MPN (Myeloproliferative Neoplasms)
Conditions
Keywords
Essential thrombocythemia, hydroxyurea-resistant, hydroxyurea-intolerant, ruxolitinib, anagrelide
Brief summary
The purpose of this study is to evaluate the efficacy and safety of ruxolitinib versus anagrelide in subjects with essential thrombocythemia who are resistant to or intolerant of hydroxyurea.
Interventions
DRUGRuxolitinib
Ruxolitinib administered orally twice daily (BID) at the protocol-defined starting dose.
DRUGAnagrelide
Anagrelide administered orally at a starting dose of 1 mg BID.
DRUGPlacebo
Anagrelide-placebo administered orally BID
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of essential thrombocythemia according to revised World Health Organization (WHO) 2016 criteria. * Resistant to or intolerant of hydroxyurea, that is, fulfilling at least 1 of the following criteria: * Platelet count \> 600 × 10\^9/L after 3 months of at least 2 g/day of hydroxyurea (2.5 g/day in subjects with a body weight over 80 kg) OR at the subject's maximally tolerated dose if that dose is \< 2 g/day. * Platelet count \> 400 × 10\^9/L and WBC count \< 2.5 × 10\^9/L or hemoglobin \< 10 g/dL at any dose of hydroxyurea. * Presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of hydroxyurea. * Hydroxyurea-related fever. * Platelet count ≥ 650 × 10\^9/L at screening. * WBC ≥ 11.0 × 10\^9/L at screening.
Exclusion criteria
* Subjects previously treated with anagrelide or Hydroxyurea (HU). 1. Prior anagrelide use is allowed provided the reason for discontinuation is not AE-related and anagrelide is stopped at least 28 days before the start of study medications (ie, Day 1). 2. Treatment with HU can be stopped at any time once one of the inclusion criteria for HU refractoriness or resistance have been met, and up to the day before the first dose of study treatment (ie, Day 1). * Inadequate liver function at screening and Day 1 (before drug administration) as demonstrated by: * Total bilirubin \> 1.5 × upper limit of normal (ULN) * Aspartate aminotransferase or alanine aminotransferase \> 1.5 × ULN * Hepatocellular disease (eg, cirrhosis) * Inadequate renal function at screening as demonstrated by creatinine clearance \< 40 mL/min calculated by Cockcroft-Gault equation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Who Achieve Platelet and White Blood Cell (WBC) Control | 52 weeks | Defined as proportion of subjects who achieve a simultaneous reduction of platelet counts to \< 600 × 10\^9/L with a reduction of WBC counts to \< 10 × 10\^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Who Achieve Complete Remission or Partial Remission | 32 weeks | Defined as proportion of subjects who achieve CR or PR at Week 32 based on European LeukemiaNet (ELN) 2013 response criteria. Per ELN criteria: Complete Remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease and bone marrow histological remission including disappearance of megakaryocyte hyperplasia and absence of reticulin fibrosis \>Grade 1. Partial remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease, persistance of megakaryocyte hyperplasia. No response: any response that does not satisfy partial remission. Progressive Disease: transformation in PET-MF, MDS or acute leukemia. |
| Time to Treatment Discontinuation | 98 weeks | Defined as the time when treatment is discontinued |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline through the end of randomized period -up to 14 months per participant | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. |
| Proportion of Subjects Who Achieve Reduction of Platelet Counts to < 600 × 10^9/L | Between 32 and 52 weeks | Defined as Proportion of subjects who achieve reduction of platelet counts to \< 600 × 10\^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52. |
| Proportion of Subjects Who Achieve a Reduction of WBC Counts to < 10 × 109/L | 52 weeks | Defined as Proportion of subjects who achieve a reduction of WBC counts to \< 10 × 109/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52. |
| Duration of Response | 142 weeks | Defined as measurement of response from the onset of response to the loss of response for responders. |
Countries
United States
Participant flow
Recruitment details
Approximately 120 participants were planned for enrollment and 12 participants were enrolled (6 in the ruxolitinib group and 6 in the anagrelide group). The first participant was dosed on 14 Nov 2017 and Last participant completed study on 03 Aug 2020
Pre-assignment details
Twelve participants were enrolled and randomized. One participant in the ruxolitinib group was enrolled in error and withdrawn from the study before receiving any dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Group A : Ruxolitinib and Anagrelide Placebo Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg. | 6 |
| Group B : Anagrelide and Ruxolitinib Placebo Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Study Terminated by Sponsor | 2 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Group A : Ruxolitinib and Anagrelide Placebo | Group B : Anagrelide and Ruxolitinib Placebo | Total |
|---|---|---|---|
| Age, Continuous | 71.8 years STANDARD_DEVIATION 13.04 | 61.2 years STANDARD_DEVIATION 16.77 | 66.5 years STANDARD_DEVIATION 15.37 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White/Caucasian | 5 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 6 |
| other Total, other adverse events | 5 / 5 | 4 / 6 |
| serious Total, serious adverse events | 0 / 5 | 1 / 6 |
Outcome results
Primary
Proportion of Subjects Who Achieve Platelet and White Blood Cell (WBC) Control
Defined as proportion of subjects who achieve a simultaneous reduction of platelet counts to \< 600 × 10\^9/L with a reduction of WBC counts to \< 10 × 10\^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.
