Peginterferon α-2b Injection for Hydroxyurea Resistant or Intolerant ET

Официальное название

A Phase 2 Multicenter, Randomized, Open-label Study to Evaluate the Pharmacokinetic, Safety and Efficacy of Peginterferon Alfa-2b Injection in Subjects With Essential Thrombocythemia Who Are Resistant to or Intolerant of Hydroxyurea.

Обзор

This is a multicenter, randomized, open-label Phase 2 clinical study. It is aimed to enroll 27 essential thrombocytopenia (ET) patients who are resistant to or intolerant of hydroxyurea(HU). Eligible patients will be randomized to receive either Peginterferon α-2b 135 mcg or Peginterferon α-2b 180 mcg at a ratio of 1:2, and all subjects will go through a target treatment period (Weeks 1 \~ Week 48), an extension treatment period (Weeks 49 \~ Week 96) and a follow-up period (Weeks 97 \~ Week 100). Pharmacokinetics, safety, efficacy will be evaluated.

Вмешательства

• Препарат Peginterferon α-2b injection
  Peginterferon α-2b injection, 135 mcg, s.c., once a week, during the targeted treatment period (the first 48 week), peginterferon α-2b dose is depended on the patient's response and tolerability during the extension treatment (week 49 to week 96).
• Препарат Peginterferon α-2b injection
  Peginterferon α-2b injection, 180 mcg, s.c., once a week, during the targeted treatment period (the first 48 week), peginterferon α-2b dose is depended on the patient's response and tolerability during the extension treatment (week 49 to week 96).

Первичные конечные точки

• Maximum concentration (Cmax) [Срок оценки: week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96.]
• Time to maximum concentration (Tmax) [Срок оценки: week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96.]
• Area under the plasma concentration-time curve [Срок оценки: week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96.]
• Apparent volume of distribution after oral administration (Vz/f) [Срок оценки: week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96.]
• Apparent plasma clearance (CL/F) [Срок оценки: week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96.]
• Plasma elimination half-life (t1/2) [Срок оценки: week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96.]
• Relationship between exposure and the effect (desired-effectiveness or undesirable-toxicity) in a pharmacokinetic model and pharmacodynamic model. [Срок оценки: up to 96 weeks.]

Вторичные конечные точки (12)

• Rate of complete hematological remission. [Срок оценки: Week 24, 36, 48, 60, 72, 84, 96.]
• Platelet counts change from baseline. [Срок оценки: Week 12, 24, 36, 48, 60, 72, 84, 96.]
• White blood cell counts change from baseline. [Срок оценки: Week 12, 24, 36, 48, 60, 72, 84, 96.]
• Complete remission rate. [Срок оценки: Week 24, 36, 48, 60, 72, 84, 96.]
• Time to complete remission from baseline. [Срок оценки: Week 48, 96.]
• Duration of complete remission. [Срок оценки: Week 48, 96.]
• Remission rate of bone marrow. [Срок оценки: Week 48, 96.]
• Incidence of disease progression. [Срок оценки: Week 48, 96.]
• Change of JAK2V617F mutations load from baseline. [Срок оценки: Week 48, 96.]
• Change of CALR mutations load from baseline. [Срок оценки: Week 48, 96.]
• Change of MPL mutations load from baseline. [Срок оценки: Week 48, 96.]
• Change of MPN-SAF TSS scores from baseline [Срок оценки: Week 12, 24, 36, 48, 60, 72, 84,96.]

Критерии участия

Критерии включения

• Male or female subjects, aged greater or equal to 18 years old at screening;
• Subjects diagnosed as high-risk ET according to the World Health Organization (WHO) 2016 criteria：1) who is older than 60 years and JAK2V617F positive at screening, 2) or who previously suffered from disease-related thrombosis or hemorrhage;
• Subjects who have previously received HU for ET, and the time interval between the last HU dose and the first dose of the study drug should not be less than 7 days;
• Interferon treatment-naïve, and for those who have previously received interferon the the time interval between the last dose of interferon and randomization should not be less than 1 month;
• Patients with confirmed hydroxyurea resistance or intolerant, as at least one of the following criteria is met:

