Myelofibrosis (MF)
Conditions
Keywords
Myelofibrosis, Navitoclax, Ruxolitinib, Cancer, ABT-263, TRANSFORM-1
Brief summary
Myelofibrosis is a type of bone marrow cancer that usually develops slowly and disrupts body's normal production of blood cells. It causes bone marrow scarring, leading to severe anemia that can cause weakness and fatigue. It can also cause a low number of blood-clotting cells called platelets, which increases risk of bleeding. Myelofibrosis often causes an enlarged spleen. The purpose of this study is to see if a combination of navitoclax and ruxolitinib is more effective and safe in assessment of change in spleen volume when compared to ruxolitinib in participants with myelofibrosis. Navitoclax is an investigational drug for the treatment of myelofibrosis. Participants in this study are divided into two groups, called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of myelofibrosis will be enrolled. Around 230 participants will be enrolled in approximately 190 sites worldwide. Participants will receive oral navitoclax tablet with oral ruxolitinib tablet or oral ruxolitinib tablet with oral placebo (no active drug) tablet and treatment may continue untill the participant cannot tolerate the study drug, or benefit is not achieved, or other reasons which qualify for discontinuation of the study drug. There may be a higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, magnetic resonance imaging (MRI) or computed tomography (CT) scan, bone marrow tests, checking for side effects, and completing questionnaires.
Interventions
DRUGPlacebo for Navitoclax
Film-coated tablet; Oral
DRUGRuxolitinib
Tablet; Oral
DRUGNavitoclax
Film-coated tablet; Oral
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of Primary MyeloFibrosis (MF) as defined by World Health Organization (WHO) classification or Secondary MF (post polycythemia vera \[PPV\] - MF or Post Essential Thrombocythemia \[PET\] - MF) . * Must be able to complete the MF Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days immediately preceding the date of randomization. \-- Must have at least 2 symptoms with a score \>=3 or a total score of \>=12, as measured by the MFSAF v4.0. * Classified as intermediate-2, or high-Risk MF as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+). * Has splenomegaly defined as spleen palpation measurement \>= 5 centimeters (cm) below costal margin or spleen volume greater than or equal to 450 cubic cm as assessed centrally by magnetic resonance imaging (MRI) or computed tomography (CT) scan. * Ineligible for stem cell transplantation at time of study entry due to age, comorbidities, or unfit for unrelated or unmatched donor transplant and other criteria per National Comprehensive Cancer Network guidelines. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Exclusion criteria
* Prior treatment with a Janus Kinase-2 (JAK-2) inhibitor. * Prior treatment with a B-cell lymphoma 2 homology 3 (BH3)-mimetic compound or bromodomain and extra-terminal motif (BET) inhibitor or stem cell transplant. * Receiving medication that interferes with coagulation or platelet function within 3 days prior to the first dose of study drug or during the study treatment period except for low dose aspirin (up to 100 milligram daily) and low molecular weight heparin (LMWH).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 (SVR35W24) | Baseline, Week 24 | Reduction in spleen volume is measured by magnetic resonance imaging (MRI) or computed tomography (CT), per International Working Group (IWG) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Symptom Score (TSS) at Week 24 as Measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 | Baseline, Week 24 | TSS is assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0. Participants complete a symptom diary and rate the following seven MF symptoms: fatigue, night sweats, abdominal discomfort, pruritus, pain under the ribs on the left side, early satiety, and bone pain daily using a scale from 0 (absent) to 10 (worst imaginable), and the scores are averaged over 7 days, with a minimum of 4 days required to calculate the average score. Participants for whom a valid average score cannot be calculated either at baseline or post-baseline are considered non-responders. The TSS reflects the sum of the scores of these symptoms, for a maximum possible score of 70 (i.e., most severe symptom experience). Negative changes from Baseline indicate improvement. |
| Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume (SVR35) at Any Time | Up to Week 97 | Reduction in spleen volume is measured by magnetic resonance imaging (MRI) or computed tomography (CT), per International Working Group (IWG) criteria. |
