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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04480086
Recruitment Status : Not yet recruiting
First Posted : July 21, 2020
Last Update Posted : July 21, 2020
Sponsor:
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE July 20, 2020
First Posted Date  ICMJE July 21, 2020
Last Update Posted Date July 21, 2020
Estimated Study Start Date  ICMJE July 31, 2020
Estimated Primary Completion Date July 20, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
Percentage of Participants With Adverse Events [ Time Frame: Up To Approximately 1 year from start of study ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2020)
  • Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35) [ Time Frame: Up To Week 24 ]
    Reduction in spleen volume is measured by magnetic resonance imaging (MRI).
  • Maximum Observed Plasma Concentration (Cmax) of Mivebresib [ Time Frame: Up To Week 12 ]
    Maximum observed plasma concentration (Cmax) of Mivebresib.
  • Time to Cmax (Tmax) of Mivebresib [ Time Frame: Up To Week 12 ]
    The amount of time taken to reach Cmax.
  • Area Under Concentration vs Time Curve (AUC) of Mivebresib [ Time Frame: Up To Week 12 ]
    AUC of Mivebresib will be calculated.
  • Half-Life (t1/2) of Mivebresib [ Time Frame: Up To Week 12 ]
    Half-life of Mivebresib will be calculated.
  • Accumulation Ratio of Mivebresib [ Time Frame: Up To Week 12 ]
    Pharmacokinetic parameters will include accumulation ratio of Mivebresib.
  • Apparent Clearance (CL/F) of Mivebresib [ Time Frame: Up To Week 12 ]
    CL/F of Mivebresib will be calculated.
  • Apparent Volume of Distribution (Vd/F) of Mivebresib [ Time Frame: Up To Week 12 ]
    Vd/F of mivebresib will be calculated.
  • Percentage of Participants With >= 50% Reduction in Total Symptom Score (TSS) [ Time Frame: Week 24 ]
    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).
  • Objective Response Rate (ORR) [ Time Frame: Week 24 ]
    ORR is defined as the sum of rates of complete remission (CR) and partial remission (PR).
  • Maximum Observed Plasma Concentration (Cmax) of Navitoclax [ Time Frame: Up To Week 12 ]
    Maximum Observed Plasma Concentration (Cmax) Of Navitoclax.
  • Time to Cmax (Tmax) of Navitoclax [ Time Frame: Up To Week 12 ]
    The amount of time taken to reach Cmax.
  • Area Under Concentration vs Time Curve (AUC) of Navitoclax [ Time Frame: Up To Week 12 ]
    AUC of Navitoclax will be calculated.
  • Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib [ Time Frame: Up To Week 12 ]
    Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib.
  • Time to Cmax (Tmax) of Ruxolitinib [ Time Frame: Up To Week 12 ]
    The amount of time taken to reach Cmax.
  • Area Under Concentration vs Time Curve (AUC) of Ruxolitinib [ Time Frame: Up To Week 12 ]
    AUC of Ruxolitinib will be calculated.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Tolerability Study of Mivebresib Tablet Alone or in Combination With Ruxolitinib Tablet or Navitoclax Tablet in Adult Participants With Myelofibrosis
Official Title  ICMJE A Phase 1b Study of Mivebresib Alone or in Combination With Ruxolitinib or Navitoclax in Subjects With Myelofibrosis
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 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myelofibrosis (MF)
Intervention  ICMJE
  • Drug: Mivebresib
    Tablet: Oral
  • Drug: Navitoclax
    Tablet; Oral
    Other Name: ABT-263
  • Drug: Ruxolitinib
    Tablet; Oral
Study Arms  ICMJE
  • Experimental: Segment A: Mivebresib Dose Identification and Optimization
    Participants 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.
    Intervention: Drug: Mivebresib
  • Experimental: Segment A: Mivebresib Monotherapy
    Participants will receive the identified safe dosing regimen of mivebresib as monotherapy.
    Intervention: Drug: Mivebresib
  • Experimental: Segment B: Ruxolitinib + Mivebresib "Add-on" Therapy
    Participants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and mivebresib as "add-on" therapy.
    Interventions:
    • Drug: Mivebresib
    • Drug: Ruxolitinib
  • Experimental: Segment C: Mivebresib + Navitoclax
    Participants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax.
    Interventions:
    • Drug: Mivebresib
    • Drug: Navitoclax
  • Experimental: Segment D: Mivebresib + Ruxolitinib
    Participants who have never received JAKi will receive mivebresib and ruxolitinib.
    Interventions:
    • Drug: Mivebresib
    • Drug: Ruxolitinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 20, 2020)
130
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 22, 2022
Estimated Primary Completion Date July 20, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: ABBVIE CALL CENTER 847.283.8955 abbvieclinicaltrials@abbvie.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04480086
Other Study ID Numbers  ICMJE M20-248
2020-001226-65 ( 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  ICMJE
Plan to Share IPD: No
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP