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    Summary
    EudraCT Number:2018-002275-18
    Sponsor's Protocol Code Number:MS100036-0020
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-06-03
    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 ConcernedGermany - BfArM
    A.2EudraCT number2018-002275-18
    A.3Full title of the trial
    A multicenter study with an open-label Phase Ib part followed by a randomized, placebo-controlled, double-blind, Phase II part to evaluate efficacy,
    safety, tolerability, and pharmacokinetics of the DNA-PK inhibitor M3814 in combination with capecitabine and radiotherapy in participants with
    locally advanced rectal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase Ib/II study of M3814 in combination with capecitabine and radiotherapy in rectal cancer
    A.4.1Sponsor's protocol code numberMS100036-0020
    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 SponsorMerck KGaA
    B.1.3.4CountryGermany
    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 supportMerck KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication CenterMerck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post codeD-64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+496151725200
    B.5.6E-mailservice@merckgroup.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePeposertib
    D.3.2Product code M3814
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPeposertib
    D.3.9.1CAS number 1637542-33-6
    D.3.9.2Current sponsor codeM3814
    D.3.9.3Other descriptive nameMSC2490484A or M3814
    D.3.9.4EV Substance CodeSUB177085
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Locally advanced rectal cancer
    E.1.1.1Medical condition in easily understood language
    Locally advanced rectal cancer
    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 10038038
    E.1.2Term Rectal cancer
    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
    Phase II -
    To evaluate the efficacy of M3814 in terms of pCR/cCR when administered in combination with capecitabine and RT versus placebo, capecitabine and RT
    E.2.2Secondary objectives of the trial
    Phase II -
    To evaluate safety and tolerability of M3814 when administered in combination with capecitabine and RT versus placebo, capecitabine and RT
    To evaluate the efficacy of M3814 when administered in combination with capecitabine and RT versus placebo, capecitabine and RT
    To measure QoL
    To investigate the PK of M3814 using population PK modeling
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants are eligible to be included in the study only if all the following criteria apply:
    Age
    1. Are ≥ 18 years of age, at the time of signing the informed consent

    Type of Participant and Disease Characteristics
    2. Have an Eastern Cooperative Oncology Group Performance Status ≤ 1
    3. Have histologically confirmed and localized resectable rectal cancer (Stage II or Stage III at original staging). Participants who received induction chemotherapy are allowed to be enrolled to this study except if this induction is resulting in complete response (as per tumor evaluation charter).
    4. Have lower edge of the tumor located in rectum
    5. Have evaluable disease in MRI
    6. Have adequate hematological function: hemoglobin ≥ 9 g/dL, neutrophils ≥ 1.5 × 109/L and platelets ≥ 100 × 109/L
    7. Have adequate renal function: serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance ≥ 50 mL/min
    8. Have adequate liver function: aspartate aminotransferase, alanine transaminase, alkaline phosphatase ≤ 3 × ULN, and bilirubin ≤ 1.5 × ULN
    Sex
    9. Are male or female
     Male participants:
    Agree to the following during the study intervention period and for at least 12 weeks after the last dose of study intervention:
    o Refrain from donating sperm
    Plus, either:
    o Abstain from any activity that allows for exposure to ejaculate.
    OR
    o Use a male condom:
     When having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with
    a failure rate of <1% per year, since a condom may break or leak.
     When engaging in any activity that allows for exposure to ejaculate.
     Female Participants:
    o Are not pregnant or breastfeeding, and at least one of the following conditions applies:
     Not a WOCBP
    OR
     If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of <1% per year), preferably with low user dependency, as
    described for the following time periods:
    o Before the first dose of the study intervention(s), if using hormonal contraception:
     Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses
    OR
     Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly
    sensitive assay.
    AND
     A barrier method.
    o During the intervention period
    o After the study intervention period (i.e., after the last dose of study intervention is administered) for at least 12 weeks, after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period.
    The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
    o Have a negative serum pregnancy test, as required by local regulations, within 4 weeks before the first dose of study intervention. Additional requirements for pregnancy testing during and after study intervention .
    -The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.

