Post-Essential Thrombocythemia Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis, Primary Myelofibrosis
Conditions
Keywords
Ruxolitinib, anemia, Primary Myelofibrosis, PMF, Post-Polycythemia Vera-Myelofibrosis, PPV-MF, Post-Essential Thrombocythemia Myelofibrosis, PET-MF, adult, INC424
Brief summary
This was a study of treatment with ruxolitinib in patients who presented with transfusion dependent or independent anemia. Starting dose was 10 mg BID. This dose was maintained for the first 12 weeks of the study and up-titrated thereafter unless the subject met criteria for dose hold or dose reduction
Detailed description
This was a study of treatment with ruxolitinib in patients who present with transfusion dependent or independent anemia at screening defined as an hemoglobin \<10 g/dL with 10 mg BID starting dose with subsequent up titrations (maximum dose 25 mg BID) depending on safety and efficacy. This dosing approach for anemic MF patients will be systematically studied in this prospective multicenter phase II open label single arm trial to determine if the levels of spleen length reduction and symptom improvement are consistent with those reported in previous clinical trials with ruxolitinib in patients with anemia and doses according to platelet counts at the moment of treatment initiation, and whether this lower starting dose and up titration approach may minimize the initial hemoglobin and platelet declines and transfusion requirements.
Interventions
DRUGruxolitinib
Ruxolitinib was supplied in 5 mg tablets to be taken orally approximately 12 hours apart (morning and night)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Written informed consent must be obtained prior to any screening procedures. 1. Male or female patients aged ≥ 18 years of age. 2. Patients must have been diagnosed with PMF, according to the 2016 revised International Standard Criteria, PPV MF or PET-MF, irrespective of JAK2 mutation status. 3. Patients must have had palpable splenomegaly that is equal to or greater than 5 cm below the left costal margin. 4. Patients must have had hemoglobin less than 10 g/dL 5. Patients must have had a history of transfusions must have a documented transfusion record in the previous 12 weeks to baseline. 6. Patients must have had ECOG performance status of 0, 1, or 2. 7. Patients must have had a peripheral blood blast percentage count of \< 10%. 8. Patients must have recovered or stabilized sufficiently from any adverse drug reactions associated with prior treatments before beginning treatment with ruxolitinib.
Exclusion criteria
1. Patients who had prior treatment with any JAK1 or JAK2 inhibitor. 2. Patients who had known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to their excipients. 3. Patients who had been eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available). 4. Patients who had inadequate bone marrow reserve at baseline as demonstrated by at least one of the following: 1. ANC that is ≤ 1,000/µL. 2. Platelet count that is \<50,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions. 3. Hemoglobin count that is ≤ 6.5 g/dL despite transfusions. 5. Patients who had severely impaired renal function defined by: Creatinine clearance less than 30 mL/min. 6. Patients who had inadequate liver function defined by any of these: 1. Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 x ULN; 2. Alanine aminotransferase (ALT) \> 2.5 x ULN; 3. Aspartate aminotransferase (AST) \> 2.5 x ULN. 7. Patients who were being treated concurrently with a strong (potent) systemic inhibitor or inducer of CYP3A4 at the time of Screening. 8. Presence of active bacterial, fungal, parasitic, or viral infection which requires therapy. 9. Known history of human immunodeficiency virus (HIV) infection or other immunodeficiency syndromes such as X-linked agammaglobulinemia and common variable immune deficiency. 10. Acute viral hepatitis or active chronic hepatitis B or C infection. Patients with inactive chronic infection (without viral replication) can be enrolled 11. History of progressive multifocal leuko-encephalopathy. 12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ruxolitinib . 13. History or current diagnosis of uncontrolled or significant cardiac disease, including any of the following: 1. Myocardial infarction within last 6 months 2. Uncontrolled congestive heart failure 3. Unstable angina within last 6 months 4. Clinically significant (symptomatic) cardiac arrhythmias (e.g. bradyarrhythmias, sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker) 14. Significant concurrent, uncontrolled medical condition which, in the investigator's opinion, would have jeopardized the safety of the patient or compliance with the protocol. 15. Patients who were undergoing treatment with another investigational medication or had been treated with an investigational medication within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug. 16. Patients who had a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma. 17. Patients who were unable to comprehend or are unwilling to sign an ICF. 18. Pregnant or nursing (lactating) women 19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception throughout the study duration inclusive of 30 day safety follow up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 24 | Baseline up to week 24 | Percentage of participants achieving a 50% reduction in spleen length at week 24. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen are imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 24 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 48 | Baseline up to week 48 | Percentage of participants achieving a 50% reduction in spleen length at week 48. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 48 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method. |
| Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | baseline, weeks 24 and 48 | Participants who achieved a ≤ 50% reduction in spleen length at week 24 and 48 (reduction) and participants who had no increase greater than or equal to 50% (increase). The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0. |
| Percentage of Participants With at Least a 50% Reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24 | Baseline and week 24 | The MF-7 is a disease specific questionnaire comprised of 7 items that measures the severity of seven of the most prevalent associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. Each item was scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7 score is computed as the sum of the observed scores in the individual items to achieve a 0 to 70 score. There would be one recall period of 24 hours used in this questionnaire. A separate question on Inactivity was to be measured for severity of this symptom on a scale from 0 (absent) to 10 (worst imaginable). This would allow the computation of the MFSAF v2.0 questionnaire results, as 6 out of 7 items in the latter PRO are in overlap with MF7 (they also share same 0-10 range Likert scale and ascending order, absent to worst imaginable). |
| Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Baseline up to week 48 | The PGIC is comprised of a single question intended to measure a subject's perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where '1' equals very much improved and '7' equals very much worse. |
| Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Baseline up to week 96 | Percentage is based on number of subjects who are transfusion dependent at baseline. Transfusion dependence (TD) is defined as subjects receiving 6 or more units of transfusions 12 weeks prior to baseline. Transfusion independence (TI) rate is defined as subjects who are transfusion dependent at baseline and require no unit of transfusion for ≥ 12 weeks at any time during the study. Transfusion response rate is defined as subjects who are TD at baseline and have 5 or less units of transfusion for ≥ 12 weeks at any time during the study. |
Countries
Austria, Belgium, Bulgaria, Canada, Germany, Greece, Italy, Japan, Russia, Spain, Turkey (Türkiye)
Participant flow
Pre-assignment details
Screening evaluations were performed to determine the eligibility for the study and establish a baseline prior to dosing.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects 10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid. | 51 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 4 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Progressive disease | 2 |
| Overall Study | Protocol deviation | 2 |
| Overall Study | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 31 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Bone Marrow Fibrosis Grade at Diagnosis Grade 0 | 0 participants |
| Bone Marrow Fibrosis Grade at Diagnosis Grade 1 | 6 participants |
| Bone Marrow Fibrosis Grade at Diagnosis Grade 2 | 26 participants |
| Bone Marrow Fibrosis Grade at Diagnosis Grade 3 | 18 participants |
| Bone Marrow Fibrosis Grade at Diagnosis Missing | 1 participants |
| Constitutional symptoms Absent | 22 participants |
| Constitutional symptoms Present | 29 participants |
| Hemoglobin level | 88.6 g/dL STANDARD_DEVIATION 9.74 |
| Palpable spleen length (cm) below costal margin | 11.7 centimeters STANDARD_DEVIATION 6.2 |
| Platelets | 236.7 10E9/L STANDARD_DEVIATION 176.88 |
| Race/Ethnicity, Customized Asian | 3 participants |
| Race/Ethnicity, Customized White | 48 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 30 Participants |
| Time since intial diagnosis | 32.9 months STANDARD_DEVIATION 44.16 |
| Type of myelofibrosis Post-essential thrombocythemia myelofibrosis | 11 participants |
| Type of myelofibrosis Post-polycythemia vera myelofibrosis | 6 participants |
| Type of myelofibrosis Primary myelofibrosis | 34 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 51 |
| other Total, other adverse events | 40 / 51 |
| serious Total, serious adverse events | 17 / 51 |
Outcome results
Primary
Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 24
Percentage of participants achieving a 50% reduction in spleen length at week 24. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen are imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 24 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.
Time frame: Baseline up to week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Subjects | Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 24 | 56.0 percentage of participants |
Secondary
Patient Global Impression of Change (PGIC) at Week 24 and Week 48
The PGIC is comprised of a single question intended to measure a subject's perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where '1' equals very much improved and '7' equals very much worse.
