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    Summary
    EudraCT Number:2015-001476-22
    Sponsor's Protocol Code Number:04-30
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-07-04
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2015-001476-22
    A.3Full title of the trial
    A Phase III, International, Randomized, Controlled Study of Rigosertib versus Physicians Choice of Treatment in Patients with Myelodysplastic Syndrome after Failure of a Hypomethylating Agent.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study which compares Rigosertib with standard of care treatment in patients with ineffective production of blood cells (myelodysplastic syndrome) who have undergone treatment with azacitidine or decitabine without success
    A.4.1Sponsor's protocol code number04-30
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02562443
    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 SponsorOnconova Therapeutics, Inc.
    B.1.3.4CountryUnited States
    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 supportOnconova Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOnconova Europe GmbH
    B.5.2Functional name of contact pointSponsor Contact
    B.5.3 Address:
    B.5.3.1Street AddressKarlstr. 35
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code80333
    B.5.3.4CountryGermany
    B.5.4Telephone number+34656577065
    B.5.6E-mailwmeyer@onconova.us
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/12/987
    D.3 Description of the IMP
    D.3.1Product nameRigosertib sodium
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRigosertib sodium
    D.3.9.1CAS number 592542-59-1
    D.3.9.3Other descriptive nameON 01910.Na
    D.3.9.4EV Substance CodeSUB32475
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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
    Myelodysplastic Syndrome
    E.1.1.1Medical condition in easily understood language
    Myelodysplastic syndrome (MDS) is a group of disorders in which the red blood cells, white blood cells and platelets produced by the bone marrow do not grow and mature normally
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028533
    E.1.2Term Myelodysplastic syndrome
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary efficacy objective of this clinical trial is
    • To compare the overall survival (OS) of patients in the rigosertib group vs the Physician's Choice group, in all patients and in a subgroup of patients with IPSS-R very high risk
    E.2.2Secondary objectives of the trial
    Secondary efficacy objectives:
    • To compare rigosertib to Physician's Choice with regard to the following:
    - Overall survival of patients with monosomy 7 chromosomal aberrations
    - Overall survival of patients with trisomy 8 chromosomal aberrations
    - Overall response according to 2006 International Working Group (IWG) criteria.
    - Quality-of-life (QoL) scores using the EuroQol EQ-5D Questionnaire.
    - Overall bone marrow blast response according to 2006 IWG criteria.
    - Hematologic improvement (HI) (erythroid, platelet or neutrophil response) according to 2006 IWG criteria.

    Exploratory Objectives:
    Evaluation of the following:
    • Bone marrow genomic mutational status
    • Transformation time to AML (defined as a bone marrow or peripheral blood blast percentage >30%)

    Safety objectives:
    Evaluation of the following:
    • Safety and tolerability of rigosertib administered as 72-hour CIV infusions versus PC
    • Rigosertib population pharmacokinetics (PK)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a. 18-81 years of age;
    b. Disease classification and cytogenetics confirmed within 8 weeks prior to or during screening as follows:
    - RAEB-1 per World Health Organization (WHO) MDS criteria (5% to <10% BM blasts)
    - RAEB-2 per WHO MDS criteria (10% to <20% BM blasts)
    - RAEB-t per modified French-American-British (FAB) classification (20% to 30% BM blasts)
    c. At least one cytopenia (ANC < 1800/μL or platelet count < 100,000/μL or hemoglobin [Hgb] < 10 g/dL)
    d. Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DAC treatment
    or
    Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC administered
    or
    Relapse after initial complete or partial response or HI (according to 2006 IWG criteria)
    or
    Intolerance to AZA or DAC
    e. Total duration of prior HMA therapy ≤ 9 months and/or total ≤ 9 cycles of prior HMA therapy in ≤ 12 months
    f. Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization
    g. Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogeneic stem cell transplantation
    h. Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization; growth factors (G-CSF, erythropoietin and TPO) and transfusions are allowed before and during the study as clinically indicated
    i. Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide where available and indicated
    j. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
    k. Willing to adhere to the prohibitions and restrictions specified in this protocol
    l. Patient must sign an Informed Consent form indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study. In case a patient is incapable of giving consent, the patient;’s legally authorized representative (as defined by local regulation) must give consent. However, should the patient in any manner indicate the will not to participate this takes precedence and must be respected.
