Hairy cell leukemia (HCL)carrying the BRAF-V600 mutation MedDRA version: 14.1 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: Zelboraf
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VEMURAFENIB
CAS Number: 918504.65-1
Current Sponsor code: PLX4032, RO5185426
Concentration unit: mg milligram(s)
Conce
Sponsors
UNIVERSITA' DEGLI STUDI DI PERUGIA
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 positivivity for annexin-A1) of the World Health Organization (WHO-2008) classification of lymphoid neoplasms, accompanied by the presence of the BRAF-V600E mutation 3. Patients with HCL must fall in one of the following categories: i) patients whose disease is refractory to therapy with purine analogs (no 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 = 4 years 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); iii) 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; iv) 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). 4. Any prior treatment (chemotherapy and/or immunotherapy) must have been completed at least 12 weeks prior to initiation of study medication. 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 vemurafenib: serum creatinine =2.0 mg/dl; serum aspartate transaminase (AST) and serum alanine transaminase (ALT) =2.5 times the upper limit of normal (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 6 months after completion of treatment as directed by their physician. 10. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry. 11. Signed informed consent must be obtained prior to performing any study-related procedures (including tumor testing for the V600 BRAF mutation). 12. Clinical indication for treatment (except for HCL patients falling in category iii of inclusion criterion no. 3 – see above), i.e. the presence of one or more of the following: neuthrophils =65 years) yes F.1.3.1 Number of subjects for this age range 25
Exclusion criteria
Exclusion criteria: 1. Prior allogeneic bone marrow transplant. 2. Patients with a previous malignancy within the past 2 years are excluded except for patients with treated and controlled basal or squamous cell carcinoma 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. 3. 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. 4. Known hypersensitivity to vemurafenib or another BRAF inhibitor. 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, history or presence of clinically significant ventricular or atrial dysrhythmias = Grade 2 (NCI CTCAE Version 4.0). 9. Corrected QT (QTc) interval = 450 msec at baseline. 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: Primary: to determine the anti-tumor activity of the orally administered single agent vemurafenib (PLX-4032) in HCL patients carrying the BRAF-V600E mutation and showing an unsatisfactory response to or severe toxicity from purine analogues (see below “Exclusion/inclusion criteria”).;Primary end point(s): To achieve a complete response rate of at least 30% at the end of study-drug administration (i.e., after 2, 4 or 6 cycles depending on the response after cycle 2 and cycle 4 - see study flow chart in Appendix 4).;Timepoint(s) of evaluation of this end point: maximum 24 weeks;Secondary Objective: Secondary: to assess the safety of vemurafenib, to determine the time to response, the duration of response following discontinuation of vemurafenib and to assess (when a sufficient number of leukemic cells is available for analysis) the activity of vemurafenib in purified leukemic hairy cells in vitro in comparison to the clinical response. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - To describe type, incidence, severity, seriousness and relationship to the study drug of adverse events (AE) and any laboratory abnormalities. - To describe the time to response, i.e. the time from start of treatment to the first documented objective response (including complete remission and partial remission). - To describe the duration of response in patients responding to vemurafenib (complete remission and partial remission), by monitoring them 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 vemurafenib 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, Prof. Falini
Universita' di Perugia, Dip.Medicina Clinica e Sper.
Outcome results
None listed