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    Summary
    EudraCT Number:2013-001124-19
    Sponsor's Protocol Code Number:04-24
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-05-14
    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 ConcernedGermany - BfArM
    A.2EudraCT number2013-001124-19
    A.3Full title of the trial
    Phase IIIB, Open-label, Multi-Center Study of the Efficacy and Safety of rigosertib Administered as 72-hour Continuous Intravenous Infusions in Patients with Myelodysplastic Syndrome with Excess Blasts Progressing On or After azacitidine or decitabine
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the efficacy and safety of rigosertib given by continuous intravenous infusion for 72 hours in patients with a blood disease called myelodysplastic syndrome who have failed azacitidine or decitabine treatments
    A.4.1Sponsor's protocol code number04-24
    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 organisationChiltern International Ltd.
    B.5.2Functional name of contact pointProject Manager 04-24
    B.5.3 Address:
    B.5.3.1Street AddressThe Logan Building, Roslin Biocentre
    B.5.3.2Town/ cityRoslin, Midlothian
    B.5.3.3Post codeEH25 9TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44131200 6320
    B.5.5Fax number+44131200 6322
    B.5.6E-mailregulatory.service@chiltern.com
    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.3.2Product code ON 01910.Na
    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 18.1
    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 the study is to evaluate the relationship between best bone marrow blast response and overall survival in MDS patients with excess blasts (5-30%) progressing on or after treatment with azacitidine or decitabine. Bone marrow blast response is defined as BM complete response (BMCR), ≥ 50% BM blast decrease from pretreatment value, or stable BM response (no progression) according to the International Working Group (IWG) 2006 criteria.
    E.2.2Secondary objectives of the trial
    • Overall response (complete remission [CR], partial remission [PR], bone marrow complete response [BMCR], and stable disease [SD]) according to 2006 IWG criteria;
    • Hematological improvements (erythroid response [ER], platelet response [PLR] and neutrophil response [NR]) according to 2006 IWG criteria;
    • Improvements of cytogenetics as evaluated by the change in aneuploidy in BM according to 2006 IWG criteria;
    • Progression-free survival;
    • Transition time to AML, where AML is defined as follows:
    - Increase of at least 50% BMBL, and more than 20% BMBL for RAEB-1 and RAEB-2 and CMML patients;
    - Increase of at least 50% BMBL for RAEB-t patients;
    • Quality-of-life (QOL) scores (using EORTC Quality of Life Questionnaire [QLQ]-C30 version 3;
    • Incidence of infections requiring treatment with IV antimicrobials and of bleeding episodes.
    • Population pharmacokinetics.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a. ≥18 years of age;
    b. Diagnosis of MDS confirmed within 6 weeks prior to Screening according to WHO criteria or FAB classification;
    c. MDS classified as follows, according to WHO criteria and FAB classification:
    • RAEB-1 (5% to 9% BM blasts)
    • RAEB-2 (10% to 19% BM blasts)
    • CMML (10% to 20% BM blasts) and white blood cells (WBC) < 13,000/μL
    • RAEB-t (20% to 30% BM blasts), meeting the following criteria:
    - WBC < 25 x 10e9/L at study entry
    - Stable WBC at least 4 weeks prior to Screening and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukophoresis;
    d. At least one cytopenia (ANC < 1800/μL or PLT count < 100,000/μL or hemoglobin [Hgb] < 10 g/dL);
    e. Progression (according to 2006 IWG criteria) at any time after initiation of subcutaneous or intravenous AZA or DEC treatment per labeling during the past 2 years, defined as follows:
    • For patients with < 5% BMBL, ≥ 50% increase in BMBL to > 5% BMBL
    • For patients with 5-10% BMBL, ≥ 50% increase in BMBL to > 10% BMBL
    • For patients with 10-20% BMBL, ≥ 50% increase in BMBL to > 20% BMBL
    • For patients with 20-30% BMBL, ≥ 50% increase in BMBL to > 30% BMBL
    • Any of the following:
    - ≥ 50% decrease from maximum remission/response levels in granulocytes or PLT
    - Decrease in Hgb concentration by ≥ 2 g/dL
    - Transfusion dependence, defined as administration of at least 4 RBC units in the past 8 weeks before Screening (patients must have Hgb values < 9 g/dL prior to transfusion to be considered), in the absence of another explanation.
