Myelofibrosis (MF)
Conditions
Keywords
Post-polycythemia vera MF (PPV-MF), Post-essential thrombocythemia (PET-MF), ruxolitinib, navitoclax, splenic volume, Primary Myelofibrosis, Jakafi, enlarged spleen, splenomegaly, ABT 263, bone marrow fibrosis
Brief summary
This is a Phase 2 open-label, multicenter study evaluating tolerability and efficacy of navitoclax alone or when added to ruxolitinib in participants with myelofibrosis.
Interventions
DRUGRuxolitinib
Tablet; Oral
DRUGNavitoclax
Film-coated tablet; Oral
Sponsors
AbbVie
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with documented diagnosis of intermediate-2 or high-risk primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis. * Participant must be ineligible due to age, comorbidities, or unfit for unrelated or unmatched donor transplantation or unwilling to undergo stem cell transplantation at time of study entry. * Eastern Cooperative Oncology Group (ECOG) of 0, 1, or 2. * Prior treatment must meet at least one of the following criteria: * Prior or current treatment with ruxolitinib and no prior treatment with a Bromodomain and Extra-Terminal motif (BET) proteins inhibitor or another Janus Kinase 2 (JAK-2) inhibitor, and meet all of the following criteria: * Ruxolitinib treatment must meet at least one of the following criteria: * Ruxolitinib treatment for \>=24 weeks with lack of efficacy defined as a lack of spleen response (refractory) or a loss of spleen or symptom response (relapsed) * Ruxolitinib treatment for \<24 weeks with documented disease progression on spleen measurements while on ruxolitinib as defined in the protocol: * Ruxolitinib treatment for \>=28 days with intolerance defined as new red blood cell transfusion requirement (at least 2 units/month for 2 months) while receiving a total daily ruxolitinib dose of \>=30 mg but unable to reduce dose further due to lack of efficacy. * If receiving ruxolitinib at the time of screening, must currently be on a stable dose \>=10 mg twice daily of ruxolitinib for \>=4 weeks prior to the 1st dose of navitoclax. * Participant has at least 2 symptoms each with a score \>=3 or a total score of \>=12, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days during screening prior to study drug dosing; OR * Prior treatment with a JAK-2 inhibitor and meet one of the following criteria: * Prior treatment with a JAK-2 inhibitor for at least 12 weeks * Prior treatment with a JAK-2 inhibitor for \>=28 days complicated by either development of red blood cell transfusion requirement (at least 2 units/month for 2 months) OR Grade \>= 3 adverse events of thrombocytopenia, anemia, hematoma and/or hemorrhage while on JAK-2 inhibitor treatment; OR * No prior treatment with a JAK-2 or BET inhibitor. * Participant has splenomegaly as defined in the protocol. * Participant must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol.
Exclusion criteria
* Splenic irradiation within 6 months prior to screening, or prior splenectomy. * Leukemic transformation (\> 10% blasts in peripheral blood or bone marrow aspirate/biopsy). * Participant is currently on medications that interfere with coagulation (including warfarin) or platelet function within 3 days prior to the first dose of study drug or during the study treatment period with the exception of low dose aspirin (up to 100 mg/day) and low-molecular-weight heparin. * Prior therapy with a BH3 mimetic compound or stem cell transplantation. * Participant has received strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A inhibitors (e.g., fluconazole) within 14 days prior to the administration of the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 | Baseline, Week 24 | Reduction in spleen volume is measured by magnetic resonance imaging/computerized tomography (MRI/CT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at Week 24 | 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). |
| Percentage of Participants Achieving Anemia Response | Up to 254 weeks | 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. |
| Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Up to 254 weeks | Bone marrow grading is assessed according to the European Consensus Grading System. The 4-point grading scale ranges from MF-0, which corresponds to normal bone marrow, to MF-3, diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. |
| Time to First Reduction in Fibrosis Grade | Up to 254 weeks | Grade of bone marrow fibrosis was assessed by investigators according to the European Consensus Grading System. The 4-point grading scale ranges from MF-0, which corresponds to normal bone marrow, to MF-3, diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. The time to first achieving a reduction of at least 1 grade in bone marrow fibrosis from Baseline was summarized. |
Countries
Australia, Canada, Croatia, Greece, Hungary, Israel, Italy, Japan, Puerto Rico, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORABBVIE INC.
