Study to Determine the Safety and Efficacy of INCB018424 in Patients With Polycythemia Vera or Essential Thrombocythemia

Study Overview
=================
Brief Summary
-----------------
To evaluate the safety and efficacy profile of different treatment regimens of Ruxolitinib (INCB018424) administered to two groups of patients; those with polycythemia vera (PV) and those with essential thrombocythemia (ET). Patients in each group were refractory to hydroxyurea or for whom hydroxyurea is contraindicated.

Detailed Description
-----------------
The study consisted of a 2-stage design, which included a dose-ranging phase (during which patients received treatment at their randomized dose) and an expansion phase (after adjustment of dose/regimen to achieve an optimal balance of efficacy and safety). During the dose-ranging phase, patients in each disease group (PV or ET) were randomly assigned in a 1:1:1 ratio independent of each other to receive 1 of 3 treatment regimens with Ruxolitinib, 10 mg twice daily (bid), 25 mg bid, or 50 mg once daily (qd). After patients completed 2 cycles of treatment with Ruxolitinib at the randomized dose, Investigators were permitted to adjust the dose/regimen on an individual basis using their discretion in order to achieve an optimal balance of efficacy and safety. During the expansion phase (ie, after optimization of dose), additional patients with PV or ET were enrolled to receive Ruxolitinib at the dose that was selected upon review of data from the dose-ranging phase. Treatment continued until a patient met a withdrawal criterion, had intolerable toxicity, progression of disease, or withdrew consent.

Official Title
-----------------
A Phase 2, Open Label, Dose Regimen Ranging Clinical Study to Determine the Safety and Efficacy of INCB018424 in Patients With Advanced Polycythemia Vera or Essential Thrombocythemia Refractory to Hydroxyurea

Conditions
-----------------
Myeloproliferative Neoplasm (MPN)

