Post-Essential Thrombocythemia (ET) MF, Post-Polycythemia Vera (PV) MF, Primary Myelofibrosis (MF)
Conditions
Keywords
Primary Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, Post-Essential Thrombocythemia (ET) MF, post-PV MF, post-ET MF, INC424, Ruxolitinib, Myelofibrosis, MF
Brief summary
The objective of this study was to determine the efficacy of INC424 as assessed by reduction in spleen volume in patients with primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF. The safety and tolerability of INC424 and the effects of INC424 on patient reported outcomes and the duration of response as assessed by reduction in spleen volume was also assessed.
Interventions
DRUGRuxolitinib
INC424 Tablet for oral use, provided in 5 mg bottles. The dosage strength was 5 mg/tablet INC424 phosphate (free base equivalent).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. 18 years or older 2. Diagnosis of primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF 3. Enlarged spleen, measuring 5 cm or greater from the costal margin 4. Must have two or more of the following risk factors: 1. Over 65 years old 2. Have the following symptoms often associated with MF: loss of weight, fever, night sweats 3. Have a low red blood cell count (anemia - hemoglobin \< 10 g/dL) 4. Have a high white blood cell count (history of white blood cell count \> 25,000/uL) 5. Have high circulating blasts (\> or = 1%) as measured by blood tests 5. Should have circulating blasts \<10% (as measured by blood tests) 6. Should be capable of self-care 7. Should have adequate bone marrow reserve 8. Should not have the option of stem cell transplantation 9. Should discontinue any prior or ongoing treatment for myelofibrosis prior to entering the study 10. Had no prior treatment with another JAK inhibitor
Exclusion criteria
1. Does not have adequate liver or kidney function (as measured by blood tests) 2. Has an active infection (bacterial, viral, etc.) 3. Has active hepatitis A, B, or C or positive for HIV 4. Has another cancer that needs active intervention 5. Had a history of bleeding disorder 6. Had a history of very low platelet counts (as measured by blood tests) not related to treatment of MF 7. Had radiation of the spleen within 1 year of joining the study 8. Does not have adequate heart function 9. Sufficient time has elapsed between stopping previous treatment for MF and joining the study 10. Females who are pregnant or breast-feeding 11. Not able to sign informed consent 12. Has any other active medical conditions that the doctor deems may compromise your safety or ability to join in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24 | 24 weeks | The primary measure of spleen size was by MRI. MRIs were performed with a body coil because the objective was to measure organ volume only, not to assess for lesions. MRIs were performed by local radiologists who were instructed not to provide a quantitative measure of spleen volume, but could provide a qualitative assessment such as enlarged, smaller, larger, etc. The scans from an individual patient were to be read by a central reader upon transfer from the site radiologist. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Weeks 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, at any time point | The best response rate was defined as the proportion of patients achieving a ≥ 35% reduction in spleen volume from baseline at any post-baseline assessment. The best response rate was estimated with an associated 95% confidence interval. |
| Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | Weeks 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 | For patients who had at least one ≥ 35% reduction in spleen volume from baseline at postbaseline, the duration of response was calculated. The start date of the duration was defined as the first spleen volume measurement that was ≥ 35% reduction from baseline, and the end date of the response duration was defined as the earliest of the following: death, A ≥ 25% increase in spleen volume by MRI (or CT in applicable patients) compared to baseline, Splenic irradiation, Leukemic transformation as defined by a bone marrow or a peripheral blood blast count of ≥ 20%, Splenectomy. Duration of response is calculated only for participants who achieved at least one measured \>= 35% reduction in spleen volume at any time. |
| Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Baseline, Week 24 | Patient reported outcomes regarding the impact of MF on patients were assessed using the EORTC QLQ-C30. Data from the EORTC QLQ-C30 questionnaire was analyzed using the standardized scores. There were 2 categories to this scale: Functional/QOL scale and Symptom and Other items scale. For each sub-scale, the raw scores were standardized in order to obtain scores ranging from 0 to 100. For Functional/QOL subscales: a higher score represents a higher/better level of functioning. For Symptoms and Other items subscales: a higher score represents worse level of symptoms. The absolute change from baseline was calculated for each scale and summarized descriptively by scheduled visit. |
| Change in Total Symptom Score From Baseline at Week 24 as Measured by Seven-day Modified MFSAF v2.0 | Baseline, Week 24 | The Seven-day modified MFSAF v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. Symptoms of myelofibrosis (MF) were assessed using this instrument & included filling up quickly/early satiety, abdominal discomfort, pain under the ribs, night sweats, itching, bone/muscle pain & inactivity. The first 6 items assessed MF symptom severity at its worst as recalled & the seventh captured MF-related inactivity in the 7 days prior to the clinic visit assessment. All 7 items asked subjects to record their answers on an 11-point numeric rating scale (NRS) (0=Absent, 10=Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score, defined as the sum of the 6 individual symptom scores other than the inactivity score (each with 0-10 point scale) collected on the same week. The total symptom scale ranges from 0 -60 where higher score indicates a worse level of the condition. |
Countries
China, Japan, South Korea, Taiwan
Participant flow
Recruitment details
A total of 110 patients were planned, 120 patients were enrolled and analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Ruxolitinib Ruxolitinib was taken twice daily, unless instructed. Starting dose 15 mg BID for patients with baseline platelet count of 100,000/μL to 200,000/μL (inclusive) or 20 mg BID for those with baseline platelet count \>200,000/μL (approximately 12 hours apart: morning and night), increased or decreased per standardized dosing paradigm. | 120 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 24 |
| Overall Study | Death | 7 |
| Overall Study | Disease progression | 30 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Ruxolitinib |
|---|---|
| Age, Continuous | 59.0 Years STANDARD_DEVIATION 12.25 |
| Race/Ethnicity, Customized Chinese | 63 Participants |
| Race/Ethnicity, Customized Japanese | 30 Participants |
| Race/Ethnicity, Customized Korean | 17 Participants |
| Race/Ethnicity, Customized Taiwanese | 10 Participants |
| Sex: Female, Male Female | 62 Participants |
| Sex: Female, Male Male | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 120 |
| other Total, other adverse events | 117 / 120 |
| serious Total, serious adverse events | 60 / 120 |
Outcome results
Primary
Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24
The primary measure of spleen size was by MRI. MRIs were performed with a body coil because the objective was to measure organ volume only, not to assess for lesions. MRIs were performed by local radiologists who were instructed not to provide a quantitative measure of spleen volume, but could provide a qualitative assessment such as enlarged, smaller, larger, etc. The scans from an individual patient were to be read by a central reader upon transfer from the site radiologist.
Time frame: 24 weeks
Population: Full Analysis Set (FAS): comprised of all patients who received at least one dose of ruxolitinib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24 | 38 Participants |
p-value: 0.0007single-sample biniminal test
Secondary
Change in EORTC QLQ-C30 Scores From Baseline in at Week 24
Patient reported outcomes regarding the impact of MF on patients were assessed using the EORTC QLQ-C30. Data from the EORTC QLQ-C30 questionnaire was analyzed using the standardized scores. There were 2 categories to this scale: Functional/QOL scale and Symptom and Other items scale. For each sub-scale, the raw scores were standardized in order to obtain scores ranging from 0 to 100. For Functional/QOL subscales: a higher score represents a higher/better level of functioning. For Symptoms and Other items subscales: a higher score represents worse level of symptoms. The absolute change from baseline was calculated for each scale and summarized descriptively by scheduled visit.
