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

Primary Purpose

Polycythemia Vera (PV)

Status
Completed
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
P1101
Low-dose aspirin
Phlebotomy
Sponsored by
PharmaEssentia Japan K.K.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Polycythemia Vera (PV) focused on measuring Myeloproliferative Neoplasms

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male or female patients ≥20 years old
  2. Patients diagnosed with PV according to the WHO 2008 or WHO 2016 criteria
  3. 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
  4. Total HU treatment duration shorter than 3 years (cumulatively) at screening
  5. 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)
  6. 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
  7. Hemoglobin (HGB) ≥10 g/dL at screening
  8. Neutrophil count ≥1.5 x 10^9/L at screening
  9. Serum creatinine ≤1.5 x ULN at screening
  10. 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.).
  11. 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
  12. 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:

  1. Patients with symptomatic splenomegaly
  2. Previous use of IFNα for any indication
  3. Any contraindications or hypersensitivity to interferon-alfa
  4. Co-morbidity with severe or serious conditions which may impact patient participation in the study in investigator's opinion
  5. History of major organ transplantation
  6. Pregnant or lactating females
  7. 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

  8. Uncontrolled diabetes mellitus (HbA1c level of > 7% at baseline)
  9. History of any malignancy within for the past 5 years
  10. History of alcohol or drug abuse within the last year
  11. History or evidence of post polycythemia vera-myelofibrosis (PPV-MF), essential thrombocythemia, or any non-PV MPN
  12. Presence of circulating blasts in the peripheral blood within the last 3 months
  13. 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

Sites / Locations

  • Ehime University Hospital
  • Mie University Hospital
  • Osaka University Hospital
  • Juntendo University Hospital
  • NTT Medical Center Tokyo
  • Tokyo Medical University Hospital
  • Keio University Hospital
  • University of Yamanashi Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

P1101

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Changes in Hct from baseline
Hct will be recorded every 3 months.
Changes in WBC count from baseline
WBC count will be recorded every 3 months.
Changes in Plt count from baseline
Plt count will be recorded every 3 months.
Changes in spleen size from baseline
Spleen size will be recorded every 3 months.
Time to requiring no phlebotomy
Time to requiring no phlebotomy is recorded.
Time required to first response
Time required to first response is defined as time to achieve complete hematological response (CHR) without phlebotomy.
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.
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).
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.
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.

Full Information

First Posted
November 15, 2019
Last Updated
December 8, 2021
Sponsor
PharmaEssentia Japan K.K.
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1. Study Identification

Unique Protocol Identification Number
NCT04182100
Brief Title
Efficacy and Safety of P1101 in Polycythemia Vera Patients for Whom the Standard of Treatment is Difficult to Apply
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Completed
Study Start Date
December 20, 2019 (Actual)
Primary Completion Date
March 8, 2021 (Actual)
Study Completion Date
March 8, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
PharmaEssentia Japan K.K.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycythemia Vera (PV)
Keywords
Myeloproliferative Neoplasms

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
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)
Allocation
N/A
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
P1101
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
P1101
Other Intervention Name(s)
ropeginterferon alfa-2b
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Low-dose aspirin
Other Intervention Name(s)
Low-dose acetylsalicylic acid
Intervention Description
Low-dose aspirin (acetylsalicylic acid) (75-150 mg/day) will be given as background therapy during the 12 months of study treatment, unless contraindicated.
Intervention Type
Procedure
Intervention Name(s)
Phlebotomy
Intervention Description
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.
Primary Outcome Measure Information:
Title
Proportion of subjects achieving durable phlebotomy-free complete hematological response (CHR) at Month 12
Description
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
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Changes in Hct from baseline
Description
Hct will be recorded every 3 months.
Time Frame
Baseline, 3 months, 6 months, 9 months and 12 months
Title
Changes in WBC count from baseline
Description
WBC count will be recorded every 3 months.
Time Frame
Baseline, 3 months, 6 months, 9 months and 12 months
Title
Changes in Plt count from baseline
Description
Plt count will be recorded every 3 months.
Time Frame
Baseline, 3 months, 6 months, 9 months and 12 months
Title
Changes in spleen size from baseline
Description
Spleen size will be recorded every 3 months.
Time Frame
Baseline, 3 months, 6 months, 9 months and 12 months
Title
Time to requiring no phlebotomy
Description
Time to requiring no phlebotomy is recorded.
Time Frame
Up to 12 months
Title
Time required to first response
Description
Time required to first response is defined as time to achieve complete hematological response (CHR) without phlebotomy.
Time Frame
Up to 12 months
Title
Duration of response maintenance
Description
Duration of maintained complete hematologic response (CHR) since first achievement of CHR after administration of the study drug will be calculated.
Time Frame
Up to 12 months
Title
Proportion of subjects without thrombotic or hemorrhagic events
Description
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).
Time Frame
Up to 12 months
Title
Change of JAK2 mutant allelic burden over time vs. baseline
Description
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.
Time Frame
Baseline, 3 months, 6 months, 9 months and 12 months
Title
PK of P1101
Description
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.
Time Frame
Up to 12 months
Other Pre-specified Outcome Measures:
Title
Status of bone marrow histological remission (optional)
Description
Status of bone marrow histological remission defined as the disappearance of hypercellularity (age-adjusted), trilineage growth (panmyelosis) and absence of >grade 1 reticulin fibrosis
Time Frame
0 month, 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Ehime University Hospital
City
Toon-shi
State/Province
Ehime
ZIP/Postal Code
791-0295
Country
Japan
Facility Name
Mie University Hospital
City
Tsu-shi
State/Province
Mie
Country
Japan
Facility Name
Osaka University Hospital
City
Suita-shi
State/Province
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
Juntendo University Hospital
City
Bunkyo-ku
State/Province
Tokyo
ZIP/Postal Code
113-8431
Country
Japan
Facility Name
NTT Medical Center Tokyo
City
Shinagawa-ku
State/Province
Tokyo
ZIP/Postal Code
141-8625
Country
Japan
Facility Name
Tokyo Medical University Hospital
City
Shinjuku-ku
State/Province
Tokyo
ZIP/Postal Code
160-0023
Country
Japan
Facility Name
Keio University Hospital
City
Shinjuku-ku
State/Province
Tokyo
ZIP/Postal Code
160-8582
Country
Japan
Facility Name
University of Yamanashi Hospital
City
Chuo-shi
State/Province
Yamanashi
ZIP/Postal Code
409-3898
Country
Japan

12. IPD Sharing Statement

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

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