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Safety and Tolerability Study of Oral ABBV-744 Tablet Alone or in Combination With Oral Ruxolitinib Tablet or Oral Navitoclax Tablet in Adult Participants With Myelofibrosis

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ClinicalTrials.gov Identifier: NCT04454658
Recruitment Status : Recruiting
First Posted : July 1, 2020
Last Update Posted : November 22, 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 see how safe and tolerable ABBV-744 is, when given alone, and in combination with ruxolitinib or navitoclax, for adult participants with MF.

ABBV-744 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 ABBV-744 is identified and then, given alone as monotherapy. In Segment B, C, and D, combination therapies of ABBV-744 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 ABBV-744 tablet to identify safe dosing regimen. Additional participants will be enrolled at the identified monotherapy dosign regimen. In Segment B, participants will receive oral ruxolitinib and ABBV-744 will be given as "add-on" therapy. In Segment C, participants will receive ABBV-744 and oral navitoclax. In Segment D, participants will receive ABBV-744 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: ABBV-744 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 ABBV-744 Alone Or In Combination With Ruxolitinib Or Navitoclax In Subjects With Myelofibrosis
Actual Study Start Date : November 11, 2020
Estimated Primary Completion Date : November 22, 2022
Estimated Study Completion Date : July 26, 2024


Arm Intervention/treatment
Experimental: Segment A: ABBV-744 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 ABBV-744 to identify the safe dosing regimen and schedule.
Drug: ABBV-744
Tablet; Oral

Experimental: Segment A: ABBV-744 Monotherapy
Participants will receive the identified safe dosing regimen of ABBV-744 as monotherapy.
Drug: ABBV-744
Tablet; Oral

Experimental: Segment B: Ruxolitinib + ABBV-744 "Add on" Therapy
Participants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and ABBV-744 as "add-on" therapy.
Drug: ABBV-744
Tablet; Oral

Drug: Ruxolitinib
Tablet; Oral

Experimental: Segment C: ABBV-744 + Navitoclax
Participants who have previously been exposed to JAKi, and stopped such therapy, will receive ABBV-744 and navitoclax.
Drug: ABBV-744
Tablet; Oral

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

Experimental: Segment D: ABBV-744 + Ruxolitinib
Participants who have never received JAKi will receive ABBV-744 and ruxolitinib.
Drug: ABBV-744
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 ABBV-744 [ Time Frame: Up To Week 12 ]
    Maximum observed plasma concentration (Cmax) of ABBV-744.

  3. Time To Cmax (Tmax) Of ABBV-744 [ Time Frame: Up To Week 12 ]
    The amount of time taken to reach Cmax.

  4. Area Under The Concentration Versus Time Curve (AUC) Of ABBV-744 [ Time Frame: Up To Week 12 ]
    AUC of ABBV-744 will be calculated.

  5. Half-Life (t1/2) Of ABBV-744 [ Time Frame: Up To Week 12 ]
    Half-life of ABBV-744 will be calculated.

  6. Accumulation Ratio Of ABBV-744 [ Time Frame: Up To Week 12 ]
    Pharmacokinetic parameters will include accumulation ratio of ABBV-744.

  7. Apparent Clearance (CL/F) Of ABBV-744 [ Time Frame: Up To Week 12 ]
    CL/F of ABBV-744 will be calculated.

  8. Apparent Volume Of Distribution (Vd/F) Of ABBV-744 [ Time Frame: Up To Week 12 ]
    Vd/F of ABBV-744 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 partial remission (PR) or better.

  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 The Concentration Versus 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 The Concentration Versus 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 MF (PPV-MF) or post-essential thrombocytopenia MF (PET-MF) as defined by the 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 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, and are intolerant, resistant, refractory or lost response to the JAKi.
  • Segment B:

    • Currently receiving ruxolitinib AND
    • Willingness to reduce ruxolitinib 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 therapy;
      2. < 24 weeks duration of current ruxolitinib course with documented resistance, refractories, or loss of response, 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.
        • >=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 the 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 (BCL-2) and/or BCL- XL 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): NCT04454658


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: NCT04454658    
Other Study ID Numbers: M20-247
2020-001225-32 ( EudraCT Number )
First Posted: July 1, 2020    Key Record Dates
Last Update Posted: November 22, 2021
Last Verified: November 2021
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:
ABBV-744
Navitoclax
Ruxolitinib
ABT-263
Cancer
Myelofibrosis
MF
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Navitoclax
Antineoplastic Agents