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

A Phase 3, Open-Label, Multicenter, Randomized, Active-controlled Study to Assess PK and Compare the Efficacy, Safety, and Tolerability of P1101 vs Anagrelide as 2nd Line Therapy for Essential Thrombocythemia (SURPASS ET): The Core Study and Its Extension Study.

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Essential Thrombocythemia
• Intervention / Treatment: Biological: Ropeginterferon alfa-2b; Drug: Anagrelide

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.

In core study phase, 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.

Subjects who completed the end of treatment (EoT) and safety follow-up (EoS) visits of the SURPASS ET study and may benefit from P1101 therapy have the opportunity to receive P1101 treatment.

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul'S Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C1
      • Princess Margaret Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• China
  • Beijing
    • Beijing, Beijing, China
      • Peking Union Medical College Hospital
    • Beijing, Beijing, China
      • Peking University People's Hospital
  • Chongqing
    • Chongqing, Chongqing, China
      • The First Affiliated Hospital, Chongqing Medical University
  • Guangdong
    • Guangzhou, Guangdong, China
      • Nanfang Hospital of Southern Medical University
  • Hubei
    • Wuhan, Hubei, China
      • Zhongnan Hospital of Wuhan University
    • Wuhan, Hubei, China
      • Union Hospital Tongji Medical College Huazhong University of science and technolog
  • Jiangsu
    • Suzhou, Jiangsu, China
      • The First Affiliated Hospital Of Soochow University
  • Liaoning
    • Shenyang, Liaoning, China
      • Shengjing Hospital of China Medical University
  • Shaanxi
    • Xi'an, Shaanxi, China
      • Shaanxi provincial people's hospital
  • Shandong
    • Jinan, Shandong, China
      • Qilu Hospital of Shandong University
  • Shanghai
    • Shanghai, Shanghai, China
      • Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital, Sichuan University
  • Tianjin
    • Tianjin, Tianjin, China, 300211
      • The Second Hospital of Tianjin Medical University
    • Tianjin, Tianjin, China
      • Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • The First Affiliated Hospital, College of Medicine, Zhejiang University
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
• Japan
  • Ehime
    • Toon, Ehime, Japan, 791-0204
      • Ehime University Hospital
  • Kanagawa
    • Sagamihara, Kanagawa, Japan, 252-0329
      • Kitasato University Hospital
  • Mie
    • Tsu, Mie, Japan, 514-8507
      • Mie University Hospital
  • Miyazaki
    • Miyazaki City, Miyazaki, Japan, 889-1692
      • University of Miyazaki Hospital
  • Osaka
    • Hirakata, Osaka, Japan, 573-1191
      • Kansai Medical University Hospital
    • Osakasayama, Osaka, Japan, 589-8511
      • Kindai University Hospital
    • Suita, Osaka, Japan, 565-0871
      • Osaka University Hospital
  • Shizuoka
    • Izunokuni, Shizuoka, Japan, 410-2295
      • Juntendo University Shizuoka Hospital
  • Tokyo
    • Bunkyo City, Tokyo, Japan, 113-8431
      • Juntendo University Hospital
    • Bunkyo City, Tokyo, Japan, 113-8603
      • Nippon Medical School Hospital
    • Shinagawa City, Tokyo, Japan, 141-0022
      • NTT Medical Center Tokyo
    • Shinjuku City, Tokyo, Japan, 160-0023
      • Tokyo Medical University Hospital
  • Yamanashi
    • Chuo, Yamanashi, Japan, 409-3898
      • University of Yamanashi Hospital
• Korea, Republic of
  • Daegu, Korea, Republic of, 30566
    • Daegu Catholic University Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 08308
    • Korea University Guro Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 06591
    • Seoul St. Mary's Hospital, The Catholic University of Korea
  • Seoul, Korea, Republic of, 04401
    • SoonChunHyang University Seoul Hospital
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
  • Singapore, Singapore, 119074
    • National University Hospital
• Taiwan
  • Hualien City, Taiwan, 97002
    • Hualien Tzu Chi Hospital
  • Kaohsiung City, Taiwan, 83301
    • Kaohsiung Chang Gung Memorial Hospital
  • Kaohsiung City, Taiwan, 81362
    • Kaohsiung Veterans General Hospital
  • Kaohsiung City, Taiwan, 82445
    • E-Da Hospital
  • Kaohsiung City, Taiwan, 80756
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Kaohsiung City, Taiwan, 82445
    • E-DA Cancer Hospital
  • New Taipei City, Taiwan, 22060
    • Far Eastern Memorial Hospital
  • Taichung City, Taiwan, 40447
    • China Medical University Hospital
  • Tainan City, Taiwan, 70403
    • National Cheng Kung University Hospital
  • Tainan City, Taiwan, 70965
    • Tainan Municipal An-Nan Hospital
  • Tainan City, Taiwan, 71004
    • Chi Mei Medical Center
  • Tainan City, Taiwan, 73657
    • Chi-Mei Hospital - Liouying Branch
  • Taipei City, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei City, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taipei City, Taiwan, 10449
    • Mackay Memorial Hospital
  • Taipei City, Taiwan, 11101
    • Shin Kong Wu Ho-Su Memorial Hospital
  • Taipei City, Taiwan, 11449
    • Tri-Service General Hospital
  • Taipei City, Taiwan, 11696
    • Taipei Municipal Wan Fang Hospital
  • Taoyuan City, Taiwan, 33305
    • Linkou Chang Gung Memorial Hospital
  • Chiayi County
    • Chiayi City, Chiayi County, Taiwan, 60002
      • Chia-Yi Christian Hospital
    • Chiayi City, Chiayi County, Taiwan, 61363
      • Chiayi Chang Gung Memorial Hospital
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine - Division of Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 7 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 10^9/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 10^9/L and WBC count <2.5 x 10^9/L at any dose and any duration of HU, or Platelet count >400 x 10^9/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 10^9/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 10^9/L at screening
7. WBC >10 x 10^9/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 10^9/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
   6. Previous suicide attempts or at any risk of suicide at screening, in the judgement of the Investigator
   7. History or presence of clinically significant neurologic diseases
   8. History of any malignancy within 5 years (except Stage 0 chronic lymphocytic leukemia, basal cell, squamous cell, and superficial melanoma)
   9. History of alcohol or drug abuse within the last year
   10. History or evidence of any other MPN
   11. History of splenectomy
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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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; Other Names: P1101
Active Comparator: Anagrelide; Capsules, Daily, p.o.	Drug: Anagrelide; Anagrelide dosage: 0.5 mg per capsule, according to label and physician's judgement

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral blood count remission	platelets ≤400 x 10^9/L AND white blood cells (WBC) <9.5 x 10^9/L	month 9 and month 12
Improvement or non-progression in disease-related signs	splenomegaly	month 9 and month 12
Large symptoms improvement or maintain non-progression	based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)	month 9 and month 12
Absence of hemorrhagic or thrombotic events	absence of hemorrhagic or thrombotic events	month 9 and month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Durable response	measure durable response at month 3 and 6	month 3 and month 6
Longitudinal rate	measure longitudinal rate of change in the ELN response rates over the 12 months	over the 12 months
Response rates	measure response rate based on peripheral blood count remission, no signs of progressive disease, and absence of any hemorrhagic or thrombotic events	3, 6, 9, and 12 months
Occurrence of thromboembolic events	measure occurrence of thromboembolic events over the 12 months	over the 12 months
Time to first peripheral blood count remission response	measure time to first peripheral blood count remission response over the 12 months	over the 12 months
Duration of peripheral blood count remission response	measure duration of peripheral blood count remission response over the 12 months	over the 12 months
Symptomatic improvement assessed by the EuroQOL 5 dimensions 3 level version (EQ-5D-3L) questionnaire	measure symptomatic improvement assessed by the EuroQOL 5 dimensions 3 level version (EQ-5D-3L) questionnaire over the 12 months	over the 12 months
Symptomatic improvement assessed by the 10-item MPN-SAF TSS	measure symptomatic improvement assessed by the 10-item MPN-SAF TSS over the 12 months	over the 12 months
Change of CALR, MPL, and JAK-2 allelic burden over time	measure change of CALR, MPL, and JAK-2 allelic burden over time	over the 12 months
Improvement or non-progression of spleen size assessment	measure spleen size over time	over the 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone marrow histological remission	the disappearance of megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis	over the 12 months

Collaborators and Investigators

• Sponsor: PharmaEssentia
• Collaborators: Medpace, Inc.; EPS International; Brightech International
• Investigators: Study Director: Toshiaki Sato, MD/PhD, PharmaEssentia Japan K.K.; Study Director: Craig Zimmerman, PhD, PharmaEssentia USA Corp.

Publications and helpful links

General Publications

• Verstovsek S, Komatsu N, Gill H, Jin J, Lee SE, Hou HA, Sato T, Qin A, Urbanski R, Shih W, Zagrijtschuk O, Zimmerman C, Mesa RA. SURPASS-ET: phase III study of ropeginterferon alfa-2b versus anagrelide as second-line therapy in essential thrombocythemia. Future Oncol. 2022 Sep;18(27):2999-3009. doi: 10.2217/fon-2022-0596. Epub 2022 Aug 4.

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2020
• Primary Completion (Estimated): November 30, 2024
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: February 23, 2020
• First Submitted That Met QC Criteria: February 23, 2020
• First Posted (Actual): February 26, 2020

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MPN; P1101; Essential Thrombocythemia; JAK2; IFN; Myeloproliferative neoplasms; Ropeginterferon; PharmaEssentia; CALR; ET; MPL
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Thrombocytosis; Thrombocythemia, Essential; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Anagrelide
• Other Study ID Numbers: P1101 ET

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No