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

NCT04480086 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: M20-2482020-001226-65
• Study Type: interventional
• Target: 1
• Locations: 3 countries
• Sites: 7

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.

Conditions

Myelofibrosis (MF)

Keywords

mivebresib; Navitoclax; Ruxolitinib; ABT-263; Cancer; Myelofibrosis; MF; ABBV-075

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35)

  Up To Week 24

• Maximum Observed Plasma Concentration (Cmax) of Mivebresib

  Up To Week 12

• Time to Cmax (Tmax) of Mivebresib

  Up To Week 12

• Area Under Concentration vs Time Curve (AUC) of Mivebresib

  Up To Week 12

• Half-Life (t1/2) of Mivebresib

  Up To Week 12

Study Arms (5)

Segment A: Mivebresib Dose Identification and Optimization

EXPERIMENTAL

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

Segment A: Mivebresib Monotherapy

EXPERIMENTAL

Participants will receive the identified safe dosing regimen of mivebresib as monotherapy.

Drug: Mivebresib

Segment B: Ruxolitinib + Mivebresib "Add-on" Therapy

EXPERIMENTAL

Participants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and mivebresib as "add-on" therapy.

Drug: Mivebresib; Drug: Ruxolitinib

Segment C: Mivebresib + Navitoclax

EXPERIMENTAL

Participants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax.

Drug: Mivebresib; Drug: Navitoclax

Segment D: Mivebresib + Ruxolitinib

EXPERIMENTAL

Participants who have never received JAKi will receive mivebresib and ruxolitinib.

Drug: Mivebresib; Drug: Ruxolitinib

Interventions

Mivebresib DRUG

Tablet: Oral

Segment A: Mivebresib Dose Identification and Optimization; Segment A: Mivebresib Monotherapy; Segment B: Ruxolitinib + Mivebresib "Add-on" Therapy; Segment C: Mivebresib + Navitoclax; Segment D: Mivebresib + Ruxolitinib

Navitoclax DRUG

Tablet; Oral

Also known as: ABT-263

Segment C: Mivebresib + Navitoclax

Ruxolitinib DRUG

Tablet; Oral

Segment B: Ruxolitinib + Mivebresib "Add-on" Therapy; Segment D: Mivebresib + Ruxolitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):
• \>= 24 weeks duration of current ruxolitinib course, with evidence of disease that is resistant, refractory, or has lost response to ruxolitinib monotherapy;
• \< 24 weeks duration of current ruxolitinib course with documented disease progression as defined by any of the following:

You may not qualify if:

• 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.

Sponsors & Collaborators

• AbbVie: lead

Study Sites (7)

Stony Brook University Hospital /ID# 222653

Stony Brook, New York, 11794-8183, United States

Location

UC Health - Cincinnati /ID# 224079

Cincinnati, Ohio, 45267-2800, United States

Location

Thompson Cancer Survival Ctr /ID# 225802

Knoxville, Tennessee, 37916, United States

Location

University of Texas MD Anderson Cancer Center /ID# 221652

Houston, Texas, 77030, United States

Location

Wits Clinical Research , Wits Health Consortium (PTY) Ltd /ID# 222669

Johannesburg, Gauteng, 2193, South Africa

Location

Alberts Cellular Therapy /ID# 222667

Pretoria, Gauteng, 0044, South Africa

Location

Inje University Busan Paik Hospital /ID# 224043

Busan, 47392, South Korea

Location

MeSH Terms

Conditions

Primary Myelofibrosis; Neoplasms

Interventions

mivebresib; navitoclax; ruxolitinib

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2020
• First Posted: July 21, 2020
• Study Start: March 17, 2021
• Primary Completion: July 28, 2023
• Study Completion: July 28, 2023
• Last Updated: August 29, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1); US (4); ZA (2)