A Phase 3, Open-Label, Multicenter, Randomized, Active-controlled Study to Assess Pharmacokinetics and Compare the Efficacy, Safety, and Tolerability of P1101 vs Anagrelide as Second Line Therapy for Essential Thrombocythemia
Ropeginterferon Alfa-2b (P1101) vs. Anagrelide in Essential Thrombocythemia Patients With Hydroxyurea Resistance or Intolerance
Kawase Hiroaki
PharmaEssentia Japan K.K.
Akasaka Center Bldg. 12F, 1-3-13 Moto-akasaka, Minato, Tokyo
+81-3-6910-5103
hiroaki_kawase@pharmaessentia.com
Kawase Hiroaki
PharmaEssentia Japan K.K.
Akasaka Center Bldg. 12F, 1-3-13 Moto-akasaka, Minato, Tokyo
+81-3-6910-5103
hiroaki_kawase@pharmaessentia.com
recruiting
July. 01, 2020
160
Interventional
This is a Phase 3, open-label, multicenter, randomized, active controlled study to assess PK and to compare the efficacy, safety and tolerability of P1101 compared with ANA afler12 months of treatment for subjects with ET who have shown resistance or intolerance to hydroxyurea (HU). Total duration is approximately 14 months, with a screening period of28 days, a treatment period of 12 months, and a follow-up period of 28 days. Subject visits will be scheduled every 2 weeks in both treatment arms. A safety follow-up visit or end of study (EoS) visit will take place 28 days after the end of treatment (EoT)visit.
There may be a post-study care opportunity for study subjects who benefit from P1101 therapy.
treatment purpose
3
1. Male or female subjects greater than or equal to 18 years old
2. Subjects diagnosed with high-risk ET (either older than 60 years and JAK2V617-positive at screening, or having disease-related thrombosis or hemorrhage in the past), diagnosed according to the World Health Organization
(WHO) 2016 criteria
3. Subjects have received prior HU for ET, while the washout between the last dose of HU and the screening visit should not be shorter than 14 days
4. Interferon treatment-naive
5. Documented resistance/intolerance to prior HU for ET, as defined by ELN criteria (Barosi, et al, 2007), whereby at least one of the following criteria is met:
- Platelet count greater than 600,000/microliter at greater than or equal to 2 g/day (or greater than or equal to 2.5 g/day if subject body weight greater than 80 kg) or maximally tolerated dose if less than 2 g/day after at least 3 months of HU, or
- Platelet count greater than 400,000/microliter and WBC count less than 2,500/microliter at any dose and any duration of HU, or
- Platelet count greater than 400,000/microliter and hemoglobin (HGB) less than 10 g/dL at any dose and any duration of HU, or
- Presence of HU-related toxicities at any dose and any duration of therapy (e.g., leg ulcers, mucocutaneous manifestations, pneumonitis, or HU-related fever)
6. Platelets greater than 450,000/microliter at screening
7. WBC greater than 10,000/microliter at screening
8. HGB greater than or equal to 11 g/dL at screening for males and 10 g/dL at screening for females
9. Neutrophil count greater than or equal to 1,000/microliter at screening
10. Adequate hepatic function defined as bilirubin less than or equal to 1.5 x upper limit normal (ULN), international normalized ratio less than or equal to 1.5 x ULN, albumin greater than 3.5 g/dL, alanine aminotransferase less than or equal to 2.0 x ULN, aspartate aminotransferase less than or equal to 2.0 x ULN at screening
11. Creatinine clearance greater than or equal to 40 mL/min (by Cockcroft-Gault equation)
12. Males and females of childbearing potential, as well as all women less than 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, and females must agree to not breastfeed during the study
13. Written informed consent obtained from the subject and ability for the subject to comply with the requirements of the study
1. Any subject requiring a legally authorized representative
2. Any contraindications or hypersensitivity to IFN-alpha or ANA and their excipients
3. Known risk factors for QT-prolongation (e.g., congenital long QT, known history of acquired QT-prolongations)
4. Co-morbidity with severe or serious condition that, in the Investigator's opinion, would jeopardize the safety of the subject or their compliance with the protocol, including significant cardiac disease (including New York Heart Association Class III-IV congestive heart failure and clinically significant arrhythmias) and pulmonary hypertension
5. History of major organ transplantation
6. Pregnant or lactating females
7. Subjects with any other significant medical conditions that, in the opinion of the Investigator, would compromise the results of the study or may impair compliance with the requirements of the protocol, including but not limited to:
7-a) Documented autoimmune disease at screening or in the history (e.g., thyroid dysfunction, hepatitis, idiopathic thrombocytopenic purpura, scleroderma, psoriasis, or any arthritis of autoimmune origin)
7-b) Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening that, in the Investigator's opinion, would jeopardize the safety of the subject or their compliance with the protocol
7-c) Infections with systemic manifestations (e.g., bacterial, fungal, or human immunodeficiency virus [HIV], except hepatitis B [HBV] and/or hepatitis C [HCV], at screening)
7-d) Evidence of severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension)
7-e) History or presence of clinically relevant depression
7-f) Previous suicide attempts or at any risk of suicide at screening, in the judgement of the Investigator
7-g) History or presence of clinically significant neurologic diseases
7-h) History of any malignancy within 5 years (except Stage 0 chronic lymphocytic leukemia, basal cell, squamous cell, and superficial melanoma)
