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

Sponsor

PharmaEssentia (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04285086

Collaborator

Medpace, Inc. (Industry), EPS International (Other), Brightech International (Other)

160

Enrollment

Locations

Arms

40.2

Anticipated Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 Drug: Anagrelide	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.

Study Design

Study Type:

Interventional

Anticipated 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.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 :

Aug 25, 2020

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Durable response [month 3 and month 6]
measure durable response at month 3 and 6
Longitudinal rate [over the 12 months]
measure longitudinal rate of change in the ELN response rates over the 12 months
Response rates [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
Occurrence of thromboembolic events [over the 12 months]
measure occurrence of thromboembolic events over the 12 months
Time to first peripheral blood count remission response [over the 12 months]
measure time to first peripheral blood count remission response over the 12 months
Duration of peripheral blood count remission response [over the 12 months]
measure duration of peripheral blood count remission response over the 12 months
Symptomatic improvement assessed by the EuroQOL 5 dimensions 3 level version (EQ-5D-3L) questionnaire [over the 12 months]
measure symptomatic improvement assessed by the EuroQOL 5 dimensions 3 level version (EQ-5D-3L) questionnaire over the 12 months
Symptomatic improvement assessed by the 10-item MPN-SAF TSS [over the 12 months]
measure symptomatic improvement assessed by the 10-item MPN-SAF TSS over the 12 months
Change of CALR, MPL, and JAK-2 allelic burden over time [over the 12 months]
measure change of CALR, MPL, and JAK-2 allelic burden over time
Improvement or non-progression of spleen size assessment [over the 12 months]
measure spleen size over time

Other Outcome Measures

Bone marrow histological remission [over the 12 months]
the disappearance of megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female subjects ≥18 years old
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
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
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.
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.

Platelets >450 x 10^9/L at screening
WBC >10 x 10^9/L at screening
HGB ≥11 g/dL at screening for males and 10 g/dL at screening for females
Neutrophil count ≥1.0 x 10^9/L at screening
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
Creatinine clearance ≥40 mL/min (by Cockcroft-Gault equation)
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
Written informed consent obtained from the subject and ability for the subject to comply with the requirements of the study

Exclusion Criteria:

Any subject requiring a legally authorized representative
Any contraindications or hypersensitivity to IFN-α or ANA and their excipients
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.
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
History of major organ transplantation
Pregnant or lactating females
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:
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)
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
Infections with systemic manifestations (e.g., bacterial, fungal, or human immunodeficiency virus [HIV], except hepatitis B [HBV] and/or hepatitis C [HCV], at screening)
Evidence of severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension)
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
History or presence of clinically significant neurodegenerative diseases
History of any malignancy within 5 years (except Stage 0 chronic lymphocytic leukemia, basal cell, squamous cell, and superficial melanoma)
History of alcohol or drug abuse within the last year
History or evidence of any other MPN
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
Subjects with documented ANA resistance or intolerance (see Appendix 8 for definition).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
3	Washington University School of Medicine - Division of Oncology	Saint Louis	Missouri	United States	63110
4	Mount Sinai Medical Center	New York	New York	United States	10029
5	Weill Medical College of Cornell University	New York	New York	United States	10065
6	MD Anderson Cancer Center	Houston	Texas	United States	77030
7	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
8	University of Utah	Salt Lake City	Utah	United States	84112
9	Froedtert Hospital and Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
10	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
11	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2C1
12	Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
13	Peking Union Medical College Hospital	Beijing	Beijing	China
14	Peking University People's Hospital	Beijing	Beijing	China
15	The First Affiliated Hospital, Chongqing Medical University	Chongqing	Chongqing	China
16	NanFang Hospital of Southern Medical University	Guangzhou	Guangdong	China
17	Union Hospital Tongji Medical College Huazhong University of Science and Technolog	Wuhan	Hubei	China
18	Zhongnan Hospital of Wuhan University	Wuhan	Hubei	China
19	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu	China
20	Shengjing Hospital of China Medical University	Shenyang	Liaoning	China
21	Shaanxi Provincial People's Hospital	Xi'an	Shaanxi	China
22	Qilu Hospital of Shandong University	Jinan	Shandong	China
23	Ruijin Hospital affiliated to Shanghai Jiao Tong University school of Medicine	Shanghai	Shanghai	China
24	West China Hospital, Sichuan University	Chengdu	Sichuan	China
25	Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences	Tianjin	Tianjin	China
26	The First Affiliated Hospital, College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China
27	Queen Mary Hospital	Hong Kong		Hong Kong
28	Ehime University Hospital	Toon	Ehime	Japan	791-0204
29	Kitasato University Hospital	Sagamihara	Kanagawa	Japan	252-0329
30	Mie University Hospital	Tsu	Mie	Japan	514-8507
31	University of Miyazaki Hospital	Miyazaki City	Miyazaki	Japan	889-1692
32	Kansai Medical University Hospital	Hirakata	Osaka	Japan	573-1191
33	Kindai University Hospital	Osakasayama	Osaka	Japan	589-8511
34	Osaka University Hospital	Suita	Osaka	Japan	565-0871
35	Juntendo University Shizuoka Hospital	Izunokuni	Shizuoka	Japan	410-2295
36	Juntendo University Hospital	Bunkyo City	Tokyo	Japan	113-8431
37	Nippon Medical School Hospital	Bunkyo City	Tokyo	Japan	113-8603
38	NTT Medical Center Tokyo	Shinagawa City	Tokyo	Japan	141-0022
39	Tokyo Medical University Hospital	Shinjuku City	Tokyo	Japan	160-0023
40	University of Yamanashi Hospital	Chuo	Yamanashi	Japan	409-3898
41	Gachon University Gil Medical Center	Incheon		Korea, Republic of	21565
42	Seoul National University Hospital	Seoul		Korea, Republic of	03080
43	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
44	SoonChunHyang University Seoul Hospital	Seoul		Korea, Republic of	04401
45	Konkuk University Hospital	Seoul		Korea, Republic of	05030
46	Samsung Medical Center	Seoul		Korea, Republic of	06351
47	Seoul St. Mary's Hospital, The Catholic University of Korea	Seoul		Korea, Republic of	06591
48	Korea University Guro Hospital	Seoul		Korea, Republic of	08308
49	National University Hospital	Singapore		Singapore	119074
50	Singapore General Hospital	Singapore		Singapore	169608
51	Chiayi Chang Gung Memorial Hospital	Puzi City	Chiayi County	Taiwan	61363
52	Hualien Tzu Chi Hospital	Hualien City		Taiwan	97002
53	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung City		Taiwan	80756
54	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung City		Taiwan	83301
55	China Medical University Hospital	Taichung City		Taiwan	40447
56	National Cheng Kung University Hospital	Tainan City		Taiwan	70403
57	National Taiwan University Hospital	Taipei City		Taiwan	10002
58	Mackay Memorial Hospital	Taipei City		Taiwan	10449
59	Taipei Veterans General Hospital	Taipei City		Taiwan	11217
60	Tri-Service General Hospital	Taipei City		Taiwan	11449
61	Linkou Chang Gung Memorial Hospital	Taoyuan City		Taiwan	33305