Intervention / Treatment
-----------------
* Drug: Ruxolitinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of polycythemia vera or essential thrombocythemia as determined by treating physician Disease refractory to hydroxyurea or for whom treatment with hydroxyurea is contraindicated or have refused further treatment with hydroxyurea due to side effects. Patient meets baseline clinical lab parameters Exclusion Criteria: Treatment with interferon alpha or anagrelide within 7 days and hydroxyurea within 1 day of starting INCB018424. Patients diagnosed with another malignancy unless the malignancy was cervical intraepithelial neoplasia or basal or squamous cell skin cancer and the patient has been disease free for > 3 years Patients receiving therapy with intermediate or high dose steroids greater than the equivalent of 10 mg prednisone per day Clinically significant cardiac disease (New York Heart Association (NYHA) Class III or IV)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib 10 mg BID<br>Participants received 10 mg Ruxolitinib orally twice a day (BID) for 56 days (two 28-day cycles) during the dose-ranging phase. After patients completed 2 cycles of treatment at the randomized dose, Investigators were permitted to adjust the dose/regimen on an individual basis to achieve an optimal balance of efficacy and safety. Treatment continued until a patient met a withdrawal criterion, had intolerable toxicity, progression of disease, or withdrew consent. | Drug: Ruxolitinib<br>* Ruxolitinib was administered orally and supplied as 5 mg and 25 mg tablets.<br>* Other names: INCB018424;|
| Experimental: Ruxolitinib 25 mg BID<br>Participants received 25 mg Ruxolitinib orally twice a day (BID) for 56 days (two 28-day cycles) during the dose-ranging phase. After patients completed 2 cycles of treatment at the randomized dose, Investigators were permitted to adjust the dose/regimen on an individual basis to achieve an optimal balance of efficacy and safety. Treatment continued until a patient met a withdrawal criterion, had intolerable toxicity, progression of disease, or withdrew consent. | Drug: Ruxolitinib<br>* Ruxolitinib was administered orally and supplied as 5 mg and 25 mg tablets.<br>* Other names: INCB018424;|
| Experimental: Ruxolitinib 50 mg QD<br>Participants received 50 mg Ruxolitinib orally once a day (QD) for 56 days (two 28-day cycles) during the dose-ranging phase. After patients completed 2 cycles of treatment at the randomized dose, Investigators were permitted to adjust the dose/regimen on an individual basis to achieve an optimal balance of efficacy and safety. Treatment continued until a patient met a withdrawal criterion, had intolerable toxicity, progression of disease, or withdrew consent. | Drug: Ruxolitinib<br>* Ruxolitinib was administered orally and supplied as 5 mg and 25 mg tablets.<br>* Other names: INCB018424;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Polycythemia Vera Participants With a Confirmed Clinical Partial Response (PR) or Complete Response (CR) | For a confirmed response all criteria must have been sustained for at least 2 months. CR: Hematocrit < 45% in men and < 42% in women No phlebotomy for 1 month No palpable splenomegaly White blood cells < 10 x 10^9/L with normal differential and platelets < 400 x 10^9/L No sustained leucopenia or thrombocytopenia (>2 weeks) No systemic PV symptoms (pruritus, night sweats, bone pain, fever, weight loss) PR: Hematocrit < 45% in men and < 42% in women 50% reduction in phlebotomy requirements from 6 months before treatment started 50% reduction in palpable splenomegaly | Assessed after 2 cycles (56 days) of treatment on Day 1 of Cycle 3 | 
| Percentage of Essential Thrombocythemia (ET) Participants With a Confirmed Clinical Partial Response (PR) or Complete Response (CR) | For a confirmed response all criteria must have been sustained for at least 2 months. Complete Clinical Response: Platelet count < 400 x 10^9/L White blood cell count < 10 x 10^9/L with normal differential and Hematocrit ≤ upper limit of normal Absence of sustained (> 2 weeks) anemia or leucopenia based on institutional normal ranges Absence of systemic ET symptoms (pruritus, bone pain, weakness, night sweats, paresthesias) Absence of palpable splenomegaly Partial Clinical Response: Platelet count < 400 x 10^9/L 50% reduction in palpable splenomegaly | Assessed after 2 cycles (56 days) of treatment on Day 1 of Cycle 3. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Polycythemia Vera Participants Who Achieved Individual Components of Clinical Response at 12 Weeks | The individual components of clinical response included: Hematocrit (Hct) < 45% without phlebotomy Absence of palpable splenomegaly 50% reduction in spleen size Platelet count ≤ 400 x 10^9/L White blood cell (WBC) count ≤ 10 x 10^9/L | Baseline and Week 12 (Cycle 4, Day 1) | 
| Percentage of Polycythemia Vera Participants Who Achieved Individual Components of Clinical Response at 24 Weeks | The individual components of clinical response included: Hematocrit (Hct) < 45% without phlebotomy Absence of palpable splenomegaly 50% reduction in spleen size Platelet count ≤ 400 x 10^9/L White blood cell (WBC) count ≤ 10 x 10^9/L | Baseline and Week 24 (Cycle 7, Day 1) | 
| Percentage of Polycythemia Vera Participants Who Achieved Individual Components of Clinical Response at 36 Weeks | The individual components of clinical response included: Hematocrit (Hct) < 45% without phlebotomy Absence of palpable splenomegaly 50% reduction in spleen size Platelet count ≤ 400 x 10^9/L White blood cell (WBC) count ≤ 10 x 10^9/L | Baseline and Week 36 (Cycle 10, Day 1) | 
| Percentage of Essential Thrombocythemia Participants Who Achieved Individual Components of Clinical Response at 4 Weeks | The individual components of clinical response included: Platelet count ≤ 400 x 10^9/L White blood cell (WBC) count ≤ 10 x 10^9/L 50% reduction in spleen size Absence of palpable splenomegaly | Baseline and 4 weeks (Cycle 2, Day 1) | 
| Percentage of Essential Thrombocythemia Participants Who Achieved Individual Components of Clinical Response at 24 Weeks | The individual components of clinical response included: Platelet count ≤ 400 x 10^9/L White blood cell (WBC) count ≤ 10 x 10^9/L 50% reduction in spleen size Absence of palpable splenomegaly | Baseline and 24 weeks (Cycle 7, Day 1) | 
| Percentage of Essential Thrombocythemia Participants Who Achieved Individual Components of Clinical Response at 36 Weeks | The individual components of clinical response included: Platelet count ≤ 400 x 10^9/L White blood cell (WBC) count ≤ 10 x 10^9/L 50% reduction in spleen size Absence of palpable splenomegaly | Baseline and 36 weeks (Cycle 10, Day 1) | 
| Change From Baseline to Week 4 in Polycythemia Vera Symptoms | Patients were asked to rate their symptoms on a scale of 0 (none) to 10 (worse possible) for the prior week giving the worst level of symptoms experienced during the preceding 7 days. A negative change from baseline score indicates improvement in symptoms. For patients with Polycythemia Vera, queried symptoms included fever, itching/pruritus, bone pain and night sweats. | Baseline and Week 4 (Cycle 2, Day 1) | 
| Change From Baseline to Week 4 in Essential Thrombocythemia Symptoms | Patients were asked to rate their symptoms on a scale of 0 (none) to 10 (worse possible) for the prior week giving the worst level of symptoms experienced during the preceding 7 days. A negative change from baseline score indicates improvement in symptoms. For patients with essential thrombocythemia, queried symptoms included itching/pruritus, bone pain, night sweats, paresthesias (tingling or numbness), and weakness. | Baseline and Week 4 (Cycle 2, Day 1) | 
| Change From Baseline to Week 4 in Health-related Quality of Life | Health-related Quality of Life was assessed using the Global Health Status/Quality of Life Scale of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). This scale ranges from 0 to 100, with higher scores indicating higher quality of life. | Baseline and Week 4 (Cycle 2, Day 1) |