    E.4Principal exclusion criteria
    a. Previous participation in a clinical study of IV or oral rigosertib; patients who failed screening for other rigosertib studies may be screened for participation in this study
    b. Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside and 2-3 days of an anthracycline, or high-dose cytarabine (HDAC)
    c. Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood blast percentage >30%)
    d. Suitable candidate to receive allogeneic stem cell transplantation; patient is eligible for study if a suitable candidate refuses to undergo an
    allogeneic stem cell transplant or a suitable donor cannot be found
    e. Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ that is unlikely to progress in two years
    f. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
    g. Active infection not adequately responding to appropriate therapy
    h. Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert's disease
    i. Alanine transaminase (ALT)/aspartate transaminase (AST) ≥ 2.5 x upper limit of normal (ULN)
    j. Serum creatinine ≥ 2.0 mg/dL or eGFR (estimated Glomerular Filtration Rate) <40 mL/min.
    k. Known active HIV, hepatitis B or hepatitis C, where active is defined as follows:
    a. HIV or Hepatitis C – presence of viral load
    b. Hepatitis B – antigen positive
    l. Uncorrected hyponatremia (defined as serum sodium value of <130 mEq/L)
    m. Female patients of child-bearing potential (pre-menopausal and not surgically sterilized), who are breast-feeding or have a positive blood
    beta-human chorionic gonadotropin (β-HCG) pregnancy test at Screening
    n. Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements before entry and throughout the study, up to and including the 30-day non-treatment follow-up period
    Examples of acceptable contraception methods include:
    − estrogen-gestagen based contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal),
    − gestagen-only based contraceptives associated with inhibition of ovulation (oral, injectable, implantable),
    − intra-uterine devices (IUDs),
    − intra-uterine hormone-releasing systems (IUSs),
    − bilateral tubal occlusion,
    − vasectomized partner,
    − sexual abstinence in accordance with an individual's lifestyle
    o. Major surgery without full recovery or major surgery within 3 weeks before planned randomization
    p. Uncontrolled hypertension
    q. New onset seizures (within 3 months before planned randomization) or poorly controlled seizures
    r. Any other concurrent investigational agent or chemotherapy, radiotherapy, immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions)
    s. Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted to the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization
    t. Investigational therapy within 4 weeks of planned randomization
    u. Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoints are overall survival of all randomized patients (ITT population), and overall survival of patients scored as IPSS-R very high risk.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At each individual patient's death
    E.5.2Secondary end point(s)
    - Overall survival of patients with monosomy 7 chromosomal aberrations.
    - Overall survival of patients with trisomy 8 chromosomal aberrations.
    - Overall response rate according to 2006 IWG criteria.
    - Quality-of-life scores using the EuroQol EQ-5D Questionnaire.
    - Bone marrow blast response rate according to 2006 IWG criteria.
    - Hematologic improvement (erythroid, platelet, or neutrophil response)according to 2006 IWG criteria.
    - Worst-grade adverse events (AEs).
    - Deaths, other serious AEs, and other AEs leading to discontinuation of study treatment.
    - Worst-grade laboratory abnormalities.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not applicable
    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 No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    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
    Physician's Choice of Treatment
    E.8.2.4Number of treatment arms in the trial2
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA68
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Bulgaria
    Canada
    Croatia
    Czech Republic
    Estonia
    France
    Germany
    Hungary
    India
    Ireland
    Israel
    Italy
    Japan
    Netherlands
    Poland
    Russian Federation
    Spain
    Sweden
    Switzerland
    United Kingdom
    United States
    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
    Patients will be treated until 2006 IWG progression criteria are met (ie, 50% increase of BM blasts or worsening of cytopenias).
    The end of the trial is given by the last patient's death.
    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 months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days12
    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: 181
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 179
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 241
    F.4.2.2In the whole clinical trial 360
    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)
    In case of termination of clinical trial treatment (2006 IWG progression criteria are met, ie, 50% increase of BM blasts or worsening of cytopenias, or upon occurrence of an unacceptable toxicity or intolerance) patients will receive treatment (except for rigosertib) as per their consent and the discretion of their physician.
    Patients will be followed up in this clinical trial until death.
    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 Decision2016-08-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-08-23
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