    Informed Consent
    10. Can give signed informed consent, which includes compliance with the requirements and restrictions listed in an informed consent
    form (ICF) and this protocol.
    E.4Principal exclusion criteria
    Participants are excluded from the study if any of the following criteria apply:
    Medical Conditions
    1. History of any other significant medical disease or psychiatric conditions that might in the assessment of the Investigator preclude safe participation in the study
    2. History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study intervention
    3. Unstable cardiovascular function within 6 months prior to enrollment (i.e., ischemia, symptomatic angina, congestive heart failure, Class III to IV New York Heart Association uncontrolled conduction abnormalities including a history of long QTc syndrome [QTcF > 480 ms] and/or pacemaker, or myocardial infarction)
    4. Hypertension uncontrolled by medication (i.e., systolic blood pressure ≥ 150 mmHg and diastolic blood pressure ≥ 90 mmHg)
    5. History of other malignant disease within the past 5 years, other than successfully treated basal carcinoma of the skin or carcinoma in situ of the cervix
    6. Known human immunodeficiency virus positivity, known active viral hepatitis, current alcohol abuse, or cirrhosis.
    7. Ongoing active infection other than human immunodeficiency virus, hepatitis B virus, or hepatitis C virus, or treatment with a live attenuated vaccine within 4 weeks of dosing

    Prior/Concomitant Therapy
    8. Previous radiation therapy to the pelvis
    9. Concurrent use of other anticancer therapy
    10. Major surgical intervention within 4 weeks prior to the first dose of study intervention. Biopsy(s) to establish the diagnosis for rectal cancer is permitted. Diverting ostomy is permitted
    11. Concomitant or prior use of medications or herbal supplements, known to be strong inhibitors of cytochrome P450 (CYP) 3A and/or CYP2C19, unless use can be discontinued 1 week prior to receiving the first dose of study intervention. Concomitant or prior use of medications or herbal supplements, known to be strong inducers of CYP3A and/or CYP2C19, unless use can be discontinued at least 3 weeks prior to receiving study
    intervention. Concomitant or prior therapy use of medications or herbal supplements mainly metabolized by CYP3A with a narrow therapeutic index must be stopped at least 1 day prior to receiving study intervention
    12. Concomitant use of H2-blocker or proton pump inhibitors (PPIs) (or unable to stop at least 5 days prior to the first treatment). Note that calcium carbonate is acceptable
    13. Treatment with sorivudine or its chemically related analogues, such as brivudine

    Prior/Concurrent Clinical Study Experience
    14. Participation in any interventional clinical study within 28 days prior to Screening or during participation in this study

    Diagnostic Assessments
    15. Contraindications to MRI imaging

    Other Exclusions
    16. Pregnant or nursing (lactating) women
    17. Known dihydropyrimidine dehydrogenase deficiency
    18. History of severe and unexpected reactions to fluoropyrimidine therapy
    19. Hypersensitivity to capecitabine or to any of the excipients or fluorouracil.
    E.5 End points
    E.5.1Primary end point(s)
    Phase II -
    Composite endpoint of pCR/cCR
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase II -
    Pathology evaluation of specimen after surgery (pCR) and clinical evaluation 1 to 2 weeks prior to surgery (cCR)
    E.5.2Secondary end point(s)
    Phase II -
    -Occurrence of TEAEs and treatment-related adverse events according to the NCI-CTCAE version 5.0
    -Occurrence of abnormalities (Grade ≥ 3) in laboratory test values, markedly abnormal vital sign measurements, and clinically significantly abnormal ECGs
    - Disease-free Survival
    -Overall Survival
    -pCR
    -cCR
    -Best Overall Response assessed by the Investigator
    -Local and/or distant recurrence
    -Neoadjuvant Rectal Score
    -Surgical intervention in participants who have not undergone primary surgery due to cCR
    -R0 resection (no residual tumor)
    -Patient-reported outcomes / health related QoL as reported using the EORTC QLQ-C30, EORTC-CR29, and EQ-5D-5L
    -PK profile of M3814 in terms of PK parameter estimates (e.g., AUC0-t, CL/f and Vz/f)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the trial
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    placebo-controlled
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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 EEA36
    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
    Canada
    France
    Germany
    Italy
    Poland
    Spain
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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 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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 126
    F.4.2.2In the whole clinical trial 150
    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 a participant has completed the study or has withdrawn prematurely, usual treatment will be administered, if required, in accordance with the study site’s SoC and generally accepted medical practice and depending on the participant’s individual medical needs.
    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 Decision2020-07-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-29
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-04-12
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