Efficacy and Safety of P1101 in Polycythemia Vera Patients for Whom the Standard of Treatment is Difficult to Apply

Study Overview
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Brief Summary
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This is a Phase 2 single arm study to investigate efficacy and safety of P1101 for adult Japanese patients with PV.

Detailed Description
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Eligible patients will be treated with P1101, starting at 100 μg (or 50 μg in patients under another cytoreductive therapy). The dose should be gradually increased by 50 μg every two weeks (in parallel, other cytoreductive therapy should be decreased gradually, as appropriate) until stabilization of the hematological parameters is achieved (hematocrit <45%, platelets <400 x 10^9/L and leukocytes <10 x 10^9/L). The maximum recommended single dose is 500 μg injected every two weeks. At week 36 (month 9) and week 52 (month 12), the primary study endpoint, phlebotomy-free CHR, will be analyzed. After completion of the 52-week study duration, provision and administration of P1101, collection of the long-term follow up information (blood parameters, molecular and cytogenetic data, safety parameters and as also the optional bone marrow data) will be continued until the drug becomes commercially available for all study subjects..

Official Title
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Phase 2 Single Arm Study of Efficacy and Safety of P1101 for Polycythemia Vera (PV) Patients for Whom the Current Standard of Treatment is Difficult to Apply

Conditions
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Polycythemia Vera (PV)

