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

Phase 1

Terminated

• Conditions: Myelofibrosis (MF)
• Interventions: Drug: Mivebresib; Drug: Ruxolitinib; Drug: Navitoclax

• Registration Number: NCT04480086
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-07-20
• Study First Submitted QC: 2020-07-20
• Study First Posted: 2020-07-21
• Study Start: 2021-03-17
• Primary Completion: 2023-07-28
• Study Completion: 2023-07-28
• Status Verified: 2023-08
• Last Update Submitted: 2023-08-25
• Last Update Posted: 2023-08-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 1

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Segment A: Mivebresib Monotherapy	Mivebresib	Participants will receive the identified safe dosing regimen of mivebresib as monotherapy.
Segment C: Mivebresib + Navitoclax	Mivebresib	Participants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax.
Segment D: Mivebresib + Ruxolitinib	Mivebresib	Participants who have never received JAKi will receive mivebresib and ruxolitinib.
Segment B: Ruxolitinib + Mivebresib "Add-on" Therapy	Mivebresib	Participants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and mivebresib as "add-on" therapy.
Segment A: Mivebresib Dose Identification and Optimization	Mivebresib	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.
Segment D: Mivebresib + Ruxolitinib	Ruxolitinib	Participants who have never received JAKi will receive mivebresib and ruxolitinib.
Segment B: Ruxolitinib + Mivebresib "Add-on" Therapy	Ruxolitinib	Participants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and mivebresib as "add-on" therapy.
Segment C: Mivebresib + Navitoclax	Navitoclax	Participants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Adverse Events	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

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

Trial Locations

Locations (7)

Stony Brook University Hospital /ID# 222653; 🇺🇸 Stony Brook, New York, United States

Inje University Busan Paik Hospital /ID# 224043; 🇰🇷 Busan, Korea, Republic of

UC Health - Cincinnati /ID# 224079; 🇺🇸 Cincinnati, Ohio, United States

University of Texas MD Anderson Cancer Center /ID# 221652; 🇺🇸 Houston, Texas, United States

Wits Clinical Research , Wits Health Consortium (PTY) Ltd /ID# 222669; 🇿🇦 Johannesburg, Gauteng, South Africa

Alberts Cellular Therapy /ID# 222667; 🇿🇦 Pretoria, Gauteng, South Africa

Thompson Cancer Survival Ctr /ID# 225802; 🇺🇸 Knoxville, Tennessee, United States