7-i) History of alcohol or drug abuse within the last year
7-j) History or evidence of any other (than ET) MPN
8. Use of any investigational drug shorter than 4 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent
9. Subjects with documented ANA resistance or intolerance.
18age old over
No limit
Both
Essential Thrombocythemia
investigational material(s)
Generic name etc : P1101 (Ropeginterferon alfa-2b)
INN of investigational material : Ropeginterferon alfa-2b
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : P1101 will be administered subcutaneously (SC) every 2 weeks at the starting dose of 250 micro-grams (Week 0) 350 micro-grams (Week 2) and target optimal dose of 500 micro-grams (Week 4) and then remain fixed for the treatment period.
Dose adjustment to prior dose will be allowed if triggered by safety or tolerability.
control material(s)
Generic name etc : Anagrelide Hydrochloride Hydrate
INN of investigational material : Anagrelide
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : The starting dose will be according to the local country product label and treatment practices.
efficacy
confirmatory
European Leukemia Net (ELN) Criteria will be employed to assess the response, defined as:
- peripheral blood count remission (platelets less than or equal to 400,000/microliter AND white blood cells (WBC) less than 9,500/microliter), AND
- improvement or non-progression in disease-related signs (splenomegaly),* AND
- large symptoms improvement based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)^, AND
- absence of hemorrhagic or thrombotic events
*Improvement in disease signs is possible only in subjects with palpable splenomegaly at baseline. Improvement requires resolution of palpable splenomegaly, meaning no palpable splenomegaly. For other subjects (i.e. in subjects without palpable splenomegaly at baseline), the item of improvement is not applicable (NA), thus not a requirement. Non progression in disease signs is possible only in subjects with no palpable splenomegaly at baseline. Non-progression requires lack of palpable splenomegaly. For other subjects, this item is NA, and thus not a requirement.
^ Large symptom improvement for essential thrombocythemia (ET) subjects is defined as follows:
- Baseline TSS scores Greater than or equal to 20: 10-points reduction in TSS score
- Baseline TSS scores 15-19, inclusive: 5-points reduction in TSS score
- Baseline TSS scores 10-14, inclusive: TSS score decreases to less than or equal to 10
- Baseline TSS score less than 10: TSS score stays less than 10
The primary endpoint is the durable response at both Months 9 and 12.
safety
efficacy
confirmatory
- Durable response at Months 3 and 6
- Longitudinal rate of change in the ELN response rates over the 12 months
- Response rates based on peripheral blood count remission, no signs of progressive disease, and absence of any hemorrhagic or thrombotic events at 3, 6, 9, and 12 months
- Occurrence of thromboembolic events
- Time to first peripheral blood count remission response
- Duration of peripheral blood count remission response
- Symptomatic improvement assessed by the EuroQOL 5 dimensions 3-level version (EQ-5D-3L) questionnaire
- Symptomatic improvement assessed by the 10-item MPN-SAF TSS
- Change of CALR, MPL, and JAK-2 allelic burden over time
- Spleen size assessment
efficacy
exploratory
Bone marrow histological remission defined as the disappearance of megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis
safety
- Adverse events (AEs), according to Common Terminology Criteria for Adverse Events (CTCAE version 5.0)
- AEs of special interest (AESIs; e.g., cardiovascular events, hemorrhagic, thrombotic events, psychiatric events)
- Vital signs, clinical laboratory tests, physical examinations, electrocardiograms (ECGs), heart echocardiogram (ECHO), lung X-rays, bone marrow biopsy, Eastern Cooperative Oncology Group (ECOG) performance status, and ocular examinations
pharmacokinetics
pharmacodynamics
PK parameters of P1101, including (but not limited to) Cmin, Tmax, Cmax, and AUC will be derived using PPK analysis and the relationship between exposure and efficacy and safety endpoints will be examined using E-R analysis.
safety
Proportion of subjects who are ADA positive and negative will be determined.
PharmaEssentia Corporation
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Institutional Review Board of Juntendo University Hospital
