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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)

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ClinicalTrials.gov Identifier: NCT04468984
Recruitment Status : Recruiting
First Posted : July 13, 2020
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
AbbVie

Brief Summary:

Myelofibrosis (MF) is a bone marrow illness that affects blood-forming tissues in the body. MF disturbs the body's normal production of blood cells, causing extensive scarring in the bone marrow. This leads to severe anemia, weakness, fatigue, and an enlarged spleen. The purpose of this study is to assess safety and change in spleen volume when navitoclax is given in combination with ruxolitinib, as 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. The study has 2 arms - A and B. 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 relapsed/refractory (R/R) MF will be enrolled. Approximately 330 participants will be enrolled in approximately 190 sites across the world.

In Arm A, participants will receive oral navitoclax tablet once daily with oral ruxolitinib tablet twice daily. In Arm B, participants will receive the BAT as identified by the investigator. Treatment will continue until clinical benefit is not seen, 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.


Condition or disease Intervention/treatment Phase
Myelofibrosis (MF) Drug: Navitoclax Drug: Ruxolitinib Drug: Best Available Therapy (BAT) Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 330 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : August 31, 2020
Estimated Primary Completion Date : February 28, 2022
Estimated Study Completion Date : August 16, 2028


Arm Intervention/treatment
Experimental: Arm A: Navitoclax + Ruxolitinib
Participants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily.
Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263

Drug: Ruxolitinib
Tablet; Oral

Active Comparator: Arm B: Best Available Therapy (BAT)
Participants will receive one of the BAT options, per the investigator's discretion.
Drug: Best Available Therapy (BAT)
Tablet/Capsule; Oral or Solution for Subcutaneous Injection




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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)-C30, or death.

  6. 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.

  7. 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.

  8. 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.

  9. Overall Response of Clinical Improvement [ Time Frame: Baseline (Week 0) Up to Week 96 ]
    Clinical improvement is defined as the achievement of anemia, spleen or symptoms response without progressive disease, per International Working Group (IWG) criteria.

  10. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

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

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

  • Documented diagnosis of primary myelofibrosis (MF), post polycythemia vera (PPV)-MF, or post essential thrombocytopenia (PET)-MF as defined by the World Health Organization (WHO) classification.
  • 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 loss 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 or current treatment with ruxolitinib 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.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • Splenomegaly defined as palpable spleen measurement >= 5 cm below 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.
  • Eligible for allogeneic stem cell transplantation at the time of study entry.
  • Receiving medication that interferes with coagulation or platelet function except for low dose aspirin (up to 100 milligrams daily) and low molecular weight heparin (LMWH) within 3 days prior to the first dose of study drug or during the study treatment period.
  • Receiving anticancer therapy including chemotherapy, radiation therapy, hormonal therapy (with the exception of hormones for thyroid conditions or estrogen replacement therapy) within 30 days prior to first dose of study drug, and during the study treatment period (other than any overlapping therapy as part of the selected BAT).

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): NCT04468984


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

Locations
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Sponsors and Collaborators
AbbVie
Investigators
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Study Director: AbbVie Inc. AbbVie
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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT04468984    
Other Study ID Numbers: M20-178
2020-000557-27 ( EudraCT Number )
First Posted: July 13, 2020    Key Record Dates
Last Update Posted: April 1, 2021
Last Verified: March 2021
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 and 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: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
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 (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html

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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.: Yes
Keywords provided by AbbVie:
ABT-263
Navitoclax
Ruxolitinib
MF
Myelofibrosis
Cancer
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Navitoclax
Antineoplastic Agents