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    Summary
    EudraCT Number:2010-022221-15
    Sponsor's Protocol Code Number:PM104-B-003-10
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2010-10-11
    Trial results View 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 number2010-022221-15
    A.3Full title of the trial
    Phase II Multicenter, Open-label, Clinical and Pharmacokinetic Study of Zalypsis®
    (PM00104) in Patients with Unresectable Locally Advanced and/or Metastatic Ewing
    Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy.

    Étude de phase II , multicentrique, ouverte, clinique et pharmacocinétique de Zalypsis® (PM00104) chez des patients atteints d’un sarcome de la famille des tumeurs d’Ewing (EFT) non resécable, localement avancé et/ou métastatique en progression après au moins une première ligne chimiothérapique
    A.4.1Sponsor's protocol code numberPM104-B-003-10
    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 SponsorPharma Mar S.A., Sociedad Unipersonal
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    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 No
    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 nameZALYPSIS (PM00104)
    D.3.2Product code PM00104
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous 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
    Advanced and/or Metastatic Ewing Family of Tumors (EFT)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10057846
    E.1.2Term Primitive neuroectodermal tumour
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10015560
    E.1.2Term Ewing's sarcoma
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10015759
    E.1.2Term Extra-osseous Ewing's sarcoma
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10057656
    E.1.2Term Askin's tumour
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the antitumor activity of Zalypsis® administered as a 1-hour intravenous (i.v.) infusion on Day 1, 8 and 15 every four weeks (d1, d8 and d15, q4wk) to patients with advanced and/or metastatic EFT.
    E.2.2Secondary objectives of the trial
    To determine time-to-event efficacy parameters.
    -To characterize the safety profile and tolerability of Zalypsis® in patients with unresectable advanced and/or metastatic EFT.
    -To characterize the pharmacokinetics (PK) of Zalypsis® when administered as a single-agent to patients with EFT.
    -To determine the pharmacodynamic profile by measuring the effect of Zalypsis® on the number of Ewing’s sarcoma circulating tumor cells (CTCs) at different times of treatment and its correlation with the clinical outcome.
    -To determine the pharmacogenomic (PGx) profile.
    Hypothesis-generating exploratory PGx analyses will be conducted to correlate the molecular parameters found in the tumor and blood samples of the patients with the clinical results achieved with Zalypsis®.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The aim of this investigation is to identify and validate molecular markers whose expression may be associated with the clinical outcome of patients treated with Zalypsis®. These molecular markers might allow the identification of those patients who will benefit from the treatment with Zalypsis®, thus improving health
    care by an individualized medicine.
    E.3Principal inclusion criteria
    1. Voluntary written informed consent, obtained from the patient or his/her representative before the beginning of any specific study procedures.
    2. Age ≥ 16 years.
    3. Histologically or cytologically confirmed EFT, with recurrent disease.
    4. Documented failure to at least one prior chemotherapy regimen for their disease.
    5. Radiographic documentation of disease progression at study entry.
    6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 2.
    7. Life expectancy ≥ 3 months.
    8. Complete recovery from the effects of drug-related adverse events (AEs) derived from previous treatments, excluding alopecia and grade 1 peripheral neuropathy, according to the National Cancer Institute Common Terminology Criteria for
    Adverse Events (NCI-CTCAE) v. 4.0.
    9. At least one measurable lesion (“target lesion” according to the RECIST v.1.1), located in a non-irradiated area and adequately measured less than four weeks before study entry.
    Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is clearly documented or biopsy proven.
    10.Absolute neutrophil count (ANC) ≥ 1.5 x 109/l; platelet count ≥ 100 x 109/l, and hemoglobin ≥ 9 g/dl.
    11.Adequate renal function: calculated creatinine clearance (using Cockcroft and Gault‘s formula) ≥ 30 ml/min.
    12.Adequate hepatic function:
    a) Total bilirubin ≤ 1.5 x upper limit or normality (ULN),
    unless due to Gilbert’s syndrome.
    b) Alanine aminotransferase (ALT), aspartate
    aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN in case of hepatic metastases), and alkaline phosphatase (AP) ≤ 2.5 x ULN (≤ 5 x ULN in case of extensive bone
    involvement).
    c) Albumin ≥ 25 g/l.
    13.Left ventricular ejection fraction (LVEF) within normal limits (LVEF of at least 50%).
    14.Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for three months after
    discontinuation of treatment. Acceptable methods of contraception include complete abstinence, intrauterine device (IUD), oral contraceptive, subdermal implant and
    double barrier (condom with a contraceptive sponge or contraceptive suppository).
    E.4Principal exclusion criteria
    1. Prior therapy with Zalypsis®.
    2. Pregnant or lactating women or women of childbearing potential not using an appropriate contraceptive method.
    3. Less than three weeks from prior radiation therapy, biological therapy or chemotherapy.
    4. Less than six weeks from prior nitrosourea, mitomycin C, high-dose chemotherapy or radiotherapy involving the whole pelvis or over 50% of the spine, provided that acute effects of radiation treatment have resolved. Hormonal therapy and
    palliative radiation therapy (i.e., for control of pain from bone metastases) must be discontinued before study entry.
    5. Patients with a prior invasive malignancy (except nonmelanoma skin cancer and in situ cervix carcinoma) who have had any evidence of disease within the last five years or whose prior malignancy treatment contraindicates the current protocol therapy.
    6. Evidence of progressive or symptomatic central nervous system (CNS) metastases or leptomeningeal metastases.
    7. Other diseases or serious conditions:
    a) Increased cardiac risk, as defined by:
    -Unstable angina or myocardial infarction within 12 months before inclusion in the study.
    - New York Heart Association (NYHA) grade II or greater congestive heart failure.
    -Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment.
    - Abnormal electrocardiogram (ECG), i.e., patients with the following are excluded: QT prolongation - QTc > 480 msec; signs of cardiac enlargement or hypertrophy; bundle branch block; partial blocks; signs of ischemia or necrosis, and Wolff Parkinson White patterns.
    - History or presence of valvular heart disease.
    - Uncontrolled arterial hypertension despite optimal medical therapy.
    - Previous mediastinal radiotherapy.
    - Previous treatment with doxorubicin at cumulative doses exceeding 400 mg/m2.
    b) History of significant neurological or psychiatric disorders.
    c) Active infection requiring systemic treatment.
    d) Significant non-neoplastic liver disease (e.g., cirrhosis).
    e) Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
    f) Immunocompromised patients, including those known to be infected with the human immunodeficiency virus (HIV).
    g) Uncontrolled (i.e., requiring relevant changes in medication within the last month or hospital admission within the last three months) endocrine diseases (e.g.,
    diabetes mellitus, hypo- or hyperthyroidism, adrenal disorder).
    8. Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in the study. The Investigator should feel free to consult the Study Coordinator or the Sponsor(s) in
    case of uncertainty in this regard.
    9. Limitation of the patient’s ability to comply with the treatment or to follow-up at a participating center. Patients enrolled into this trial must be treated and followed at a
    participating center.
    10.Treatment with any investigational product within 30 days prior to inclusion in the study.
    11.Known hypersensitivity to any component of Zalypsis®.
    E.5 End points
    E.5.1Primary end point(s)
    Overall response rate (ORR), defined as the percentage of patients with confirmed OR, either CR or PR, according to the RECIST v 1.1.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    Planned study termination will occur:

    Depending on the development/extension of the trial:
    o Three months after the last treatment visit of the last evaluable patient if the study ends at the first stage.
    o Six months after the last treatment visit of the last evaluable patient, if the study proceeds to the second stage.

    Or 12 months after the last patient included in the study, if neither of the above have occurred.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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) Yes
    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 state6
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 29
    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 Decision2010-11-26
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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