Clinical Trials /

Safety, Efficacy, and Assessment of Change in Spleen Volume Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet in Adult Participants With Relapsed/Refractory Myelofibrosis

NCT04468984

Description:

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, tolerability, 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 the study at approximately 23 countries worldwide. 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.

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Safety, Efficacy, and Assessment of Change in Spleen Volume Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet 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)

Clinical Trial IDs

  • ORG STUDY ID: M20-178
  • SECONDARY ID: 2020-000557-27
  • NCT ID: NCT04468984

Conditions

  • Myelofibrosis (MF)

Interventions

DrugSynonymsArms
NavitoclaxABT-263Arm A: Navitoclax + Ruxolitinib
RuxolitinibArm A: Navitoclax + Ruxolitinib
Best Available Therapy (BAT)Arm B: Best Available Therapy (BAT)

Purpose

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, tolerability, 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 the study at approximately 23 countries worldwide. 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.

Trial Arms

NameTypeDescriptionInterventions
Arm A: Navitoclax + RuxolitinibExperimentalParticipants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily.
  • Navitoclax
  • Ruxolitinib
Arm B: Best Available Therapy (BAT)Active ComparatorParticipants will receive one of the BAT options, per the investigator's discretion.
  • Best Available Therapy (BAT)

Eligibility Criteria

        Inclusion 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 (DIPSS).

          -  Must have received prior treatment with a single Janus Kinase 2 (JAK2) inhibitor and
             meet one of the following criteria (in addition to the minimum splenomegaly and
             symptom burden also required for eligibility):

               -  Prior treatment with JAK2 inhibitor 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.

               -  Prior treatment with JAK2 inhibitor for < 24 weeks with documented disease
                  progression while on JAK2 inhibitor 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 JAK2 inhibitor.

                    -  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 JAK2 inhibitor.

                    -  A >= 50% increase in the palpable distance below the LCM in participants
                       with measurable spleen distance > 10 cm prior to the initiation of JAK2
                       inhibitor.

                    -  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 JAK2 inhibitor.

                         -  Splenomegaly defined as spleen palpation measurement >= 5 cm below
                            costal margin or spleen volume >= 450 cm3 as assessed centrally by MRI
                            or CT scan.

                         -  Baseline platelet count >= 100 × 109/L.

        Exclusion Criteria:

          -  Received prior treatment with a BH3-mimetic compound or prior use of > 1 JAK2
             inhibitor.

          -  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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants who achieve Spleen Volume Reduction of at least 35% at Week 24 (SVR35W24)
Time Frame:At Week 24
Safety Issue:
Description:Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), per International Working Group (IWG) criteria.

Secondary Outcome Measures

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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AbbVie

Trial Keywords

  • ABT-263
  • Navitoclax
  • Ruxolitinib
  • MF
  • Myelofibrosis
  • Cancer

Last Updated

July 10, 2020