NCT04468984
• Recruitment Status: Recruiting
• First Posted: July 13, 2020
• Last Update Posted: April 4, 2024
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: July 10, 2020
• First Posted Date: July 13, 2020
• Last Update Posted Date: April 4, 2024
• Actual Study Start Date: August 31, 2020
• Estimated Primary Completion Date: August 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 10, 2020)

Percentage of Participants who achieve Spleen Volume Reduction of at least 35% at Week 24 (SVR35W24) [ Time Frame: At Week 24 ]

Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), per International Working Group (IWG) criteria.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 3, 2022)

• Percentage of Participants who achieve at least 50% Reduction in Total Symptom Score (TSS) [ Time Frame: Baseline (Week 0) Up to Week 24 ]
  Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
• Percentage of Participants who achieve Spleen Volume Reduction of at least 35% at any time [ Time Frame: 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.
• Percentage of Participants with Reduction in Grade of Bone Marrow Fibrosis [ Time Frame: 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.
• Percentage of Participants with Anemia Response [ Time Frame: Baseline (Week 0) Up to Week 97 ]
  Anemia response per International Working Group (IWG) criteria will be assessed.
• Percentage of Participants with Overall Survival [ Time Frame: 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.
• Percentage of Participants with Leukemia-free Survival [ Time Frame: Last Visit Up to 5 Years ]
  Leukemia free survival is the time from start of study to the date of development of leukemia.
• Percentage of Participants with Change in Fatigue [ Time Frame: 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.
• Time to Deterioration of Physical Functioning [ Time Frame: 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.
• Percentage of Participants with at Least 50% Reduction in TSS [ Time Frame: Baseline (Week 0) Up to Week 97 ]
  At least 50% reduction in TSS from baseline (at any time) as measured by MFSAF v4.0.

Original Secondary Outcome Measures (submitted: July 10, 2020)

• Percentage of Participants who achieve at least 50% Reduction in Total Symptom Score (TSS) [ Time Frame: Baseline (Week 0) Up to Week 24 ]
  Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
• Percentage of Participants who achieve Spleen Volume Reduction of at least 35% (SVR35) [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), per International Working Group (IWG) criteria.
• Duration of SVR35 [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  Duration of SVR35 is defined as the time between the date of first response of spleen volume reduction of 35% achievement to the date of disease progression, or to the date of death, whichever occurs first.
• Change in Fatigue [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  Change in fatigue will be assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a.
• Time to Deterioration of Physical Functioning [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  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)-30.
• Proportion of Participants who achieved Anemia Response [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  The rate of anemia response will be assessed according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria.
• Overall Survival [ Time Frame: Up to approximately 3 years ]
  Overall survival is defined as the time from start of study to the date of death from any cause.
• Leukemia-Free Survival [ Time Frame: Up to approximately 3 years ]
  Leukemia free survival is the time from start of study to the date of development of leukemia.
• Overall Response Rate (ORR) [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  ORR is defined as percentage of participants with documented response of partial response (PR) or better, according to the International Working Group (IWG) criteria.
• Composite Response Rate [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  Achievement of anemia, spleen or symptoms response without progressive disease, per International Working Group (IWG) criteria.
• Percentage of Participants who achieve Reduction in Grade of Bone Marrow Fibrosis [ Time Frame: Baseline (Week 0) Up to Week 96 ]
  Change in grade of bone marrow fibrosis will be measured per the European consensus grading system through bone marrow biopsy.

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

Descriptive Information

• Brief Title: Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet to Assess Change in Spleen Volume in Adult Participants With Relapsed/Refractory Myelofibrosis
• Official Title: A Randomized, Open-Label, Phase 3 Study Evaluating Efficacy and Safety of Navitoclax in Combination With Ruxolitinib Versus Best Available Therapy in Subjects With Relapsed/Refractory Myelofibrosis (TRANSFORM-2)

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. 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 210 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. 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myelofibrosis (MF)

Intervention

• Drug: Navitoclax
  Tablet; Oral
  Other Name: ABT-263
• Drug: Ruxolitinib
  Tablet; Oral
• Drug: Best Available Therapy (BAT)
  Tablet/Capsule; Oral or Solution for Subcutaneous Injection

Study Arms

• Experimental: Arm A: Navitoclax + Ruxolitinib
  Participants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily.
  Interventions:

  • Drug: Navitoclax
  • Drug: Ruxolitinib
• Active Comparator: Arm B: Best Available Therapy (BAT)
  Participants will receive one of the BAT options, per the investigator's discretion.
  Intervention: Drug: Best Available Therapy (BAT)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 10, 2020): 330
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 3, 2031
• Estimated Primary Completion Date: August 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 BH3-mimetic compound, bromodomain and extra-terminal (BET) inhibitor, or 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: ABBVIE CALL CENTER; 844-663-3742; abbvieclinicaltrials@abbvie.com

• Listed Location Countries: Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, New Zealand, Poland, Puerto Rico, Russian Federation, Serbia, South Africa, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04468984
• Other Study ID Numbers: M20-178; 2020-000557-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

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.: Yes

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: April 2024