Time frame: Baseline, Week 24
Population: Full Analysis Set (FAS): comprised of all patients who received at least one dose of ruxolitinib.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom and Other items: Insomnia | -2.0 scores on a scale | Standard Deviation 30.12 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Func./QOL scales: Global Health Status/QOL | 5.2 scores on a scale | Standard Deviation 22.04 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Func./QOL scales: Physical Functioning | 0.6 scores on a scale | Standard Deviation 14.7 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Func./QOL scales:Role Functioning | -0.2 scores on a scale | Standard Deviation 21.54 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Func./QOL scales: Emotional Functioning | 1.9 scores on a scale | Standard Deviation 14.14 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Func./QOL scales: Cognitive Functioning | -4.0 scores on a scale | Standard Deviation 18.43 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Func./QOL scales: Social Functioning | 0.2 scores on a scale | Standard Deviation 21.41 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom and Other items: Fatigue | -1.3 scores on a scale | Standard Deviation 20.32 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom & Other items: Nausea and Vomiting | 0.0 scores on a scale | Standard Deviation 9.43 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom and Other items: Pain | -1.8 scores on a scale | Standard Deviation 18.99 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom and Other items: Dyspnea | 2.3 scores on a scale | Standard Deviation 25.93 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom and Other items: Appetite Loss | -6.3 scores on a scale | Standard Deviation 25.26 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom and Other items: Constipation | 4.6 scores on a scale | Standard Deviation 20.02 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom and Other items: Diarrhea | 1.7 scores on a scale | Standard Deviation 23.75 |
| Ruxolitinib | Change in EORTC QLQ-C30 Scores From Baseline in at Week 24 | Symptom & Other items: Fin. difficulties | -2.0 scores on a scale | Standard Deviation 23.49 |
Secondary
Change in Total Symptom Score From Baseline at Week 24 as Measured by Seven-day Modified MFSAF v2.0
The Seven-day modified MFSAF v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. Symptoms of myelofibrosis (MF) were assessed using this instrument & included filling up quickly/early satiety, abdominal discomfort, pain under the ribs, night sweats, itching, bone/muscle pain & inactivity. The first 6 items assessed MF symptom severity at its worst as recalled & the seventh captured MF-related inactivity in the 7 days prior to the clinic visit assessment. All 7 items asked subjects to record their answers on an 11-point numeric rating scale (NRS) (0=Absent, 10=Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score, defined as the sum of the 6 individual symptom scores other than the inactivity score (each with 0-10 point scale) collected on the same week. The total symptom scale ranges from 0 -60 where higher score indicates a worse level of the condition.
Time frame: Baseline, Week 24
Population: Full Analysis Set (FAS): comprised of all patients who received at least one dose of ruxolitinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib | Change in Total Symptom Score From Baseline at Week 24 as Measured by Seven-day Modified MFSAF v2.0 | -5.0 scores on a scale |
Secondary
Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates
For patients who had at least one ≥ 35% reduction in spleen volume from baseline at postbaseline, the duration of response was calculated. The start date of the duration was defined as the first spleen volume measurement that was ≥ 35% reduction from baseline, and the end date of the response duration was defined as the earliest of the following: death, A ≥ 25% increase in spleen volume by MRI (or CT in applicable patients) compared to baseline, Splenic irradiation, Leukemic transformation as defined by a bone marrow or a peripheral blood blast count of ≥ 20%, Splenectomy. Duration of response is calculated only for participants who achieved at least one measured \>= 35% reduction in spleen volume at any time.
Time frame: Weeks 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240
Population: Full Analysis Set (FAS): comprised of all patients who received at least one dose of ruxolitinib.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 12 weeks | 1.00 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 24 weeks | 0.96 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 36 weeks | 0.96 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 48 weeks | 0.93 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 60 weeks | 0.93 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 72 weeks | 0.91 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 84 weeks | 0.89 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 96 weeks | 0.89 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 120 weeks | 0.89 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 144 weeks | 0.85 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 168 weeks | 0.79 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 192 weeks | 0.75 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 216 weeks | 0.75 weeks |
| Ruxolitinib | Kaplan Meier Estimates of Duration of Response of at Least ≥ 35% Reduction From Baseline in Spleen Volume Per Kaplan Meier Estimates | 240 weeks | NA weeks |
Secondary
Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response
The best response rate was defined as the proportion of patients achieving a ≥ 35% reduction in spleen volume from baseline at any post-baseline assessment. The best response rate was estimated with an associated 95% confidence interval.
Time frame: Weeks 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, at any time point
Population: Full Analysis Set (FAS): comprised of all patients who received at least one dose of ruxolitinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 240 | 47.5 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 24 | 35.8 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 36 | 40.0 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 48 | 44.2 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 72 | 44.2 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 96 | 45.8 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 120 | 45.8 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 144 | 46.7 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 168 | 47.5 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 192 | 47.5 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | Week 216 | 47.5 Percentage of participants |
| Ruxolitinib | Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Each Scheduled Time Point - Best Response | at any time point | 47.5 Percentage of participants |