| Duration of 35% Spleen Volume Reduction (SVR35) | Baseline (Week 0) Up to Month 48 | Duration of SVR35 is defined as the time between the date of first response of spleen volume reduction of 35% achievement to the date of the first assessment where the spleen volume is less than 35% reduction from Baseline and is at least 25% increase from the nadir (the lowest spleen volume), confirmed relapse, or leukemic transformation per International Working Group (IWG) criteria, whichever is earlier. |
| Change From Baseline In Fatigue at Week 24 as Measured by the PROMIS Fatigue Short Form (SF) 7a | Baseline, Week 24 | The PROMIS Fatigue SF 7a is a 7-item patient-reported outcome measure that assesses the impact and experience of participants with fatigue over the past 7 days. Each item is scored on a 5-point Likert scale (1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 5 = Always). Raw scores range from 7 to 35 and are subsequently transformed into a standardized T-score using the PROMIS wave 1 calibration (where a score of 50 represents the U.S. general population mean with a standard deviation of 10). Higher T-scores indicate greater fatigue severity. A decrease in T-score from Baseline represents a clinical improvement in fatigue symptoms. |
| Change From Baseline at Week 24 in Physical Functioning as Measured by the Physical Functioning Domain of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 | Baseline, Week 24 | EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a physical functioning scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the physical functioning scale indicates a better level of functioning, and positive changes from Baseline indicate improvement. |
| Percentage of Participants Achieving Anemia Response | Up to Week 97 | For a participant who is transfusion independent (TI) at Baseline with hemoglobin value \< 10 g/dL, anemia response is achieved if the post-Baseline hemoglobin level increases by ≥2 g/dL without receiving packed red blood cells (PRBC) transfusion (for any reason) within 2 weeks and without any erythropoietin or mimetics within the last 4 weeks prior to the increase in hemoglobin level by ≥2g/dL was observed. Hemoglobin values more than 30 days after the last dose of study treatment or after the start of post-study treatment or disease progression, whichever is earlier, will not be considered in the analysis of anemia response. For a participant who is transfusion dependent (TD) at Baseline, anemia response is defined as a period of at least 12 consecutive weeks without PRBC transfusion at any time after the first dose of study drug and on or prior to 30 days post last dose of study drug, the start of post-study treatment, disease progression or death, whichever occurs earlier. |
| Overall Survival (OS) | Up to 50 months | OS is defined as the time from the date of randomization to the date of death from any cause. |
| Leukemia-Free Survival | Up to 50 months | Leukemia-free survival is defined as the number of days from the date of randomization to the onset date of documented leukemia, disease progression due to leukemia, or death due to leukemia, whichever occurs first. |
| Percentage of Participants Who Achieved Reduction in Grade of Bone Marrow Fibrosis From Baseline at Any Time | Up to Week 97 | Change in grade of bone marrow fibrosis was measured per the European consensus grading system through bone marrow biopsy. The percentage of participants who achieved reduction of at least 1 grade in bone marrow fibrosis compared to Baseline is reported. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Croatia, France, Germany, Greece, Israel, Italy, Japan, Netherlands, New Zealand, Russia, Serbia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORABBVIE INC.
AbbVie
Participant flow
Recruitment details
This trial was conducted in 24 countries.
Pre-assignment details
Participants were randomized in a 1:1 ratio to one of two treatment arms, with stratification factors of intermediate-2 versus high risk (Dynamic International Prognostic Scoring System Plus \[DIPSS+\]) 1 and platelet count ≤ 200 × 10\^9 /L versus \> 200 × 10\^9 /L: Control group: Placebo for Navitoclax + Ruxolitinib; Experimental group: Navitoclax + Ruxolitinib
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 8.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 50 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 199 Participants |
| Sex: Female, Male Female | 108 Participants |
| Sex: Female, Male Male | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 127 | 35 / 125 |
| other Total, other adverse events | 115 / 127 | 121 / 125 |
| serious Total, serious adverse events | 56 / 127 | 42 / 125 |
Outcome results
None listed