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Safety and Tolerability Study of Mivebresib Tablet Alone or in Combination With Ruxolitinib Tablet or Navitoclax Tablet in Adult Participants With Myelofibrosis

NCT04480086

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 see how safe and tolerable mivebresib is, when given alone, and in combination with navitoclax or ruxolitinib, for adult participants with MF. Mivebresib is an investigational drug being developed for the treatment of MF. The study has 4 segments - A, B, C, and D. In Segment A, the safe dosing regimen of mivebresib is identified, and then given alone as monotherapy. In Segment B, C, and D, combination therapies of mivebresib with either ruxolitinib or navitoclax are given. Adult participants with a diagnosis of MF will be enrolled. Around 130 participants will be enrolled in 60 sites worldwide. In Segment A, participants will receive different doses and schedules of oral mivebresib tablet to identify a safe dosing regimen. Additional participants will be enrolled at the identified monotherapy dosing regimen. In Segment B, participants will receive oral ruxolitinib and mivebresib will be given as "add-on" therapy. In Segment C, participants will receive mivebresib and oral navitoclax. In Segment D, participants will receive mivebresib and ruxolitinib. Participants will receive treatment until disease progression or the participants are not able to tolerate the study drugs. 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:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety and Tolerability Study of Mivebresib Tablet Alone or in Combination With Ruxolitinib Tablet or Navitoclax Tablet in Adult Participants With Myelofibrosis
  • Official Title: A Phase 1b Study of Mivebresib Alone or in Combination With Ruxolitinib or Navitoclax in Subjects With Myelofibrosis

Clinical Trial IDs

  • ORG STUDY ID: M20-248
  • SECONDARY ID: 2020-001226-65
  • NCT ID: NCT04480086

Conditions

  • Myelofibrosis (MF)

Interventions

DrugSynonymsArms
MivebresibSegment A: Mivebresib Dose Identification and Optimization
NavitoclaxABT-263Segment C: Mivebresib + Navitoclax
RuxolitinibSegment B: Ruxolitinib + Mivebresib "Add-on" Therapy

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 see how safe and tolerable mivebresib is, when given alone, and in combination with navitoclax or ruxolitinib, for adult participants with MF. Mivebresib is an investigational drug being developed for the treatment of MF. The study has 4 segments - A, B, C, and D. In Segment A, the safe dosing regimen of mivebresib is identified, and then given alone as monotherapy. In Segment B, C, and D, combination therapies of mivebresib with either ruxolitinib or navitoclax are given. Adult participants with a diagnosis of MF will be enrolled. Around 130 participants will be enrolled in 60 sites worldwide. In Segment A, participants will receive different doses and schedules of oral mivebresib tablet to identify a safe dosing regimen. Additional participants will be enrolled at the identified monotherapy dosing regimen. In Segment B, participants will receive oral ruxolitinib and mivebresib will be given as "add-on" therapy. In Segment C, participants will receive mivebresib and oral navitoclax. In Segment D, participants will receive mivebresib and ruxolitinib. Participants will receive treatment until disease progression or the participants are not able to tolerate the study drugs. 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
Segment A: Mivebresib Dose Identification and OptimizationExperimentalParticipants who have been previously treated with Janus Kinase inhibitor(s) (JAKi) and stopped such therapy, will receive different dosing regimens and schedules of mivebresib to identify the safe dosing regimen and schedule.
  • Mivebresib
Segment A: Mivebresib MonotherapyExperimentalParticipants will receive the identified safe dosing regimen of mivebresib as monotherapy.
  • Mivebresib
Segment B: Ruxolitinib + Mivebresib "Add-on" TherapyExperimentalParticipants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and mivebresib as "add-on" therapy.
  • Mivebresib
  • Ruxolitinib
Segment C: Mivebresib + NavitoclaxExperimentalParticipants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax.
  • Mivebresib
  • Navitoclax
Segment D: Mivebresib + RuxolitinibExperimentalParticipants who have never received JAKi will receive mivebresib and ruxolitinib.
  • Mivebresib
  • Ruxolitinib

Eligibility Criteria

        Inclusion Criteria:

          -  Laboratory values indicative of adequate bone marrow, renal, and hepatic function
             meeting protocol criteria

          -  Completion of the Myelofibrosis System Assessment Form (MFSAF) on at least 4 out of
             the 7 days prior to Day 1 with at least 2 symptoms with a score >=3 or a total score
             of >=10.

          -  Documented diagnosis of intermediate or high-risk primary myelofibrosis (PMF),
             post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocytopenia
             myelofibrosis (PET-MF) as defined by World Health Organization (WHO).

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          -  Intermediate - 2, or High-Risk disease as defined by the Dynamic International
             Prognostic Scoring System (For Segment A only, Intermediate - 1 with palpable
             splenomegaly >=5 centimeters [cm] below costal margin are also eligible).

          -  Splenomegaly defined as spleen palpation measurement >= 5 centimeters (cm) below
             costal margin or spleen volume >= 450 cubic cms as assessed by Magnetic Resonance
             Imaging (MRI) or Computed Tomography (CT) scan (for Segments A and c, baseline spleen
             assessment must be obtained > 7 days after discontinuation of most recent
             Myelofibrosis (MF) therapy. If possible, this assessment should occur within 10 days
             of Cycle 1 Day 1).

        Segment-Specific Prior Therapy Criteria:

          -  Segment A:

               -  Prior exposure to one or more Janus Kinase Inhibitors (JAKi), the most recent of
                  which was discontinued > 28 days prior to Cycle 1 Day 1.

