Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
M20-248
- SECONDARY ID:
2020-001226-65
- NCT ID:
NCT04480086
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Mivebresib | | Segment A: Mivebresib Dose Identification and Optimization |
Navitoclax | ABT-263 | Segment C: Mivebresib + Navitoclax |
Ruxolitinib | | Segment B: Ruxolitinib + Mivebresib "Add-on" Therapy |
Purpose
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 Arms
Name | Type | Description | Interventions |
---|
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. | |
Segment A: Mivebresib Monotherapy | Experimental | Participants will receive the identified safe dosing regimen of mivebresib as monotherapy. | |
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. | |
Segment C: Mivebresib + Navitoclax | Experimental | Participants who have previously been exposed to JAKi, and stopped such therapy, will receive mivebresib and navitoclax. | |
Segment D: Mivebresib + Ruxolitinib | Experimental | Participants who have never received JAKi will receive mivebresib and ruxolitinib. | |
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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Percentage of Participants With Adverse Events |
Time Frame: | Up To Approximately 1 year from start of study |
Safety Issue: | |
Description: | 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
Measure: | Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35) |
Time Frame: | Up To Week 24 |
Safety Issue: | |
Description: | Reduction in spleen volume is measured by magnetic resonance imaging (MRI). |
Measure: | Maximum Observed Plasma Concentration (Cmax) of Mivebresib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | Maximum observed plasma concentration (Cmax) of Mivebresib. |
Measure: | Time to Cmax (Tmax) of Mivebresib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | The amount of time taken to reach Cmax. |
Measure: | Area Under Concentration vs Time Curve (AUC) of Mivebresib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | AUC of Mivebresib will be calculated. |
Measure: | Half-Life (t1/2) of Mivebresib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | Half-life of Mivebresib will be calculated. |
Measure: | Accumulation Ratio of Mivebresib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | Pharmacokinetic parameters will include accumulation ratio of Mivebresib. |
Measure: | Apparent Clearance (CL/F) of Mivebresib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | CL/F of Mivebresib will be calculated. |
Measure: | Apparent Volume of Distribution (Vd/F) of Mivebresib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | Vd/F of mivebresib will be calculated. |
Measure: | Percentage of Participants With >= 50% Reduction in Total Symptom Score (TSS) |
Time Frame: | Week 24 |
Safety Issue: | |
Description: | 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). |
Measure: | Objective Response Rate (ORR) |
Time Frame: | Week 24 |
Safety Issue: | |
Description: | ORR is defined as the sum of rates of complete remission (CR) and partial remission (PR). |
Measure: | Maximum Observed Plasma Concentration (Cmax) of Navitoclax |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | Maximum Observed Plasma Concentration (Cmax) Of Navitoclax. |
Measure: | Time to Cmax (Tmax) of Navitoclax |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | The amount of time taken to reach Cmax. |
Measure: | Area Under Concentration vs Time Curve (AUC) of Navitoclax |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | AUC of Navitoclax will be calculated. |
Measure: | Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib. |
Measure: | Time to Cmax (Tmax) of Ruxolitinib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | The amount of time taken to reach Cmax. |
Measure: | Area Under Concentration vs Time Curve (AUC) of Ruxolitinib |
Time Frame: | Up To Week 12 |
Safety Issue: | |
Description: | AUC of Ruxolitinib will be calculated. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | AbbVie |
Trial Keywords
- mivebresib
- Navitoclax
- Ruxolitinib
- ABT-263
- Cancer
- Myelofibrosis
- MF
- ABBV-075
Last Updated
May 19, 2021