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

A Phase 1b Study of Mivebresib Alone or in Combination With Ruxolitinib or Navitoclax in Subjects With Myelofibrosis

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.

Study Overview

• Status: Terminated
• Conditions: Myelofibrosis (MF)
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Navitoclax; Drug: Mivebresib

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Busan, Korea, Republic of, 47392
    • Inje University Busan Paik Hospital /ID# 224043
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2193
      • Wits Clinical Research , Wits Health Consortium (PTY) Ltd /ID# 222669
    • Pretoria, Gauteng, South Africa, 0044
      • Alberts Cellular Therapy /ID# 222667
• United States
  • New York
    • Stony Brook, New York, United States, 11794-8183
      • Stony Brook University Hospital /ID# 222653
  • Ohio
    • Cincinnati, Ohio, United States, 45267-2800
      • UC Health - Cincinnati /ID# 224079
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • Thompson Cancer Survival Ctr /ID# 225802
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center /ID# 221652

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / 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: Ruxolitinib; Tablet; Oral; Drug: Mivebresib; 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: Navitoclax; Tablet; Oral; Other Names: ABT-263; Drug: Mivebresib; Tablet: Oral
Experimental: Segment D: Mivebresib + Ruxolitinib; Participants who have never received JAKi will receive mivebresib and ruxolitinib.	Drug: Ruxolitinib; Tablet; Oral; Drug: Mivebresib; Tablet: Oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Adverse Events	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.	Up To Approximately 1 year from start of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35)	Reduction in spleen volume is measured by magnetic resonance imaging (MRI).	Up To Week 24
Maximum Observed Plasma Concentration (Cmax) of Mivebresib	Maximum observed plasma concentration (Cmax) of Mivebresib.	Up To Week 12
Time to Cmax (Tmax) of Mivebresib	The amount of time taken to reach Cmax.	Up To Week 12
Area Under Concentration vs Time Curve (AUC) of Mivebresib	AUC of Mivebresib will be calculated.	Up To Week 12
Half-Life (t1/2) of Mivebresib	Half-life of Mivebresib will be calculated.	Up To Week 12
Accumulation Ratio of Mivebresib	Pharmacokinetic parameters will include accumulation ratio of Mivebresib.	Up To Week 12
Apparent Clearance (CL/F) of Mivebresib	CL/F of Mivebresib will be calculated.	Up To Week 12
Apparent Volume of Distribution (Vd/F) of Mivebresib	Vd/F of mivebresib will be calculated.	Up To Week 12
Percentage of Participants With >= 50% Reduction in Total Symptom Score (TSS)	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).	Week 24
Objective Response Rate (ORR)	ORR is defined as the sum of rates of complete remission (CR) and partial remission (PR).	Week 24
Maximum Observed Plasma Concentration (Cmax) of Navitoclax	Maximum Observed Plasma Concentration (Cmax) Of Navitoclax.	Up To Week 12
Time to Cmax (Tmax) of Navitoclax	The amount of time taken to reach Cmax.	Up To Week 12
Area Under Concentration vs Time Curve (AUC) of Navitoclax	AUC of Navitoclax will be calculated.	Up To Week 12
Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib	Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib.	Up To Week 12
Time to Cmax (Tmax) of Ruxolitinib	The amount of time taken to reach Cmax.	Up To Week 12
Area Under Concentration vs Time Curve (AUC) of Ruxolitinib	AUC of Ruxolitinib will be calculated.	Up To Week 12

Collaborators and Investigators

• Sponsor: AbbVie
• Investigators: Study Director: ABBVIE INC., AbbVie

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2021
• Primary Completion (Actual): July 28, 2023
• Study Completion (Actual): July 28, 2023

Study Registration Dates

• First Submitted: July 20, 2020
• First Submitted That Met QC Criteria: July 20, 2020
• First Posted (Actual): July 21, 2020

Study Record Updates

• Last Update Posted (Actual): August 29, 2023
• Last Update Submitted That Met QC Criteria: August 25, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Cancer; Ruxolitinib; Myelofibrosis; MF; Navitoclax; ABT-263; mivebresib; ABBV-075
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Primary Myelofibrosis; Antineoplastic Agents; Navitoclax
• Other Study ID Numbers: M20-248; 2020-001226-65 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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