• Platelet count remain greater than 600×10\^9 /L after at least 3 months of HU treatment at a dose ≥2g/d (dose ≥2.5 g/d if subject weight > 80 kg);
• Platelet count greater than 400\*10\^9/L while white blood cell (WBC) count lower than 2.5\*10\^9/L, or platelet count greater than 400\*10\^9 /L while hemoglobin lower than 100 g/L at any dose of HU;
• Presence of HU-related toxicities at any dose of HU: e.g. ulcers in legs, or any unacceptable skin mucosal manifestations or fever;
• Platelet counts > 450\*10\^9/L at screening;
• Neutrophil count ≥1.0\*10\^9/L at screening;
• Haemoglobin ≥11 g/dL at screening for males and 10 g/dL for females at screening;
• There is no serious function damage in liver and kidney: total bilirubin ≤1.5 upper limit of normal (ULN), alanine aminotransferase≤2.0 ULN, aspartate aminotransferase≤2.0 ULN, prothrombin time is prolonged by less than 4 seconds, Creatinine clearance ≥50 mL/min (according to Cockcroft-Gault formula) at screening;
• Both male and female subjects must agree take an appropriate contraceptive method, including:

• Male subjects: must agree to use reliable contraception from inform consent until 6 months following the last dose of the study drug.
• Female subjects: Must meet at least one of the following conditions:

i) Women without childbearing potential; ii) Women of childbearing potential: no pregnant or breastfeed, negative in blood pregnancy test within 4 days prior to the first dosing, and must agree to use reliable contraception from inform consent until 6 months following the last dose of the study drug;

• Subjects understand the objective, characteristic, method and possible adverse reactions of the study, voluntarily participate in this study, and sign informed consent.

Критерии исключения

• History of any other myeloproliferative tumors, or evidence of the presence of any other myeloproliferative tumors;
• Contraindications or hypersensitivities to interferons of any of its excipients;
• Severe medical conditions or serious comorbidities that the investigators determined could jeopardize the safety or protocol adherence, e.g. New York Heart Association \[NYHA\] Class III-IV, congestive heart failure, symptomatic arrhythmias，pulmonary hypertension;
• History of major organ transplantation;
• Documented autoimmune disease or history of autoimmune disease at screening, e.g. medication un-controlled thyroid dysfunction, autoimmune hepatitis, idiopathic thrombocytopenic purpura, scleroderma, psoriasis, or any autoimmune arthritis;
• Clinically significant pulmonary infiltration, infectious pneumonia, and non-infectious pneumonia at screening that, in the investigator's opinion, would jeopardize the safety of the subject or their compliance with the protocol;
• Infection with systemic clinical manifestations at screening, e.g., bacteria, fungi, human immunodeficiency virus, excluding hepatitis B and/or C;
• Evidence of severe retinopathy, e.g., cytomegalovirus retinitis, symptomatic macular degeneration, or clinically significant eye disease, e.g. due to diabetes mellitus or hypertension;
• Diagnosed clinically significant depression or a history of depression and, in the investigator's opinion, previous suicide attempts or at any risk of suicide at screening;
• Diagnosed clinically significant neurological disease or a history of clinically significant neurological disease, except for a history of stable cerebral thrombosis or cerebral hemorrhage;
• History of any malignancy within 5 years (except stage 0 chronic lymphocytic leukemia, basal cell carcinoma, squamous cell carcinoma, and superficial melanoma);
• A history of alcohol or drug abuse within 1 year;
• Have used any investigational drug within 4 weeks prior to first dose of investigational drug, or not recovered from the effects of prior investigational drug administration;
• Other situations that, in the investigator's opinion, not appropriate for inclusion.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 8 центров

• Peking Union Hospital, Chinese Academy of Medical Sciences — Пекин
• Peking University People's Hospital — Пекин
• Union Hospital affiliated to Fujian Medical University — Fujian
• Nanfang Hospital, Southern Medical University — Гуанчжоу
• Harbin First Hospital — Харбин
• Henan Cancer Hospital — Henan
• Ruijin Hospital, Shanghai Jiao Tong University School of Medicine — Шанхай
• The First Affiliated Hospital of Zhejiang University School of Medicine — Zhejiang

Идентификаторы

NCT: NCT06552429 · P2b-4-3-002

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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