Time frame: 52 weeks
Population: The intent-to-treat (ITT) population will include subjects randomized in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A : Ruxolitinib and Anagrelide Placebo | Proportion of Subjects Who Achieve Platelet and White Blood Cell (WBC) Control | 0 proportion of participants |
| Group B : Anagrelide and Ruxolitinib PLacebo | Proportion of Subjects Who Achieve Platelet and White Blood Cell (WBC) Control | 0.17 proportion of participants |
Secondary
Duration of Response
Defined as measurement of response from the onset of response to the loss of response for responders.
Time frame: 142 weeks
Population: The intent-to-treat (ITT) population who are responders
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group B : Anagrelide and Ruxolitinib PLacebo | Duration of Response | 442 Days |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment.
Time frame: Baseline through the end of randomized period -up to 14 months per participant
Population: The safety population includes all randomized subjects who received at least 1 dose of study drug. AE has been summarized only in randomized period. End of randomized period is defined as the earliest of discontinuation or the individual unblinding date.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A : Ruxolitinib and Anagrelide Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 5 participants |
| Group B : Anagrelide and Ruxolitinib PLacebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 4 participants |
Secondary
Proportion of Subjects Who Achieve a Reduction of WBC Counts to < 10 × 109/L
Defined as Proportion of subjects who achieve a reduction of WBC counts to \< 10 × 109/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.
Time frame: 52 weeks
Population: The intent-to-treat (ITT) population will include subjects randomized in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A : Ruxolitinib and Anagrelide Placebo | Proportion of Subjects Who Achieve a Reduction of WBC Counts to < 10 × 109/L | 0 Proportion of participants |
| Group B : Anagrelide and Ruxolitinib PLacebo | Proportion of Subjects Who Achieve a Reduction of WBC Counts to < 10 × 109/L | 0.33 Proportion of participants |
Secondary
Proportion of Subjects Who Achieve Complete Remission or Partial Remission
Defined as proportion of subjects who achieve CR or PR at Week 32 based on European LeukemiaNet (ELN) 2013 response criteria. Per ELN criteria: Complete Remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease and bone marrow histological remission including disappearance of megakaryocyte hyperplasia and absence of reticulin fibrosis \>Grade 1. Partial remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease, persistance of megakaryocyte hyperplasia. No response: any response that does not satisfy partial remission. Progressive Disease: transformation in PET-MF, MDS or acute leukemia.
Time frame: 32 weeks
Population: The intent-to-treat (ITT) population will include subjects randomized in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A : Ruxolitinib and Anagrelide Placebo | Proportion of Subjects Who Achieve Complete Remission or Partial Remission | 0 proportion of participants |
| Group B : Anagrelide and Ruxolitinib PLacebo | Proportion of Subjects Who Achieve Complete Remission or Partial Remission | 0.17 proportion of participants |
Secondary
Proportion of Subjects Who Achieve Reduction of Platelet Counts to < 600 × 10^9/L
Defined as Proportion of subjects who achieve reduction of platelet counts to \< 600 × 10\^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.
Time frame: Between 32 and 52 weeks
Population: The intent-to-treat (ITT) population will include subjects randomized in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A : Ruxolitinib and Anagrelide Placebo | Proportion of Subjects Who Achieve Reduction of Platelet Counts to < 600 × 10^9/L | 0 Proportion of participants |
| Group B : Anagrelide and Ruxolitinib PLacebo | Proportion of Subjects Who Achieve Reduction of Platelet Counts to < 600 × 10^9/L | 0.50 Proportion of participants |
Secondary
Time to Treatment Discontinuation
Defined as the time when treatment is discontinued
Time frame: 98 weeks
Population: The intent-to-treat (ITT) population will include subjects randomized in the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A : Ruxolitinib and Anagrelide Placebo | Time to Treatment Discontinuation | 261.2 Days | Standard Deviation 238.85 |
| Group B : Anagrelide and Ruxolitinib PLacebo | Time to Treatment Discontinuation | 437.2 Days | Standard Deviation 183.99 |