Essential Thrombocythemia
Conditions
Keywords
Essential Thrombocythemia, Peginterferon α-2b, hydroxyurea resistant, hydroxyurea intolerant
Brief summary
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.
Interventions
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).
Sponsors
Xiamen Amoytop Biotech Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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: 1. 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); 2. 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; 3. 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: 1. Male subjects: must agree to use reliable contraception from inform consent until 6 months following the last dose of the study drug. 2. 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum concentration (Cmax) | week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96. |
| Time to maximum concentration (Tmax) | week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96. |
| Area under the plasma concentration-time curve | week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96. |
| Apparent volume of distribution after oral administration (Vz/f) | week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96. |
| Apparent plasma clearance (CL/F) | week1,4, 8, 12, 24, 36, 48, 60, 72, 84, 96. |
| Plasma elimination half-life (t1/2) | 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. | up to 96 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of disease progression. | Week 48, 96. | — |
| Change of JAK2V617F mutations load from baseline. | Week 48, 96. | JAK2V617F mutations were quantitatively detected using next-generation sequencing |
| Change of CALR mutations load from baseline. | Week 48, 96. | CALR mutations were quantitatively detected using next-generation sequencing |
| Change of MPL mutations load from baseline. | Week 48, 96. | MPL mutations were quantitatively detected using next-generation sequencing |
| Change of MPN-SAF TSS scores from baseline | Week 12, 24, 36, 48, 60, 72, 84,96. | — |
| Rate of complete hematological remission. | Week 24, 36, 48, 60, 72, 84, 96. | — |
| Rate of complete hematological remission maintenance in patients received dose-reduction extension therapy | Week 96. | — |
| Duration of complete hematological remission in patients received dose-reduction extension therapy | Week 96. | — |
| Change of 3-level Version of EuroQol Five Dimensions(EQ-5D-3L) scores from baseline. | Week 12, 24, 36, 48, 60, 72, 84, 96. | — |
| Incidence of thrombotic and bleeding events. | through study completion, an average of 2 year | — |
| Change of spleen size from baseline | Week 12, 24, 36, 48, 60, 72, 84, 96. | The maximum length of the spleen was measured by ultrasound. |
| Platelet counts change from baseline. | Week 12, 24, 36, 48, 60, 72, 84, 96. | — |
| White blood cell counts change from baseline. | Week 12, 24, 36, 48, 60, 72, 84, 96. | — |
| Complete remission rate. | Week 24, 36, 48, 60, 72, 84, 96. | — |
| Time to complete remission from baseline. | Week 48, 96. | — |
| Duration of complete remission. | Week 48, 96. | — |
| Remission rate of bone marrow. | Week 48, 96. | — |
Countries
China
Contacts
Primary ContactLei Zhang
Backup ContactRongfeng Fu
Outcome results
None listed