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    Summary
    EudraCT Number:2014-001379-29
    Sponsor's Protocol Code Number:HCL-PG02
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-04-16
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-001379-29
    A.3Full title of the trial
    A PHASE II OPEN LABEL SINGLE CENTER STUDY OF THE CLINICAL ACTIVITY AND SAFETY OF THE BRAF-V600 INHIBITOR DABRAFENIB (TAFINLAR) IN PREVIOUSLY TREATED PATIENTS WITH HAIRY CELL LEUKEMIA (HCL) CARRYING THE BRAF-V600E MUTATION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the clinical activity and safety of dabrafenib (Tafinlar) in previously treated patients with hairy cell leukemia carrying the BRAF-V600E mutation
    A.4.1Sponsor's protocol code numberHCL-PG02
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDipartimento di Medicina
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDipartimento di Medicina Università di Perugia
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDipartimento di Medicina Università di Perugia
    B.5.2Functional name of contact pointSezione di Ematologia e Immunologia
    B.5.3 Address:
    B.5.3.1Street Addresspiazzale Menghini 1
    B.5.3.2Town/ cityPerugia
    B.5.3.3Post code06132
    B.5.3.4CountryItaly
    B.5.4Telephone number+390755783190
    B.5.5Fax number+390755783834
    B.5.6E-mailematol@unipg.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TAFINLAR
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Trading Services Limited
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hairy cell leukemia (HCL)carrying the BRAF-V600E mutation
    E.1.1.1Medical condition in easily understood language
    B lymphocytes cancer
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10019053
    E.1.2Term Hairy cell leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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,
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. [Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.]
    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 V600E BRAF mutation).
    12. Clinical indication for treatment, i.e. the presence of one or more of the following: neuthrophils <1.5x109 per liter, hemoglobin <11 g per deciliter, platelets <100x109 per liter, bulky/symptomatic splenomegaly, recurrent disease-related opportunistic infections.

    E.4Principal 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.
    E.5 End points
    E.5.1Primary end point(s)
    - To achieve an overall (complete + partial) response rate (ORR) of at least 60% at the end of study-drug administration.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after maximum 12 weeks of treatment
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    maximum 2 years
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV (includig 2 years of follow-up)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the tratment period, the drug will be discontinued and the patient closely monitored for two years by clinical and laboratory parameters. All patients who withdraw the study drug without completing the 8 or 12 weeks of treatment for whatever reason, will undergo the same follow-up period.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-17
    P. End of Trial
    P.End of Trial StatusOngoing
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