Clinical trial NCT04285086: Ropeginterferon Alfa-2b (P1101) vs. Anagrelide in Essential Thrombocythemia Patients With Hydroxyurea Resistance or Intolerance
Official title: 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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Essential Thrombocythemia
Keywords: Essential Thrombocythemia
Ropeginterferon
P1101
PharmaEssentia
MPN
Myeloproliferative neoplasms
ET
JAK2
CALR
MPL
IFN
Lead sponsor: PharmaEssentia
Sponsor class: INDUSTRY
First posted: 2020-02-26
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Experimental Drug (Biological): Ropeginterferon alfa-2b (P1101), Q2W, SC injection Control Drug: Anagrelide, capsules, daily, p.o.
Primary purpose: TREATMENT

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.

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.

Eligibility 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 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).

Primary outcomes:
measure: Peripheral blood count remission
timeFrame: month 9 and month 12
measure: Improvement or non-progression in disease-related signs
timeFrame: month 9 and month 12
measure: Large symptoms improvement or maintain non-progression
timeFrame: month 9 and month 12
measure: Absence of hemorrhagic or thrombotic events
timeFrame: month 9 and month 12
Secondary outcomes:
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine - Division of Oncology
state: Missouri
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
city: Chongqing
country: China
facility: The First Affiliated Hospital, Chongqing Medical University
state: Chongqing
city: Guangzhou
country: China
facility: NanFang Hospital of Southern Medical University
state: Guangdong
city: Wuhan
country: China
facility: Union Hospital Tongji Medical College Huazhong University of Science and Technolog
state: Hubei
city: Wuhan
country: China
facility: Zhongnan Hospital of Wuhan University
state: Hubei
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
state: Jiangsu
city: Shenyang
country: China
facility: Shengjing Hospital of China Medical University
state: Liaoning
city: Xi'an
country: China
facility: Shaanxi Provincial People's Hospital
state: Shaanxi
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
city: Shanghai
country: China
facility: Ruijin Hospital affiliated to Shanghai Jiao Tong University school of Medicine
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Tianjin
country: China
facility: The Second Hospital of Tianjin Medical University
state: Tianjin
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
state: Tianjin
city: Hangzhou
country: China
facility: The First Affiliated Hospital, College of Medicine, Zhejiang University
state: Zhejiang
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Toon
country: Japan
facility: Ehime University Hospital
state: Ehime
city: Sagamihara
country: Japan
facility: Kitasato University Hospital
state: Kanagawa
city: Tsu
country: Japan
facility: Mie University Hospital
state: Mie
city: Miyazaki City
country: Japan
facility: University of Miyazaki Hospital
state: Miyazaki
city: Hirakata
country: Japan
facility: Kansai Medical University Hospital
state: Osaka
city: Osakasayama
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Izunokuni
country: Japan
facility: Juntendo University Shizuoka Hospital
state: Shizuoka
city: Bunkyo City
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Bunkyo City
country: Japan
facility: Nippon Medical School Hospital
state: Tokyo
city: Shinagawa City
country: Japan
facility: NTT Medical Center Tokyo
state: Tokyo
city: Shinjuku City
country: Japan
facility: Tokyo Medical University Hospital
state: Tokyo
city: Chuo
country: Japan
facility: University of Yamanashi Hospital
state: Yamanashi
city: Daegu
country: Korea, Republic of
facility: Daegu Catholic University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: SoonChunHyang University Seoul Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital, The Catholic University of Korea
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Chiayi City
country: Taiwan
facility: Chia-Yi Christian Hospital
state: Chiayi County
city: Chiayi City
country: Taiwan
facility: Chiayi Chang Gung Memorial Hospital
state: Chiayi County
city: Hualien City
country: Taiwan
facility: Hualien Tzu Chi Hospital
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Veterans General Hospital
city: Kaohsiung City
country: Taiwan
facility: E-Da Cancer Hospital
city: Kaohsiung City
country: Taiwan
facility: E-Da Hospital
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: New Taipei City
country: Taiwan
facility: Far Eastern Memorial Hospital
city: Taichung City
country: Taiwan
facility: China Medical University Hospital
city: Tainan City
country: Taiwan
facility: National Cheng Kung University Hospital
city: Tainan City
country: Taiwan
facility: Tainan Municipal An-Nan Hospital
city: Tainan City
country: Taiwan
facility: Chi Mei Medical Center
city: Tainan City
country: Taiwan
facility: Chi-Mei Hospital - Liouying Branch
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei City
country: Taiwan
facility: Mackay Memorial Hospital
city: Taipei City
country: Taiwan
facility: Shin Kong Wu Ho-Su Memorial Hospital
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei City
country: Taiwan
facility: Tri-Service General Hospital
city: Taipei City
country: Taiwan
facility: Taipei Municipal Wan Fang Hospital
city: Taoyuan City
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital
Study officials:
affiliation: PharmaEssentia Japan K.K.
name: Toshiaki Sato, MD/PhD
role: STUDY_DIRECTOR
affiliation: PharmaEssentia USA Corp.
name: Craig Zimmerman, PhD
role: STUDY_DIRECTOR
References:
citation: 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.