AbbVie
Participant flow
Recruitment details
This trial was conducted at 57 sites in 13 countries./territories.
Pre-assignment details
Participants enrolled in Cohort 1a must have received ruxolitinib therapy for at least 12 weeks and currently be on a stable dose of ≥10 mg twice daily of ruxolitinib. For Cohort 1b, participants must have received prior treatment with ruxolitinib. For Cohort 2, participants must have received prior treatment with a JAK-2 inhibitor. For Cohort 3, participants must not have received prior treatment with a JAK-2 inhibitor or BET inhibitor.
Participants by arm
| Arm | Count |
|---|---|
| Navitoclax + Ruxolitinib (Cohort 1a) Participants must have received ruxolitinib for at least 12 weeks and on stable dose of ≥10 mg tablets orally twice daily (BID) for ≥8 weeks prior to the 1st dose of navitoclax. Navitoclax tablets are administered once daily (QD) at a starting dose of 50 mg. This was increased after approximately ≥7 days to next dose level if platelet count is ≥75 × 10\^9/L up to a maximum dose of navitoclax 300 mg QD. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). | 34 |
| Navitoclax + Ruxolitinib (Cohort 1b) Those receiving ruxolitinib at Screening must be on a stable dose ≥10 mg tablets orally twice daily (BID) for ≥ 4 weeks prior to 1st dose of navitoclax. Those not receiving ruxolitinib at Screening received 10 mg ruxolitinib BID starting on Day 1. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose was increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). | 91 |
| Navitoclax (Cohort 2) Participants must have received prior treatment with a Janus Kinase 2 (JAK-2) inhibitor. Those with Baseline platelet count \>150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 200 mg. Those with a Baseline platelet count ≤150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 100 mg, which could be increased to 200 mg once daily after 7 days provided the platelet count is ≥75 × 10\^9/L. Navitoclax didn't exceed 200 mg QD for the first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). | 34 |
| Navitoclax + Ruxolitinib (Cohort 3) Prior treatment with a Janus Kinase 2 (JAK-2) or Bromodomain and Extra-Terminal motif (BET) proteins inhibitor was prohibited. Ruxolitinib tablets administered orally twice daily (BID) based on Baseline platelet count as per the local approved label. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). | 32 |
| Total | 191 |
Baseline characteristics
| Characteristic | Navitoclax + Ruxolitinib (Cohort 1a) | Navitoclax + Ruxolitinib (Cohort 1b) | Navitoclax (Cohort 2) | Navitoclax + Ruxolitinib (Cohort 3) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 67.4 years STANDARD_DEVIATION 10.38 | 66.5 years STANDARD_DEVIATION 9.26 | 69.0 years STANDARD_DEVIATION 6.56 | 68.0 years STANDARD_DEVIATION 10.1 | 67.4 years STANDARD_DEVIATION 9.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 7 Participants | 4 Participants | 6 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 84 Participants | 30 Participants | 26 Participants | 172 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 15 Participants | 3 Participants | 0 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 76 Participants | 30 Participants | 29 Participants | 167 Participants |
| Sex: Female, Male Female | 11 Participants | 34 Participants | 14 Participants | 12 Participants | 71 Participants |
| Sex: Female, Male Male | 23 Participants | 57 Participants | 20 Participants | 20 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 20 / 34 | 39 / 91 | 18 / 34 | 10 / 32 |
| other Total, other adverse events | 34 / 34 | 91 / 91 | 34 / 34 | 32 / 32 |
| serious Total, serious adverse events | 21 / 34 | 35 / 91 | 18 / 34 | 12 / 32 |
Outcome results
Primary
Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24
Reduction in spleen volume is measured by magnetic resonance imaging/computerized tomography (MRI/CT).
Time frame: Baseline, Week 24
Population: Full Analysis Set (FAS): all participants who take at least one dose of navitoclax
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navitoclax + Ruxolitinib (Cohort 1a) | Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 | 26.47 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1b) | Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 | 21.98 percentage of participants |
| Navitoclax (Cohort 2) | Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 | 11.76 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 3) | Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 | 62.50 percentage of participants |
Secondary
Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at 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).
Time frame: Baseline, Week 24
Population: Full Analysis Set (FAS): all participants who take at least one dose of navitoclax
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navitoclax + Ruxolitinib (Cohort 1a) | Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at Week 24 | 20.59 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1b) | Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at Week 24 | 25.27 percentage of participants |
| Navitoclax (Cohort 2) | Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at Week 24 | 8.82 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 3) | Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at Week 24 | 34.38 percentage of participants |
Secondary
Percentage of Participants Achieving Anemia Response
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.