Time frame: Baseline up to week 48
Population: Participants with PGIC response at that time point
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 24 n=41 Very much improved | 5 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 24 n=41 Much improved | 20 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 24 n=41 Minimally improved | 9 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 24 n=41 No change | 6 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 24 n=41 Minimally worse | 1 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 24 n=41 Much worse | 0 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 24 n=41 Very much worse | 0 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 48 n=33 Very much improved | 5 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 48 n=33 Much improved | 15 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 48 n=33 Minimally improved | 9 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 48 n=33 No change | 4 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 48 n=33 Minimally worse | 0 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 48 n=33 Much worse | 0 Participants |
| All Subjects | Patient Global Impression of Change (PGIC) at Week 24 and Week 48 | Week 48 n=33 Very much worse | 0 Participants |
Secondary
Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48
Participants who achieved a ≤ 50% reduction in spleen length at week 24 and 48 (reduction) and participants who had no increase greater than or equal to 50% (increase). The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0.
Time frame: baseline, weeks 24 and 48
Population: Full analysis set n: participants with a value at both Baseline and that time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 ≤ -50% reduction n=43 | 65.1 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 -50%, -25% reduction n=43 | 11.6 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 -25%, -5% reduction n=43 | 9.3 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 -5%, 5% reduction, increase n=43 | 4.7 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 5%, 25% increase n=43 | 9.3 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 25%, 50% increase n=43 | 0 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 >50% increase n=43 | 0 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 remained non-palpable n=43 | 0 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 24 became palpable n=43 | 0 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 ≤ -50% reduction n=36 | 50.0 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 -50%, -25% reduction n=36 | 22.2 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 -25%, -5% reduction n=36 | 16.7 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 -5%, 5% reduction, increase n=36 | 5.6 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 5%, 25% increase n=36 | 2.8 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 25%, 50% increase n=36 | 2.8 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 >50% increase n=36 | 0 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 remained non-palpable n=36 | 0 percentage of participants |
| All Subjects | Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48 | Wk 48 became palpable n=36 | 0 percentage of participants |
Secondary
Percentage of Participants Transfusion Independency From Baseline up to Week 96
Percentage is based on number of subjects who are transfusion dependent at baseline. Transfusion dependence (TD) is defined as subjects receiving 6 or more units of transfusions 12 weeks prior to baseline. Transfusion independence (TI) rate is defined as subjects who are transfusion dependent at baseline and require no unit of transfusion for ≥ 12 weeks at any time during the study. Transfusion response rate is defined as subjects who are TD at baseline and have 5 or less units of transfusion for ≥ 12 weeks at any time during the study.
Time frame: Baseline up to week 96
Population: Number of participants that were transfusion dependent at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 24 transfusion independent rate | 0 percentage of participants |
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 24 transfusion responder rate | 44.4 percentage of participants |
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 48 transfusion independent rate | 0 percentage of participants |
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 48 transfusion responder rate | 66.7 percentage of participants |
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 72 transfusion independent rate | 0 percentage of participants |
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 72 transfusion responder rate | 66.7 percentage of participants |
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 96 transfusion independent rate | 0 percentage of participants |
| All Subjects | Percentage of Participants Transfusion Independency From Baseline up to Week 96 | Week 96 transfusion responder rate | 66.7 percentage of participants |
Secondary
Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 48
Percentage of participants achieving a 50% reduction in spleen length at week 48. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 48 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.
Time frame: Baseline up to week 48
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Subjects | Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 48 | 36.0 percentage of participants |
Secondary
Percentage of Participants With at Least a 50% Reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24
The MF-7 is a disease specific questionnaire comprised of 7 items that measures the severity of seven of the most prevalent associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. Each item was scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7 score is computed as the sum of the observed scores in the individual items to achieve a 0 to 70 score. There would be one recall period of 24 hours used in this questionnaire. A separate question on Inactivity was to be measured for severity of this symptom on a scale from 0 (absent) to 10 (worst imaginable). This would allow the computation of the MFSAF v2.0 questionnaire results, as 6 out of 7 items in the latter PRO are in overlap with MF7 (they also share same 0-10 range Likert scale and ascending order, absent to worst imaginable).
Time frame: Baseline and week 24
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Subjects | Percentage of Participants With at Least a 50% Reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24 | MF-7 Total Symptom score | 51.1 percentage of participants |
| All Subjects | Percentage of Participants With at Least a 50% Reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24 | Modified MFSAF v2.0 Total symptom score | 55.6 percentage of participants |