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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04480086




Registration number
NCT04480086
Ethics application status
Date submitted
20/07/2020
Date registered
21/07/2020
Date last updated
29/08/2023

Titles & IDs
Public title
Safety and Tolerability Study of Mivebresib Tablet Alone or in Combination With Ruxolitinib Tablet or Navitoclax Tablet in Adult Participants With Myelofibrosis
Scientific title
A Phase 1b Study of Mivebresib Alone or in Combination With Ruxolitinib or Navitoclax in Subjects With Myelofibrosis
Secondary ID [1] 0 0
2020-001226-65
Secondary ID [2] 0 0
M20-248
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelofibrosis (MF) 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Mivebresib
Treatment: Drugs - Navitoclax
Treatment: Drugs - Ruxolitinib

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.

Experimental: Segment A: Mivebresib Monotherapy - Participants will receive the identified safe dosing regimen of mivebresib as monotherapy.

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.

Experimental: Segment C: Mivebresib + Navitoclax - Participants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax.

Experimental: Segment D: Mivebresib + Ruxolitinib - Participants who have never received JAKi will receive mivebresib and ruxolitinib.


Treatment: Drugs: Mivebresib
Tablet: Oral

Treatment: Drugs: Navitoclax
Tablet; Oral

Treatment: Drugs: Ruxolitinib
Tablet; Oral
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Adverse Events
Timepoint [1] 0 0
Up To Approximately 1 year from start of study
Secondary outcome [1] 0 0
Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35)
Timepoint [1] 0 0
Up To Week 24
Secondary outcome [2] 0 0
Maximum Observed Plasma Concentration (Cmax) of Mivebresib
Timepoint [2] 0 0
Up To Week 12
Secondary outcome [3] 0 0
Time to Cmax (Tmax) of Mivebresib
Timepoint [3] 0 0
Up To Week 12
Secondary outcome [4] 0 0
Area Under Concentration vs Time Curve (AUC) of Mivebresib
Timepoint [4] 0 0
Up To Week 12
Secondary outcome [5] 0 0
Half-Life (t1/2) of Mivebresib
Timepoint [5] 0 0
Up To Week 12
Secondary outcome [6] 0 0
Accumulation Ratio of Mivebresib
Timepoint [6] 0 0
Up To Week 12
Secondary outcome [7] 0 0
Apparent Clearance (CL/F) of Mivebresib
Timepoint [7] 0 0
Up To Week 12
Secondary outcome [8] 0 0
Apparent Volume of Distribution (Vd/F) of Mivebresib
Timepoint [8] 0 0
Up To Week 12
Secondary outcome [9] 0 0
Percentage of Participants With >= 50% Reduction in Total Symptom Score (TSS)
Timepoint [9] 0 0
Week 24
Secondary outcome [10] 0 0
Objective Response Rate (ORR)
Timepoint [10] 0 0
Week 24
Secondary outcome [11] 0 0
Maximum Observed Plasma Concentration (Cmax) of Navitoclax
Timepoint [11] 0 0
Up To Week 12
Secondary outcome [12] 0 0
Time to Cmax (Tmax) of Navitoclax
Timepoint [12] 0 0
Up To Week 12
Secondary outcome [13] 0 0
Area Under Concentration vs Time Curve (AUC) of Navitoclax
Timepoint [13] 0 0
Up To Week 12
Secondary outcome [14] 0 0
Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib
Timepoint [14] 0 0
Up To Week 12
Secondary outcome [15] 0 0
Time to Cmax (Tmax) of Ruxolitinib
Timepoint [15] 0 0
Up To Week 12
Secondary outcome [16] 0 0
Area Under Concentration vs Time Curve (AUC) of Ruxolitinib
Timepoint [16] 0 0
Up To Week 12

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
17/03/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
28/07/2023
Sample size
Target
Accrual to date
Final
1
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
New York
Country [2] 0 0
United States of America
State/province [2] 0 0
Ohio
Country [3] 0 0
United States of America
State/province [3] 0 0
Tennessee
Country [4] 0 0
United States of America
State/province [4] 0 0
Texas
Country [5] 0 0
Korea, Republic of
State/province [5] 0 0
Busan
Country [6] 0 0
South Africa
State/province [6] 0 0
Gauteng

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
AbbVie
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04480086
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
ABBVIE INC.
Address 0 0
AbbVie
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04480086