Phase 2 Study of Ruxolitinib Versus Anagrelide in Subjects With Essential Thrombocythemia Who Are Resistant to or Intolerant of Hydroxyurea (RESET-272)

Study Overview
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Brief Summary
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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.

Official Title
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A Double-Blind, Double-Dummy Phase 2 Randomized Study to Evaluate the Efficacy and Safety of Ruxolitinib Versus Anagrelide in Subjects With Essential Thrombocythemia Who Are Resistant to or Intolerant of Hydroxyurea (RESET-272)

Conditions
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MPN (Myeloproliferative Neoplasms)

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Anagrelide
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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). 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A : Ruxolitinib and anagrelide placebo<br>Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg. | Drug: Ruxolitinib<br>* Ruxolitinib administered orally twice daily (BID) at the protocol-defined starting dose.<br>* Other names: INCB018424;Drug: Placebo<br>* Anagrelide-placebo administered orally BID<br>|
| Active Comparator: Group B : Anagrelide and Ruxolitinib PLacebo<br>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. | Drug: Anagrelide<br>* Anagrelide administered orally at a starting dose of 1 mg BID.<br>Drug: Placebo<br>* Ruxolitinib-placebo administered orally BID.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline through the end of randomized period -up to 14 months per participant | 
| 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. | 32 weeks | 
| Time to Treatment Discontinuation | Defined as the time when treatment is discontinued | 98 weeks | 
| Duration of Response | Defined as measurement of response from the onset of response to the loss of response for responders. | 142 weeks | 
| 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. | Between 32 and 52 weeks | 
| 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. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ruxolitinib, Essential thrombocythemia, hydroxyurea-resistant, hydroxyurea-intolerant, anagrelide