Clinical trial NCT04480086: Safety and Tolerability Study of Mivebresib Tablet Alone or in Combination With Ruxolitinib Tablet or Navitoclax Tablet in Adult Participants With Myelofibrosis
Official title: A Phase 1b Study of Mivebresib Alone or in Combination With Ruxolitinib or Navitoclax in Subjects With Myelofibrosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Myelofibrosis (MF)
Keywords: mivebresib
Navitoclax
Ruxolitinib
ABT-263
Cancer
Myelofibrosis
MF
ABBV-075
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2020-07-21
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Percentage of Participants With Adverse Events
timeFrame: Up To Approximately 1 year from start of study
Secondary outcomes:
measure: Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35)
timeFrame: Up To Week 24
measure: Maximum Observed Plasma Concentration (Cmax) of Mivebresib
timeFrame: Up To Week 12
measure: Time to Cmax (Tmax) of Mivebresib
timeFrame: Up To Week 12
measure: Area Under Concentration vs Time Curve (AUC) of Mivebresib
timeFrame: Up To Week 12
measure: Half-Life (t1/2) of Mivebresib
timeFrame: Up To Week 12
measure: Accumulation Ratio of Mivebresib
timeFrame: Up To Week 12
measure: Apparent Clearance (CL/F) of Mivebresib
timeFrame: Up To Week 12
measure: Apparent Volume of Distribution (Vd/F) of Mivebresib
timeFrame: Up To Week 12
measure: Percentage of Participants With >= 50% Reduction in Total Symptom Score (TSS)
timeFrame: Week 24
measure: Objective Response Rate (ORR)
timeFrame: Week 24
measure: Maximum Observed Plasma Concentration (Cmax) of Navitoclax
timeFrame: Up To Week 12
measure: Time to Cmax (Tmax) of Navitoclax
timeFrame: Up To Week 12
measure: Area Under Concentration vs Time Curve (AUC) of Navitoclax
timeFrame: Up To Week 12
measure: Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib
timeFrame: Up To Week 12
measure: Time to Cmax (Tmax) of Ruxolitinib
timeFrame: Up To Week 12
measure: Area Under Concentration vs Time Curve (AUC) of Ruxolitinib
timeFrame: Up To Week 12
Other outcomes:
Locations:
city: Stony Brook
country: United States
facility: Stony Brook University Hospital /ID# 222653
state: New York
city: Cincinnati
country: United States
facility: UC Health - Cincinnati /ID# 224079
state: Ohio
city: Knoxville
country: United States
facility: Thompson Cancer Survival Ctr /ID# 225802
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center /ID# 221652
state: Texas
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital /ID# 224043
city: Johannesburg
country: South Africa
facility: Wits Clinical Research , Wits Health Consortium (PTY) Ltd /ID# 222669
state: Gauteng
city: Pretoria
country: South Africa
facility: Alberts Cellular Therapy /ID# 222667
state: Gauteng
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References: