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    Summary
    EudraCT Number:2007-002212-26
    Sponsor's Protocol Code Number:MK-0683-065
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2007-07-30
    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 ConcernedFrance - ANSM
    A.2EudraCT number2007-002212-26
    A.3Full title of the trial
    A Phase I/II Study of Vorinostat in Combination with Low Dose Ara-C for Patients with Intermediate-2 or High Risk Myelodysplastic Syndromes
    A.3.2Name or abbreviated title of the trial where available
    GFM-VOR-2007-1
    A.4.1Sponsor's protocol code numberMK-0683-065
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGroupe Francophone des Myélodysplasies
    B.1.3.4CountryFrance
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 ZOLINZA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck and Co, INC
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.1Product nameZOLINZA
    D.3.2Product code MK-0683
    D.3.4Pharmaceutical form Capsule*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    Patients with Intermediate-2 or High Risk Myelodysplastic Syndromes (MDS)as defined by the International Prognostic Scoring System (IPSS).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10028532
    E.1.2Term Myelodysplasia
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    (1) To determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of vorinostat administered once daily for up to 14 days in a 28-day cycle sequentially or concurrently with LD Ara-C in patients with INT-2 to high risk MDS.


    (2) To evaluate the safety and tolerability of vorinostat in combination with LD Ara-C.
    study.
    E.2.2Secondary objectives of the trial
    1) To determine the clinical activity of vorinostat in combination with LD Ara-C in patients with INT-2 to high risk MDS as defined by IPSS.

    (2) To evaluate the in vivo molecular and biological effects of vorinostat in patients with INT-2 to high risk MDS as defined by IPSS, through analysis of histone modification, and gene and protein expression.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patient has MDS including the following FAB sub-types: refractory anemia with blast excess (RAEB) ,transformed refractory anemia with blast excess (RAEB-t) and non proliferative Chronic MyeloMonocytic Leukemias (WBC below 13G/l).

    2.Patient has a IPSS score > 1. 5 (INT-2 and high risk categories).

    3.Patient is male or female, and ≥ 18 years of age on day of signing informed consent.

    4.Patient has an Eastern Cooperative Oncology Group (ECOG) performance s
    tatus ≤2 (See Appendix 6.1).

    5.Patient has recovered from toxicities due to prior therapy (less than grade 2) except for cytopenia

    6.Patient must have adequate organ function as indicated by the following laboratory values:
    Serum creatinine or calculated creatinine clearancea < 2 mg/dl or ≥ 60 mL/min for patients with creatinine levels > 1.5 X institutional ULN Hepatic
    Serum total bilirubin ≤ 2.5 X ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels ≥ 2 mg/dL.
    AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN
    Alkaline Phosphatase ≤ 5 X ULN If > 2.5 X ULN, then liver fraction
    should be ≤ 2.5 X ULN
    (Creatinine clearance should be calculated per institutional standard)

    7.Patient is known to not be refractory to platelet transfusions.

    8.Female patient of childbearing potential has a negative serum pregnancy test (β-hCG) within 72 hours prior to receiving the first dose of vorinostat and or Ara-C . Female patient is not actively breastfeeding at the time of study entry.

    9.Female patient is either post-menopausal, free from menses for > 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from becoming pregnant throughout the study, starting with Visit 1.

    10.Male patient agrees to use an adequate method of contraception for the duration of the study. Men should be advised not to father a child while receiving vorinostat and for 1 month post study.

    11.Patient is available for periodic blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.

    12.Patient has the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.
    E.4Principal exclusion criteria
    1.Patient had prior treatment with an HDAC inhibitor (e.g., depsipeptide or NSC-630176, MS 275, LAQ-824, PXD-101, LBH589, MGCD0103, CRA024781, etc). Patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study. Patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period.

    2.Patient has been previously treated with low dose (20 mg/m2 SC daily) Ara-C for MDS within 3 months of beginning this study.

    3.Patient with RAEB-2 or RAEB-T eligible for intensive chemotherapy followed or not by allogeneic stem cell transplantation

    4.Patient has active and uncontrolled infection

    5.Patient has uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.

    6.Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug.

    7.Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy.

    8.Patient has clinically active hepatitis B or hepatitis C infection.

    9.Patient has a known allergy or hypersensitivity to any component of vorinostat or Ara-C.

    10.Patient with a "currently active" second malignancy, other than nonmelanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for >5 years or are considered by their physician to be at less than 30% risk of relapse.

    11.Patient has received growth factors such as epoetin alfa (EPO) or granulocyte colony-stimulating factor (G-CSF) or has received non cytotoxic agents (including low dose oral chemotherapy) in the 30 days before inclusion. In case of previous cytotoxic treatment, an interval of 3 months is required.

    12.Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs

    13.Patients with clinical evidence of CNS leukemia.

    14.Patient has a history of GI surgery or other procedures that might interfere with the absorption or swallowing of the study drugs.

    15.Patient is unable to take and/or tolerate oral medications on a continuous basis.
    E.5 End points
    E.5.1Primary end point(s)
    -Response to treatment including Complete Remission (CR), Partial Remission (PR), and Hematological Improvement (HI) as defined by the International Working Group’s modified criteria [1].

    -toxicity profile
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    study of association of cytarabine and vorinostat
    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 Yes
    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 Yes
    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 Yes
    E.8.2.3.1Comparator description
    sequential administration of the vorinostat after the aracytine vs concomitant administration.
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Yes
    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
    it is provided in the protocol
    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 months
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state52
    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 Decision2007-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-06-05
    P. End of Trial
    P.End of Trial StatusOngoing
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