Clinical trial NCT04182100: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Polycythemia Vera (PV)
Keywords: Myeloproliferative Neoplasms
Lead sponsor: PharmaEssentia Japan K.K.
Sponsor class: INDUSTRY
First posted: 2019-12-02
Enrollment: 29
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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
Primary purpose: TREATMENT

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..

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of subjects achieving durable phlebotomy-free complete hematological response (CHR) at Month 12
timeFrame: 12 months
Secondary outcomes:
measure: Changes in Hct from baseline
timeFrame: Baseline, 3 months, 6 months, 9 months and 12 months
measure: Changes in WBC count from baseline
timeFrame: Baseline, 3 months, 6 months, 9 months and 12 months
measure: Changes in Plt count from baseline
timeFrame: Baseline, 3 months, 6 months, 9 months and 12 months
measure: Changes in spleen size from baseline
timeFrame: Baseline, 3 months, 6 months, 9 months and 12 months
measure: Time to requiring no phlebotomy
timeFrame: Up to 12 months
measure: Time required to first response
timeFrame: Up to 12 months
measure: Duration of response maintenance
timeFrame: Up to 12 months
measure: Proportion of subjects without thrombotic or hemorrhagic events
timeFrame: Up to 12 months
measure: Change of JAK2 mutant allelic burden over time vs. baseline
timeFrame: Baseline, 3 months, 6 months, 9 months and 12 months
measure: PK of P1101
timeFrame: Up to 12 months
Other outcomes:
measure: Status of bone marrow histological remission (optional)
timeFrame: 0 month, 12 months
Locations:
city: Toon-shi
country: Japan
facility: Ehime University Hospital
state: Ehime
city: Tsu-shi
country: Japan
facility: Mie University Hospital
state: Mie
city: Suita-shi
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: NTT Medical Center Tokyo
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Tokyo Medical University Hospital
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: Chuo-shi
country: Japan
facility: University of Yamanashi Hospital
state: Yamanashi
Study officials:
References: