Hairy cell leukemia (HCL)carrying the BRAF-V600E mutation MedDRA version: 16.1 Level: PT Classification code 10019053 Term: Hairy cell leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: TAFINLAR
Pharmaceutical Form: Capsule, hard
Sponsors
Dipartimento di Medicina
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female HCL patients = 18 years of age. 2. Proven diagnosis of HCL according to the morphological and immunophenotypic criteria (co-expression of CD11c/CD25/CD103 and/or positivity for annexin-A1) of the World Health Organization (WHO-2008) classification of lymphoid neoplasms, accompanied by the presence of the BRAF-V600E mutation as detected using a sensitive allele-specific polymerase chain reaction (AS-PCR). 3. Patients with HCL must fall in one of the following categories: i) patients whose disease is refractory to therapy with purine analogs (no complete nor partial response or relapse =1 year following treatment); ii) patients whose disease relapses after therapy with a purine analog (pentostatin or cladribine) =1 year and = 2 years after the first course or whenever after a second or later course (in case of concomitant bone marrow hypoplasia, i.e. =20% hematopoietic cells on histological analysis, patients are eligible whenever the relapse occurs after the first course of purine analog); iii) patients who relapse after treatment with a BRAF inhibitor (e.g., Vemurafenib or Dabrafenib) or with a MEK inhibitor (e.g., Trametinib), including those who participated to our previous Vemurafenib trial (HCL-PG01); iv) patients that, after at least two courses of therapy (at least one of which including a purine analogue), still manifest a significant residual disease in the bone marrow (=30% of leukemic hairy cells; see Appendix 1 for histological and immunohistological assessment); v) patients with HCL who manifest severe side effects from therapy with purine analogs (prolonged and profound myelosuppression and immunosuppression, infectious complications, renal failure, vasculitis and autoimmune hemolytic anemia) or are deemed by the investigator medically unfit for chemotherapy with purine analogs (for example because of very old age and/or significant comorbidities). 4. Any prior treatment (chemotherapy and/or immunotherapy) must have been completed at least 12 weeks prior to initiation of study medication, except if no response to this treatment is already manifestly evident earlier. 5. ECOG PS of 0-2. 6. Patients must have recovered from all side effects of their most recent treatment for HCL. 7. Adequate renal and liver function as defined by the following laboratory values performed within 7 days prior to first dose of Dabrafenib: serum creatinine =2 times the upper limit of normal (ULN); serum aspartate transaminase (AST) and serum alanine transaminase (ALT) =2.5 times ULN, alkaline phosphatase =2.5 times ULN and bilirubin =1.5 times the ULN. Higher values are acceptable if they are directly related to the disease. 8. Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for =1 year. 9. Fertile men and women must use an effective method of contraception during treatment and for at least 16 weeks (for men) and 4 weeks (for women) after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, or intrauterine devices). Oral contraceptives are not reliable due to potential drug-drug interaction. At the discretion of the investigator, acceptable methods of
Exclusion criteria
Exclusion criteria: 1. Patients with a previous malignancy within the past 2 years are excluded except for patients with treated and controlled basal or SCC of the skin or carcinoma in-situ of the cervix or melanoma (or other tumors) carrying a BRAF-V600E mutation. Isolated elevation in PSA in absence of radiographic evidence of metastatic prostate cancer is allowed. 2 . Concurrent administration of any anti-cancer therapies (e.g. chemotherapy, other targeted therapy, experimental drug, etc) other than those administered in this study and concurrent treatment on another therapeutic clinical trial. 3 . Known hypersensitivity to Dabrafenib. 5 Pregnant (negative serum pregnancy test is required in women of child-bearing potential) or lactating women. 6. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow tablets. 7. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications. 8. History of congenital long QT syndrome, presence of clinically significant ventricular or atrial dysrhythmias = Grade 2 (NCI CTCAE Version 4.0). 9. Corrected QT (QTc) interval =500 msec at baseline or uncorrectable electrolyte abnormalities. 10. Active hepatitis infection or positivity for human immunodeficiency virus. 11. Uncontrolled medical illness. 12. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, which in the judgment of the investigator would make the patient inappropriate for entry into this study. 13. Unwillingness to practice effective birth control. 14. Inability to comply with other requirements of the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the anti-tumor activity of the orally administered single agent Dabrafenib in HCL patients carrying the BRAF-V600E mutation and fulfilling the eligibility criteria for enrollment in this study,;Secondary Objective: to assess the safety of dabrafenib, to determine the time to response, the duration of response following discontinuation of dabrafenib and to assess (when a sufficient number of leukemic cells is available for analysis) the activity of dabrafenib in purified leukemic hairy cells in vitro in comparison to the clinical response.;Primary end point(s): - To achieve an overall (complete + partial) response rate (ORR) of at least 60% at the end of study-drug administration.;Timepoint(s) of evaluation of this end point: after maximum 12 weeks of treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - To summarise the type, incidence, severity, seriousness and relationship to the study drug of adverse events (AE) and any laboratory abnormalities. - To summarise the time to response, i.e. the time from start of treatment to the first documented objective response (including complete remission and partial response). - To describe the duration of response (i.e., from the date of achievement of at least a partial remission to the date of relapse) in patients achieving at least a partial remission at the end of treatment. Patients will be monitored for two years after drug discontinuation as far as it concerns clinical and hematological parameters as well as changes in the percentage of leukemic hairy cells in the bone marrow and peripheral blood. The percentage of HCL cells will be assessed by morphology, immunohistochemistry, flow cytometry and molecular assays. - To study, in purified leukemic hairy cells, the in vitro effect of Dabrafenib on the phosporylation status of MEK and ERK, as well as on cell survival and apoptosis. ;Timepoint(s) of evaluation of this end point: maximum 2 years | — |
Countries
Italy
Contacts
Public ContactSezione di Ematologia e Immunologia
Dipartimento di Medicina Università di Perugia
Outcome results
None listed