    f. Has failed to respond to, relapsed following, not eligible, or opted not to participate in BM transplantation;
    g. Off all other treatments for MDS for at least 4 weeks, except for AZA or DEC. Filgrastim (G-CSF) and EPO are allowed before and during the study as clinically indicated;
    h. No medical need for induction chemotherapy;
    i. ECOG performance status of 0, 1 or 2;
    j. Willing to adhere to the prohibitions and restrictions specified in this protocol;
    k. Patient must sign an informed consent form (ICF) indicating that s/he understands the purpose of and procedures required for the study and is willing to participate
    E.4Principal exclusion criteria
    a. Previous participation in a clinical study of IV or oral rigosertib. However, patients who failed screening in pivotal study 04-21 may be screened for participation in this 04-24 study;
    b. Anemia due to factors other than MDS (including hemolysis or gastrointestinal [GI] bleeding) unless stabilized for 1 week after RBC transfusion;
    c. Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast;
    d. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia;
    e. Active infection not adequately responding to appropriate therapy;
    f. Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert’s disease;
    g. ALT/AST ≥ 2.5 x upper limit of normal (ULN);
    h. Serum creatinine ≥ 2.0 mg/dL;
    i. Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of <130 mEq/L);
    j. Female patients who are pregnant or lactating;
    k. Female patients of child-bearing potential and male patients with partners of child-bearing potential who are unwilling to follow strict contraception requirements (including 2 reliable methods in combination: one non-hormonal, highly-reliable method [diaphragm, condoms with spermicidal foam or jelly, or sterilization] plus one additional reliable method [birth control pills, intrauterine device, contraceptive injections, or contraceptive patches]) before entry and throughout the study, up to and including the 30-day nontreatment follow-up period;
    l. Female patients with reproductive potential who do not have a negative blood or urine beta-human chorionic gonadotropin (βHCG) pregnancy test at Screening;
    m. Major surgery without full recovery or major surgery within 3 weeks of Baseline/Cycle 1 Day 1 (C1D1) visit;
    n. Uncontrolled hypertension (defined as a systolic pressure ≥160 mmHg and/or a diastolic pressure ≥ 110 mmHg);
    o. New onset seizures (within 3 months prior to Baseline/C1D1) or poorly controlled seizures;
    p. Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy;
    q. Prior treatment with low-dose cytarabine during the past 2 years;
    r. Investigational therapy within 4 weeks of Baseline/C1D1 visit;
    s. 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)
    • Overall survival, defined as time from first study treatment to death from any cause;
    • Time to transition to AML;
    • Change in BM cytogenetics
    • Changes in ANC, PLT and Hgb values;
    • Changes in RBC and PLT transfusions requirements;
    • EORTC QLQ-C30 questionnaire version 3;
    • Incidence of infections (treated with IV antimicrobials) and bleeding episodes (and their severity);
    • Best BMBL response defined as BMCR, ≥ 50% BMBL decrease from pretreatment value, or stable BM response (no progression) according to IWG 2006 criteria;
    • Time to best BMBL response;
    • Duration of best BMBL response;
    • Time to disease progression as defined per 2006 IWG criteria;
    E.5.1.1Timepoint(s) of evaluation of this end point
    • BM aspirate/biopsy and cytogentics - 6 weeks prior to baseline;
    cytogentics repeated during study only if abnormal at screening; BM
    aspirate/biposy week 4 and every 8 weeks thereafter, and end of study
    • Changes in RBC and PLT transfusions - screening, baseline, weekly
    thereafter
    • EORTC QLQ-C30 questionnaire - baseline, every 4 weeks, and end of
    study
    • Infections and bleeding - every 4 weeks and end of study
    • Serum chemistry/CBC - screening, baseline, weekly thereafter, and at end of study
    E.5.2Secondary end point(s)
    Not applicable
    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 No
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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) 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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Denmark
    France
    Italy
    Spain
    Sweden
    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
    LVLS. Patients will be treated until progression or until death from any cause, whichever comes first.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    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 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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 90
    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)
    Normal treatment of the condition
    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 Decision2013-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-06-29
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