          -  Segment B:

               -  Currently receiving ruxolitinib; AND

               -  Willingness to reduce dose (if on a higher dose); and on a stable dose for 14
                  days or longer prior to Cycle 1 Day 1; AND

               -  At least one of the following criteria (a, b, or c):

                    1. >= 24 weeks duration of current ruxolitinib course, with evidence of disease
                       that is resistant, refractory, or has lost response to ruxolitinib
                       monotherapy;

                    2. < 24 weeks duration of current ruxolitinib course with documented disease
                       progression as defined by any of the following:

                         -  Appearance of new splenomegaly that is palpable to at least 5
                            centimeters (cm) below the left costal margin (LCM), in participants
                            with no evidence of splenomegaly prior to the initiation of
                            ruxolitinib.

                              -  100% increase in the palpable distance below the LCM, in
                                 participants with measurable spleen distance 5 - 10 cm prior to
                                 the initiation of ruxolitinib.

                              -  50% increase in the palpable distance below the LCM, in
                                 participants with measurable spleen > 10 cm prior to the
                                 initiation of ruxolitinib.

                         -  A spleen volume increase >= 25% (as assessed by MRI or CT) in
                            participants with a spleen volume assessment available prior to the
                            initiation of ruxolitinib.

                    3. Prior treatment with ruxolitinib for >= 28 days complicated by any of the
                       following:

                         -  Development of red blood cell transfusion requirement (at least 2
                            units/month for 2 months).

                         -  Grade >= 3 adverse events of neutropenia and/or anemia while on
                            ruxolitinib treatment, with improvement or resolution upon dose
                            reduction.

          -  Segment C:

               -  Prior exposure to one or more JAKi (the most recent of which was discontinued >
                  28 days prior to Cycle 1 Day 1), and are intolerant, resistant, refractory or
                  lost response to teh JAKi.

        Exclusion Criteria:

        Segment-Specific Prior Therapy Criteria:

          -  Segment A:

               -  Prior exposure to one or more Bromodomain and Extra Terminal (BET) inhibitors.

          -  Segment B:

               -  Prior exposure to one or more BET inhibitors.

          -  Segment C:

               -  Prior exposure to one or more BET inhibitors and/or any B-Cell Lymphoma 2 (BCL2)
                  and/or B-Cell Lymphoma XL (BCLXL) inhibitor, including navitoclax.

          -  Segment D:

               -  Prior exposure to JAKi and/or any BET inhibitor.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants With Adverse Events
Time Frame:Up To Approximately 1 year from start of study
Safety Issue:
Description:An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. The investigator assesses the relationship of each event to the use of study drug.

Secondary Outcome Measures

Measure:Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35)
Time Frame:Up To Week 24
Safety Issue:
Description:Reduction in spleen volume is measured by magnetic resonance imaging (MRI).
Measure:Maximum Observed Plasma Concentration (Cmax) of Mivebresib
Time Frame:Up To Week 12
Safety Issue:
Description:Maximum observed plasma concentration (Cmax) of Mivebresib.
Measure:Time to Cmax (Tmax) of Mivebresib
Time Frame:Up To Week 12
Safety Issue:
Description:The amount of time taken to reach Cmax.
Measure:Area Under Concentration vs Time Curve (AUC) of Mivebresib
Time Frame:Up To Week 12
Safety Issue:
Description:AUC of Mivebresib will be calculated.
Measure:Half-Life (t1/2) of Mivebresib
Time Frame:Up To Week 12
Safety Issue:
Description:Half-life of Mivebresib will be calculated.
Measure:Accumulation Ratio of Mivebresib
Time Frame:Up To Week 12
Safety Issue:
Description:Pharmacokinetic parameters will include accumulation ratio of Mivebresib.
Measure:Apparent Clearance (CL/F) of Mivebresib
Time Frame:Up To Week 12
Safety Issue:
Description:CL/F of Mivebresib will be calculated.
Measure:Apparent Volume of Distribution (Vd/F) of Mivebresib
Time Frame:Up To Week 12
Safety Issue:
Description:Vd/F of mivebresib will be calculated.
Measure:Percentage of Participants With >= 50% Reduction in Total Symptom Score (TSS)
Time Frame:Week 24
Safety Issue:
Description:TSS is assessed using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. MFSAF v4.0 measures the burden of myelofibrosis-related symptoms. The symptoms are assessed on a 11-point numeric rating scale (NRS) anchored from 0 (absent) to 10 (worst imaginable).
Measure:Objective Response Rate (ORR)
Time Frame:Week 24
Safety Issue:
Description:ORR is defined as the sum of rates of complete remission (CR) and partial remission (PR).
Measure:Maximum Observed Plasma Concentration (Cmax) of Navitoclax
Time Frame:Up To Week 12
Safety Issue:
Description:Maximum Observed Plasma Concentration (Cmax) Of Navitoclax.
Measure:Time to Cmax (Tmax) of Navitoclax
Time Frame:Up To Week 12
Safety Issue:
Description:The amount of time taken to reach Cmax.
Measure:Area Under Concentration vs Time Curve (AUC) of Navitoclax
Time Frame:Up To Week 12
Safety Issue:
Description:AUC of Navitoclax will be calculated.
Measure:Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib
Time Frame:Up To Week 12
Safety Issue:
Description:Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib.
Measure:Time to Cmax (Tmax) of Ruxolitinib
Time Frame:Up To Week 12
Safety Issue:
Description:The amount of time taken to reach Cmax.
Measure:Area Under Concentration vs Time Curve (AUC) of Ruxolitinib
Time Frame:Up To Week 12
Safety Issue:
Description:AUC of Ruxolitinib will be calculated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AbbVie

Trial Keywords

  • mivebresib
  • Navitoclax
  • Ruxolitinib
  • ABT-263
  • Cancer
  • Myelofibrosis
  • MF
  • ABBV-075

Last Updated

July 20, 2020