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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Stony Brook University Hospital /ID# 222653
Stony Brook, New York, United States
UC Health - Cincinnati /ID# 224079
Cincinnati, Ohio, United States
Thompson Cancer Survival Ctr /ID# 225802
Knoxville, Tennessee, 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
Inje University Busan Paik Hospital /ID# 224043
Busan, South Korea
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.
Time frame: Up To Approximately 1 year from start of study
Percentage of Participants who Achieve Spleen Volume Reduction of 35% or Greater (SVR35)
Reduction in spleen volume is measured by magnetic resonance imaging (MRI).
Time frame: Up To Week 24
Maximum Observed Plasma Concentration (Cmax) of Mivebresib
Maximum observed plasma concentration (Cmax) of Mivebresib.
Time frame: Up To Week 12
Time to Cmax (Tmax) of Mivebresib
The amount of time taken to reach Cmax.
Time frame: Up To Week 12
Area Under Concentration vs Time Curve (AUC) of Mivebresib
AUC of Mivebresib will be calculated.
Time frame: Up To Week 12
Half-Life (t1/2) of Mivebresib
Half-life of Mivebresib will be calculated.
Time frame: Up To Week 12
Accumulation Ratio of Mivebresib
Pharmacokinetic parameters will include accumulation ratio of Mivebresib.
Time frame: Up To Week 12
Apparent Clearance (CL/F) of Mivebresib
CL/F of Mivebresib will be calculated.
Time frame: Up To Week 12
Apparent Volume of Distribution (Vd/F) of Mivebresib
Vd/F of mivebresib will be calculated.
Time frame: Up To Week 12
Percentage of Participants With >= 50% Reduction in Total Symptom Score (TSS)
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).
Time frame: Week 24
Objective Response Rate (ORR)
ORR is defined as the sum of rates of complete remission (CR) and partial remission (PR).
Time frame: Week 24
Maximum Observed Plasma Concentration (Cmax) of Navitoclax
Maximum Observed Plasma Concentration (Cmax) Of Navitoclax.
Time frame: Up To Week 12
Time to Cmax (Tmax) of Navitoclax
The amount of time taken to reach Cmax.
Time frame: Up To Week 12
Area Under Concentration vs Time Curve (AUC) of Navitoclax
AUC of Navitoclax will be calculated.
Time frame: Up To Week 12
Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib
Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib.
Time frame: Up To Week 12
Time to Cmax (Tmax) of Ruxolitinib
The amount of time taken to reach Cmax.
Time frame: Up To Week 12
Area Under Concentration vs Time Curve (AUC) of Ruxolitinib
AUC of Ruxolitinib will be calculated.
Time frame: Up To Week 12
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