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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

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.


Condition or disease Intervention/treatment Phase
Myelofibrosis (MF) Drug: Mivebresib Drug: Navitoclax Drug: Ruxolitinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of Mivebresib Alone or in Combination With Ruxolitinib or Navitoclax in Subjects With Myelofibrosis
Estimated Study Start Date : July 31, 2020
Estimated Primary Completion Date : July 20, 2022
Estimated Study Completion Date : November 22, 2022


Arm Intervention/treatment
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.
Drug: Mivebresib
Tablet: Oral

Experimental: Segment A: Mivebresib Monotherapy
Participants will receive the identified safe dosing regimen of mivebresib as monotherapy.
Drug: Mivebresib
Tablet: Oral

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.
Drug: Mivebresib
Tablet: Oral

Drug: Ruxolitinib
Tablet; Oral

Experimental: Segment C: Mivebresib + Navitoclax
Participants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax.
Drug: Mivebresib
Tablet: Oral

Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263

Experimental: Segment D: Mivebresib + Ruxolitinib
Participants who have never received JAKi will receive mivebresib and ruxolitinib.
Drug: Mivebresib
Tablet: Oral

Drug: Ruxolitinib
Tablet; Oral




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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).

  2. Maximum Observed Plasma Concentration (Cmax) of Mivebresib [ Time Frame: Up To Week 12 ]
    Maximum observed plasma concentration (Cmax) of Mivebresib.

  3. Time to Cmax (Tmax) of Mivebresib [ Time Frame: Up To Week 12 ]
    The amount of time taken to reach Cmax.

  4. Area Under Concentration vs Time Curve (AUC) of Mivebresib [ Time Frame: Up To Week 12 ]
    AUC of Mivebresib will be calculated.

  5. Half-Life (t1/2) of Mivebresib [ Time Frame: Up To Week 12 ]
    Half-life of Mivebresib will be calculated.

  6. Accumulation Ratio of Mivebresib [ Time Frame: Up To Week 12 ]
    Pharmacokinetic parameters will include accumulation ratio of Mivebresib.

  7. Apparent Clearance (CL/F) of Mivebresib [ Time Frame: Up To Week 12 ]
    CL/F of Mivebresib will be calculated.

  8. Apparent Volume of Distribution (Vd/F) of Mivebresib [ Time Frame: Up To Week 12 ]
    Vd/F of mivebresib will be calculated.

  9. 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).

  10. Objective Response Rate (ORR) [ Time Frame: Week 24 ]
    ORR is defined as the sum of rates of complete remission (CR) and partial remission (PR).

  11. Maximum Observed Plasma Concentration (Cmax) of Navitoclax [ Time Frame: Up To Week 12 ]
    Maximum Observed Plasma Concentration (Cmax) Of Navitoclax.

  12. Time to Cmax (Tmax) of Navitoclax [ Time Frame: Up To Week 12 ]
    The amount of time taken to reach Cmax.

  13. Area Under Concentration vs Time Curve (AUC) of Navitoclax [ Time Frame: Up To Week 12 ]
    AUC of Navitoclax will be calculated.

  14. Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib [ Time Frame: Up To Week 12 ]
    Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib.

  15. Time to Cmax (Tmax) of Ruxolitinib [ Time Frame: Up To Week 12 ]
    The amount of time taken to reach Cmax.

  16. Area Under Concentration vs Time Curve (AUC) of Ruxolitinib [ Time Frame: Up To Week 12 ]
    AUC of Ruxolitinib will be calculated.



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:

  • 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.

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): NCT04480086


Contacts
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Contact: ABBVIE CALL CENTER 847.283.8955 abbvieclinicaltrials@abbvie.com

Locations
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United States, New York
Stony Brook University Hospital /ID# 222653
Stony Brook, New York, United States, 11794-8183
United States, Texas
University of Texas MD Anderson Cancer Center /ID# 221652
Houston, Texas, United States, 77030
Sponsors and Collaborators
AbbVie
Investigators
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Study Director: AbbVie Inc. AbbVie
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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT04480086    
Other Study ID Numbers: M20-248
2020-001226-65 ( EudraCT Number )
First Posted: July 21, 2020    Key Record Dates
Last Update Posted: July 21, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
mivebresib
Navitoclax
Ruxolitinib
ABT-263
Cancer
Myelofibrosis
MF
ABBV-075
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Navitoclax
Antineoplastic Agents