Intervention / Treatment
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* Drug: P1101
* Drug: Low-dose aspirin
* Procedure: Phlebotomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥20 years old Patients diagnosed with PV according to the WHO 2008 or WHO 2016 criteria PV patients for whom the current standard of treatment is difficult to apply. (Patients with a documented history of refractory to HU are excluded.) Younger patients (long-term treatment is anticipated) Patients who are categorized as low risk, but cytoreduction is recommended due to disease-related signs and symptoms (headache, dizziness, pruritus, night sweats, fatigue, erythromelalgia, vision disorders, scintillating scotoma, early satiety, abdominal distension). Patients with HU intolerance Total HU treatment duration shorter than 3 years (cumulatively) at screening For cytoreduction naïve patients only: PV in need of cytoreductive treatment, defined by fulfilling as one or more of the following criteria at baseline: at least one previous well documented major cardiovascular PV-related event in the medical history poor tolerance of phlebotomy (defined as a phlebotomy/ procedure-related adverse event causing significant adverse impact on the patient and limiting ability to apply phlebotomy with the intention to keep Hct <45%) frequent need of phlebotomy (more than one phlebotomy within last month prior entering the study) platelet counts greater than 1000 x 10^9/L (for two measurements within the month prior treatment start) leukocytosis (WBC>10 x 10^9/L for two measurements within the month prior treatment start) Adequate hepatic function defined as bilirubin ≤1.5 x upper limit normal (ULN), international normalized ratio (INR) ≤1.5 x ULN, albumin >3.5 g/dL, alanine aminotransferase (ALT) ≤2.0 x ULN, aspartate aminotransferase (AST) ≤2.0 x ULN at screening Hemoglobin (HGB) ≥10 g/dL at screening Neutrophil count ≥1.5 x 10^9/L at screening Serum creatinine ≤1.5 x ULN at screening Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales (Patients with a borderline of HADS score [score 7 but <10] or patients with necessity [expected benefits are higher than the risks] based on investigators' discretion are required to receive following assessment by psychiatric specialist to confirm the eligibility for IFNα therapy.). Males and females of childbearing potential, as well as all women <2 years after the onset of menopause, must agree to use an acceptable form of birth control until 28 days following the last dose of the study drug Written informed consent obtained from the patient or the patient's legal representative, and ability for the patient to comply with the requirements of the study Exclusion Criteria: Patients with symptomatic splenomegaly Previous use of IFNα for any indication Any contraindications or hypersensitivity to interferon-alfa Co-morbidity with severe or serious conditions which may impact patient participation in the study in investigator's opinion History of major organ transplantation Pregnant or lactating females Patients with any other medical conditions, which in the opinion of the Investigator would compromise the results of the study or may impair compliance with the requirements of the protocol 7-1. History or presence of thyroid dysfunction (clinical symptoms of hyper- or hypo-thyroidism) of the autoimmune origin, except late stages cases on the oral thyroid substitution therapy, where potential exacerbation under interferon therapy will not constitute any further harm to the patient 7-2.Documented autoimmune disease (e.g., hepatitis, idiopathic thrombocytopenic purpura [ITP], scleroderma, psoriasis, or any autoimmune arthritis) 7-3. Clinically relevant pulmonary infiltrates and pneumonitis at screening, patients with a history of interstitial pulmonary disease 7-4. Active infections with systemic manifestations (e.g., bacterial, fungal, hepatitis B [HBV], hepatitis C [HCV], or human immunodeficiency virus [HIV]) at screening) 7-5. Evidence of severe retinopathy (e.g., cytomegalovirus retinitis [CMV], macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension) based on the ophthalmological assessment by specialists. 7-6. Uncontrolled depression 7-7. Previous suicide attempts or at any risk of suicide at screening Uncontrolled diabetes mellitus (HbA1c level of > 7% at baseline) History of any malignancy within for the past 5 years History of alcohol or drug abuse within the last year History or evidence of post polycythemia vera-myelofibrosis (PPV-MF), essential thrombocythemia, or any non-PV MPN Presence of circulating blasts in the peripheral blood within the last 3 months Use of any investigational drug(s), or investigational drug combinations <4 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Interventional Model Description: Conventional treatment based on phlebotomies, low-dose aspirin (acetylsalicylic acid, 75-150 mg/day) plus the subcutaneous administration of P1101 (ropeginterferon alfa-2b) once every 2 weeks
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: P1101<br>Conventional treatment based on phlebotomies, low-dose aspirin (acetylsalicylic acid, 75-150 mg/day) plus the subcutaneous administration of pegylated proline-interferon alpha-2b (P1101, ropeginterferon alfa-2b) once every 2 weeks. | Drug: P1101<br>* P1101 (ropeginterferon alfa-2b) will be administered subcutaneously every 2 weeks at the starting dose of 100 μg every two weeks (or 50 μg in patients under another cytoreductive therapy). The dose should be gradually increased by 50 μg every two weeks (in parallel, other cytoreductive therapy should be decreased gradually, as appropriate) until stabilization of the hematological parameters is achieved (hematocrit <45%, platelets <400 x 10^9/L and leukocytes <10 x 10^9/L). The maximum recommended single dose is 500 μg injected every two weeks. The dose will be maintained at the highest level which can be tolerated and delivers best possible disease response.<br>* Other names: ropeginterferon alfa-2b;Drug: Low-dose aspirin<br>* Low-dose aspirin (acetylsalicylic acid) (75-150 mg/day) will be given as background therapy during the 12 months of study treatment, unless contraindicated.<br>* Other names: Low-dose acetylsalicylic acid;Procedure: Phlebotomy<br>* Phlebotomy is performed aiming at a hematocrit < 45%. When the hematocrit value is 45% or higher, phlebotomy is performed. The volume of phlebotomy per procedure should be 200 to 400 mL while monitoring the circulatory dynamics such as blood pressure and pulse. In the elderly and patients with cardiovascular disorders, a small volume (100-200 mL) should be considered to avoid rapid changes in hemodynamics.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving durable phlebotomy-free complete hematological response (CHR) at Month 12 | The primary efficacy outcome measure is the proportion of subjects achieving durable phlebotomy-free complete hematologic response (CHR) at Month 12. Durable phlebotomy-free CHR is defined as any subject achieving phlebotomy-free CHR at Month 9 and maintaining the response up to Month 12. A responder in sense of a primary outcome measure is a subject who has met all the following criteria at the time points: Hematocrit <45% phlebotomy-free (absence of phlebotomy during the previous 3 months) Platelet count ≤400 x 10^9/L, WBC count ≤10 x 10^9/L | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Hct from baseline | Hct will be recorded every 3 months. | Baseline, 3 months, 6 months, 9 months and 12 months | 
| Changes in WBC count from baseline | WBC count will be recorded every 3 months. | Baseline, 3 months, 6 months, 9 months and 12 months | 
| Changes in Plt count from baseline | Plt count will be recorded every 3 months. | Baseline, 3 months, 6 months, 9 months and 12 months | 
| Changes in spleen size from baseline | Spleen size will be recorded every 3 months. | Baseline, 3 months, 6 months, 9 months and 12 months | 
| Time to requiring no phlebotomy | Time to requiring no phlebotomy is recorded. | Up to 12 months | 
| Time required to first response | Time required to first response is defined as time to achieve complete hematological response (CHR) without phlebotomy. | Up to 12 months | 
| Duration of response maintenance | Duration of maintained complete hematologic response (CHR) since first achievement of CHR after administration of the study drug will be calculated. | Up to 12 months | 
| Proportion of subjects without thrombotic or hemorrhagic events | Thrombotic or hemorrhagic events will be recorded any time during the study. The proportion of subjects without thrombotic or hemorrhagic events is defined as the proportion of subjects experienced no thrombotic and hemorrhagic events during the study period (12 months). | Up to 12 months | 
| Change of JAK2 mutant allelic burden over time vs. baseline | Quantitative JAK2 measurements at screening, Months 3, 6, 9 and 12 (central laboratory) for subjects who signed consent form. Change of JAK2 allelic burden over time will be assessed. | Baseline, 3 months, 6 months, 9 months and 12 months | 
| PK of P1101 | Trough concentration is the measured concentration of a drug at the end of a dosing interval at steady state every 2 weeks. Additionally, serum concentration is measured at hours 0, 24, 48, 96 and 168 after administration at Week 0 and Week 28. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloproliferative Neoplasms