Study of Oral Navitoclax Tablet In Combination With Oral Ruxolitinib Tablet When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis (TRANSFORM-1)

• ClinicalTrials.gov Identifier: NCT04472598
• Recruitment Status: Active, not recruiting
• First Posted: July 15, 2020
• Last Update Posted: April 27, 2023
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: July 14, 2020
• First Posted Date: July 15, 2020
• Last Update Posted Date: April 27, 2023
• Actual Study Start Date: September 29, 2020
• Actual Primary Completion Date: April 13, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 7, 2021)

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 (submitted: July 14, 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.

Current Secondary Outcome Measures (submitted: April 26, 2023)

• Change 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 MRI or CT, per IWG criteria.
• Duration of 35% Spleen Volume Reduction (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 the first assessment where the spleen volume is less than 35% reduction from baseline and is at least 25% increase from the nadir (the lowest spleen volume).
• 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 SF 7a.
• Change in Physical Functioning [ Time Frame: Baseline (Week 0) Up to Week 24 ]
  Change in 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 who achieve 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 (OS) [ Time Frame: Up To approximately 8 Years ]
  OS is defined as the time from the date of randomization to the date of death from any cause.
• Leukemia-Free Survival [ Time Frame: Up To approximately 8 Years ]
  Leukemia-free survival is defined as the number of days from the date of randomization to the onset date of documented leukemia, disease progression due to leukemia, or death due to leukemia, whichever occurs first.
• 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.

Original Secondary Outcome Measures (submitted: July 14, 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 35% Spleen Volume Reduction (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 PROMIS Fatigue 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 achieve 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 (OS) [ Time Frame: Up To approximately 5 Years ]
  OS 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 5 Years ]
  Leukemia-free survival is defined as the number of days from the date of randomization to the onset date of documented leukemia, disease progression due to leukemia, or death due to leukemia, whichever occurs first.
• 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 (CRR) [ 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 When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Of Navitoclax In Combination With Ruxolitinib Versus Ruxolitinib In Subjects With Myelofibrosis (TRANSFORM-1)

Brief Summary

Myelofibrosis is a type of bone marrow cancer that usually develops slowly and disrupts body's normal production of blood cells. It causes bone marrow scarring, leading to severe anemia that can cause weakness and fatigue. It can also cause a low number of blood-clotting cells called platelets, which increases risk of bleeding. Myelofibrosis often causes an enlarged spleen. The purpose of this study is to see if a combination of navitoclax and ruxolitinib is more effective and safe in assessment of change in spleen volume when compared to ruxolitinib in participants with myelofibrosis.

Navitoclax is an investigational drug for the treatment of myelofibrosis. Participants in this study are divided into two groups, called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of myelofibrosis will be enrolled. Around 230 participants will be enrolled in approximately 190 sites worldwide.

Participants will receive oral navitoclax tablet with oral ruxolitinib tablet or oral ruxolitinib tablet with oral placebo (no active drug) tablet and treatment may continue untill the participant cannot tolerate the study drug, or benefit is not achieved, or other reasons which qualify for discontinuation of the study drug.

There may be a higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, magnetic resonance imaging (MRI) or computed tomography (CT) scan, 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: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Myelofibrosis (MF)

Intervention

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

Study Arms

• Experimental: Navitoclax + Ruxolitinib
  Participants will receive Navitoclax in combination with Ruxolitinib
  Interventions:

  • Drug: Navitoclax
  • Drug: Ruxolitinib
• Active Comparator: Placebo for Navitoclax + Ruxolitinib
  Participants will receive placebo for Navitoclax and Ruxolitinib
  Interventions:

  • Drug: Ruxolitinib
  • Drug: Placebo for Navitoclax

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 11, 2022): 252
• Original Estimated Enrollment (submitted: July 14, 2020): 230
• Estimated Study Completion Date: October 19, 2032
• Actual Primary Completion Date: April 13, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Documented diagnosis of Primary MyeloFibrosis (MF) as defined by World Health Organization (WHO) classification or Secondary MF (post polycythemia vera [PPV] - MF or Post Essential Thrombocytopenia [PET] - MF) .

• Must be able to complete the MF Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days immediately preceding the date of randomization.

  -- Must have at least 2 symptoms with a score >=3 or a total score of >=12, as measured by the MFSAF v4.0.

• Classified as intermediate-2, or high-Risk MF as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+).
• Has splenomegaly defined as spleen palpation measurement >= 5 centimeters (cm) below costal margin or spleen volume greater than or equal to 450 cubic cm as assessed centrally by magnetic resonance imaging (MRI) or computed tomography (CT) scan.
• Ineligible for stem cell transplantation at time of study entry due to age, comorbidities, or unfit for unrelated or unmatched donor transplant and other criteria per National Comprehensive Cancer Network guidelines.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

Exclusion Criteria:

• Prior treatment with a Janus Kinase-2 (JAK-2) inhibitor.
• Prior treatment with a B-cell lymphoma 2 homology 3 (BH3)-mimetic compound or bromodomain and extra-terminal motif (BET) inhibitor or stem cell transplant.
• 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 milligram daily) and low molecular weight heparin (LMWH).

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, Austria, Belgium, Bulgaria, Canada, Croatia, France, Germany, Greece, Israel, Italy, Japan, Korea, Republic of, Netherlands, New Zealand, Russian Federation, Serbia, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04472598
• Other Study ID Numbers: M16-191; 2020-000097-15 ( 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.: 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