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Ropeginterferon Alfa-2b (P1101) vs. Anagrelide in Essential Thrombocythemia Patients With Hydroxyurea Resistance or Intolerance (SURPASS ET)

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ClinicalTrials.gov Identifier: NCT04285086
Recruitment Status : Recruiting
First Posted : February 26, 2020
Last Update Posted : October 11, 2021
Sponsor:
Collaborators:
Medpace, Inc.
EPS International
Brightech International
Information provided by (Responsible Party):
PharmaEssentia

Brief Summary:
This is a Phase 3 open-label, multicenter, randomized, active-controlled study designed to compare the efficacy and safety and tolerability of P1101 compared with ANA after 12 months of treatment as second-line therapy for subjects with ET who have had a suboptimal or failed response to HU.

Condition or disease Intervention/treatment Phase
Essential Thrombocythemia Biological: Ropeginterferon alfa-2b Phase 3

Detailed Description:

PharmaEssentia Corporation is developing a pegylated (PEG) IFN-α product, P1101, for the treatment of ET.

Available clinical data and experience with P1101 in PV shows that the compound, with proper dose modifications, is effective in controlling disease in a significant proportion of subjects with ET. Further, its increased serum half-life presents distinct advantages for ET treatment over that of standard IFN-α and other available PEG IFN-α therapy. This pivotal Phase 3 study will establish the efficacy and safety of P1101 in ET subjects.

The enrolled subjects will be randomized into two arms, the test arm is P1101, the control arm is ANA. The overall duration for each eligible patient is 14 months, including screening (1 month), treatment (12 months) and follow-up (1 month) period. Efficacy evaluations, safety assessments, and PK and immunogenicity evaluations of P1101 will be performed.

Evaluation of efficacy will include clinical laboratory assessments, allelic burden measurements of CALR, JAK-2, and MPL, spleen size measurements, bone marrow sampling, EQ-5D-3L, and MPN-SAF TSS completion.

Evaluation of safety will include assessing vital signs, clinical safety laboratory tests, physical examinations, ECG evaluation, heart ECHO, lung X-ray, ECOG performance status, ocular examination, and AEs.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Experimental Drug (Biological): Ropeginterferon alfa-2b (P1101), Q2W, SC injection Control Drug: Anagrelide, capsules, daily, p.o.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 25, 2020
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: Ropeginterferon alfa-2b (P1101)
Pre-filled Syringe, Q2W, SC injection
Biological: Ropeginterferon alfa-2b
Ropeginterferon alfa-2b (P1101) dosage: from 250 mcg to 500 mcg Anagrelide dosage: 0.5 mg per capsule, according to label and physician's judgement
Other Name: Anagrelide

Active Comparator: Anagrelide
Capsules, Daily, p.o.
Biological: Ropeginterferon alfa-2b
Ropeginterferon alfa-2b (P1101) dosage: from 250 mcg to 500 mcg Anagrelide dosage: 0.5 mg per capsule, according to label and physician's judgement
Other Name: Anagrelide




Primary Outcome Measures :
  1. Peripheral blood count remission [ Time Frame: month 9 and month 12 ]
    platelets ≤400 x 109/L AND white blood cells (WBC) <9.5 x 109/L

  2. Improvement or non-progression in disease-related signs [ Time Frame: month 9 and month 12 ]
    splenomegaly

  3. Large symptoms improvement or maintain non-progression [ Time Frame: month 9 and month 12 ]
    based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

  4. Absence of hemorrhagic or thrombotic events [ Time Frame: month 9 and month 12 ]
    absence of hemorrhagic or thrombotic events


Secondary Outcome Measures :
  1. Durable response [ Time Frame: month 3 and month 6 ]
    measure durable response at month 3 and 6

  2. Longitudinal rate [ Time Frame: over the 12 months ]
    measure longitudinal rate of change in the ELN response rates over the 12 months

  3. Response rates [ Time Frame: 3, 6, 9, and 12 months ]
    measure response rate based on peripheral blood count remission, no signs of progressive disease, and absence of any hemorrhagic or thrombotic events

  4. Occurrence of thromboembolic events [ Time Frame: over the 12 months ]
    measure occurrence of thromboembolic events over the 12 months

  5. Time to first peripheral blood count remission response [ Time Frame: over the 12 months ]
    measure time to first peripheral blood count remission response over the 12 months

  6. Duration of peripheral blood count remission response [ Time Frame: over the 12 months ]
    measure duration of peripheral blood count remission response over the 12 months

  7. Symptomatic improvement assessed by the EuroQOL 5 dimensions 3 level version (EQ-5D-3L) questionnaire [ Time Frame: over the 12 months ]
    measure symptomatic improvement assessed by the EuroQOL 5 dimensions 3 level version (EQ-5D-3L) questionnaire over the 12 months

