Chronic myeloproliferative disease
Conditions
Interventions
Female and male individuals over 18 years of age who have been diagnosed with primary myelofibrosis, post-polycythemia vera and post-essential thrombocythemia myelofibrosis will be treated with metfor
Drug
Sponsors
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
Centro de Hematologia e Hemoterapia - Hemocentro (UNICAMP)
Hospital das Clinicas da Faculdade de Medicina de São Paulo
Eligibility
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: Patients over 18 years. Patients who were diagnosed with primary myelofibrosis, post-polycythemia vera and post-essential thombocythemia according to the World Health Organization in 2017, regardless of JAK2 mutation. Patients who are not taking another medication for the treatment of myelofibrosis or who have received treatment for myelofibrosis within 6 weeks prior to study drug initiation. Patients with oral access to the drug. Patients with life expectancy more or equal to 6 months. Palpable spleen measuring 5 cm or more below costal margin. Peripheral blood counts less or equal to 10%. ECOG less or equal to 2. Glomerular filtration rate (GFR) greater or equal to 60mL/min. Adequate liver function (AST or ALT at levels not exceeding 3x the upper limit of normal, total bilirubin at levels not higher than 2x the upper limit of normal). Negative pregnancy test prior to study initiation and agreement on contraceptive use for women of childbearing age.
Exclusion criteria
Exclusion criteria: Patients with known hypersensitivity and / or prior therapy with metformin or its excipients. Diabetes mellitus requiring use of insulin and another oral antidiabetic agent. Human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C (HCV) (except for chronic infections treated or cured for HBV and HCV, which will be accepted). Concomitant use of all herbal supplements during the study (including but not limited to St. John's wort, kava, None, gingko biloba, dehydroepiandrosterone [DHEA], or ginseng) is prohibited. Megestrol acetate (Megace) or medroxyprogesterone if used as an appetite stimulant is allowed. Uncontrolled conditions due to intercurrent illness, including, but not limited to, ongoing or active infection, refractory systemic hypertension, symptomatic congestive heart failure (New York Heart Association [NYHA] class III functional classification), unstable angina pectoris, cardiac arrhythmia, or psychiatric / social disease that would limit compliance with study requirements. Previous neoplasms, except for skin carcinomas for more than 2 years. Pregnant or breastfeeding patients. Any major surgery, extensive radiotherapy, delayed toxicity chemotherapy, biological therapy, or immunotherapy within 6 weeks prior to clinical trial screening. Any prior or concomitant use of another JAK2 inhibitor. Any investigational medication other than study drug in the 6 weeks prior to the first dose of study drug. Use of hydroxyurea, interferon, prednisone, thalidomide, busulfan, lenalidomide, anagrelide within 6 weeks prior to the first dose of study drug. Hematopoietic growth factor receptor agonists (eg erythropoietin (Epo), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag) should not be used as they may be associated with increases in spleen size. Growth factors should not have been used for at least 6 weeks before the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary safety and tolerability outcome: Safety and tolerability to treatment will be assessed by monitoring the frequency, duration and severity of adverse events from anamnesis, physical examination, and biochemical, serological, hematological test results. Method used for quantification / evaluation: The severity of each adverse event will be rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 5.0).;Primary efficacy outcome: Reduction of greater or equal to 35% in spleen volume from initiation of treatment to week 24, as measured by abdomen non-contrast-enhanced computed tomography or magnetic resonance imaging. Method used for quantification / evaluation: spleen volume measured by non-contrast-enhanced computed tomography or magnetic resonance imaging of the abdomen; 35% or greater reduction in spleen volume is expected in at least 1 of 10 patients included in phase 1, and at least 2 of 15 patients at the end of phase 2. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary efficacy outcome: Modulation of (i) hematimetric parameters, (ii) constitutional symptom score, (iii) bone marrow histological architecture, (iv) cytogenetics. Methods used for quantification / evaluation: parameters will be assessed by (i) peripheral blood counts, (ii) completion of constitutional symptom assessment questionnaire in patients with myelofibrosis, (iii) bone marrow biopsy, (iv) bone marrow cytogenetics. Descriptive or comparative analyzes will be employed as appropriate. It is expected to obtain the records of the evaluated parameters. ;Exploratory evaluations: (i) JAK2 or CALR mutation allelic load, (ii) expression of inflammatory cytokines, (iii) activation of JAK / STAT, PI3K / AKT / mTOR and MAPK signaling pathways, (iv) mitochondrial oxidative function, (v) clonogenic capacity of hematopoietic progenitors, (vi) hemostatic balance. Methods used for quantification / evaluation: Functional tests. Descriptive or comparative analyzes will be employed as appropriate. (I) reduction of JAK2 or CALR mutation allele burden, (ii) reduction of expression of inflammatory cytokines, (iii) inhibition of JAK / STAT, PI3K / AKT / mTOR and MAPK signaling pathways, (iv) reduction of oxidative function of mitochondria, (v) reduction of clonogenic capacity of hematopoietic progenitors, (vi) inhibition of hemostasis activation. | — |
Countries
Brazil
Contacts
Public ContactFabiola Traina
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
Outcome results
None listed