Time frame: Up to 254 weeks
Population: Full Analysis Set (FAS): all participants who take at least one dose of navitoclax; participants who were Baseline transfusion independent with baseline hemoglobin of ≥10 g/dL were excluded from the analysis since they were not evaluable for anemia response. Missing post-Baseline anemia response in Full Analysis Set applicable to evaluation of anemia response are considered as non-responders of anemia response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Navitoclax + Ruxolitinib (Cohort 1a) | Percentage of Participants Achieving Anemia Response | Baseline transfusion independent with Baseline HGB <10 g/dL | 28.57 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1a) | Percentage of Participants Achieving Anemia Response | Overall | 36.36 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1a) | Percentage of Participants Achieving Anemia Response | Baseline transfusion dependent | 50.00 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1b) | Percentage of Participants Achieving Anemia Response | Baseline transfusion independent with Baseline HGB <10 g/dL | 21.05 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1b) | Percentage of Participants Achieving Anemia Response | Overall | 20.00 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1b) | Percentage of Participants Achieving Anemia Response | Baseline transfusion dependent | 16.67 percentage of participants |
| Navitoclax (Cohort 2) | Percentage of Participants Achieving Anemia Response | Baseline transfusion dependent | 37.50 percentage of participants |
| Navitoclax (Cohort 2) | Percentage of Participants Achieving Anemia Response | Baseline transfusion independent with Baseline HGB <10 g/dL | 52.94 percentage of participants |
| Navitoclax (Cohort 2) | Percentage of Participants Achieving Anemia Response | Overall | 48.00 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 3) | Percentage of Participants Achieving Anemia Response | Baseline transfusion independent with Baseline HGB <10 g/dL | 38.46 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 3) | Percentage of Participants Achieving Anemia Response | Overall | 46.67 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 3) | Percentage of Participants Achieving Anemia Response | Baseline transfusion dependent | 100 percentage of participants |
Secondary
Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time
Bone marrow grading is assessed according to the European Consensus Grading System. The 4-point grading scale ranges from MF-0, which corresponds to normal bone marrow, to MF-3, diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis.
Time frame: Up to 254 weeks
Population: Full Analysis Set (FAS): all participants who take at least one dose of navitoclax; participants with missing bone marrow fibrosis grade (either Baseline or post-Baseline) or those with bone marrow fibrosis Grade 0 at Baseline were excluded from the analysis for the change in bone marrow fibrosis grade
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Navitoclax + Ruxolitinib (Cohort 1a) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Week 24 | 23.08 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1a) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Anytime during the post-Baseline period | 41.94 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1b) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Anytime during the post-Baseline period | 37.18 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 1b) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Week 24 | 24.07 percentage of participants |
| Navitoclax (Cohort 2) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Week 24 | 40.00 percentage of participants |
| Navitoclax (Cohort 2) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Anytime during the post-Baseline period | 40.91 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 3) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Week 24 | 30.43 percentage of participants |
| Navitoclax + Ruxolitinib (Cohort 3) | Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time | Anytime during the post-Baseline period | 44.44 percentage of participants |
Secondary
Time to First Reduction in Fibrosis Grade
Grade of bone marrow fibrosis was assessed by investigators according to the European Consensus Grading System. The 4-point grading scale ranges from MF-0, which corresponds to normal bone marrow, to MF-3, diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. The time to first achieving a reduction of at least 1 grade in bone marrow fibrosis from Baseline was summarized.
Time frame: Up to 254 weeks
Population: Full Analysis Set (FAS): all participants who take at least one dose of navitoclax; participants with Baseline bone marrow fibrosis grade \>0 and post-Baseline bone marrow fibrosis grade are included in the analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Navitoclax + Ruxolitinib (Cohort 1a) | Time to First Reduction in Fibrosis Grade | 24.1 weeks |
| Navitoclax + Ruxolitinib (Cohort 1b) | Time to First Reduction in Fibrosis Grade | 24.1 weeks |
| Navitoclax (Cohort 2) | Time to First Reduction in Fibrosis Grade | 12.4 weeks |
| Navitoclax + Ruxolitinib (Cohort 3) | Time to First Reduction in Fibrosis Grade | 12.2 weeks |