  8. Symptomatic improvement assessed by the 10-item MPN-SAF TSS [ Time Frame: over the 12 months ]
    measure symptomatic improvement assessed by the 10-item MPN-SAF TSS over the 12 months

  9. Change of CALR, MPL, and JAK-2 allelic burden over time [ Time Frame: over the 12 months ]
    measure change of CALR, MPL, and JAK-2 allelic burden over time

  10. Improvement or non-progression of spleen size assessment [ Time Frame: over the 12 months ]
    measure spleen size over time


Other Outcome Measures:
  1. Bone marrow histological remission [ Time Frame: over the 12 months ]
    the disappearance of megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female subjects ≥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 randomization should not be shorter than 14 days
  4. Interferon treatment-naïve, or anti-P1101 binding antibody negative at screening and the washout between last dose of interferon and randomization should not be shorter than 14 days.
  5. Documented resistance/intolerance to prior HU for ET, referencing modified ELN criteria (Barosi, et al, 2007), whereby at least one of the following criteria is met:

    Platelet count >600 x 109/L at ≥2 g/day (or ≥2.5 g/day if subject body weight >80 kg) or maximally tolerated dose if <2 g/day after at least 3 months of HU, or Platelet count >400 x 109/L and WBC count <2.5 x 109/L at any dose and any duration of HU, or Platelet count >400 x 109/L and hemoglobin (HGB) <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), or Platelet count >450 x 109/L at any dose and any duration of HU. The actual dose and duration of HU must be recorded on the eCRF. Moreover, if patient received one dose of HU, the reason why subject was judged to be HU resistance/intolerance must be recorded on the eCRF.

  6. Platelets >450 x 109/L at screening
  7. WBC >10 x 109/L at screening
  8. HGB ≥11 g/dL at screening for males and 10 g/dL at screening for females
  9. Neutrophil count ≥1.0 x 109/L at screening
  10. Adequate hepatic function defined as bilirubin ≤1.5 x upper limit normal (ULN), prothrombin time (PT) (international normalized ratio, INR) ≤1.5 x ULN, albumin >3.5 g/dL, alanine aminotransferase ≤2.0 x ULN, aspartate aminotransferase ≤2.0 x ULN at screening
  11. Creatinine clearance ≥40 mL/min (by Cockcroft-Gault equation)
  12. 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, 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

Exclusion Criteria:

  1. Any subject requiring a legally authorized representative
  2. Any contraindications or hypersensitivity to IFN-α or ANA and their excipients
  3. Known risk factors for QT-prolongation (e.g., congenital long QT, known history of acquired QT-prolongations). Medications that can prolong QTc and induce hypokalemia will not be allowed in the study.
  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:

    1. 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)
    2. 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
    3. Infections with systemic manifestations (e.g., bacterial, fungal, or human immunodeficiency virus [HIV], except hepatitis B [HBV] and/or hepatitis C [HCV], at screening)
    4. Evidence of severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension)
    5. History or presence of clinically relevant depression, or previous suicide attempts or at any risk of suicide at screening, in the judgement of the Investigator
    6. History or presence of clinically significant neurodegenerative diseases
    7. History of any malignancy within 5 years (except Stage 0 chronic lymphocytic leukemia, basal cell, squamous cell, and superficial melanoma)
    8. History of alcohol or drug abuse within the last year
    9. History or evidence of any other MPN
  8. Use of any investigational drug <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 (see Appendix 8 for definition).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04285086


Contacts
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Contact: Toshiaki Sato, MD/PhD +81 3 68669531 toshiaki_sato@pharmaessentia.com
Contact: TingFang Wang, MS/MHA +886 2 26557688 ext 7890 tingfang_wang@pharmaessentia.com

Locations
Show Show 60 study locations
Sponsors and Collaborators
PharmaEssentia
Medpace, Inc.
EPS International
Brightech International
Investigators
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Study Director: Toshiaki Sato, MD/PhD PharmaEssentia Japan K.K.
Study Director: Craig Zimmerman, PhD PharmaEssentia USA Corp.
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Responsible Party: PharmaEssentia
ClinicalTrials.gov Identifier: NCT04285086    
Other Study ID Numbers: P1101 ET
First Posted: February 26, 2020    Key Record Dates
Last Update Posted: October 11, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by PharmaEssentia:
Essential Thrombocythemia
Ropeginterferon
P1101
PharmaEssentia
Additional relevant MeSH terms:
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Thrombocytosis
Thrombocythemia, Essential
Blood Platelet Disorders
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Blood Coagulation Disorders
Hemorrhagic Disorders
Anagrelide
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors