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    Summary
    EudraCT Number:2016-004163-39
    Sponsor's Protocol Code Number:OV126b
    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:2017-06-27
    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 number2016-004163-39
    A.3Full title of the trial
    A randomized, open-label, multicentric phase II trial of PEMBROLIZUMAB (Ketruda®) with chemotherapy versus chemotherapy alone (standard of care) as neo adjuvant treatment of ovarian cancer not amenable to front line debulking surgery.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Addition of Pembrolizumab to the standard of care chemotherapy in patient with advanced ovarian cancer
    A.4.1Sponsor's protocol code numberOV126b
    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 SponsorARCAGY-GINECO
    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 supportMerck Sharp and dome limited
    B.4.2CountryUnited Kingdom
    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.2.1.2Country which granted the Marketing AuthorisationFrance
    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 namepembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form 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 INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853914
    D.3.9.2Current sponsor codeMK 3475
    D.3.9.3Other descriptive nameAnti PD 1
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 ovarian cancer
    E.1.1.1Medical condition in easily understood language
    ovarian 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 10070908
    E.1.2Term Ovarian cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10070907
    E.1.2Term Ovarian cancer stage III
    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
    The primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab and chemo-therapy or chemotherapy alone measured by the complete resection rate after interval debulking surgery. Complete resection will be defined as the removal of all macroscopic residual tumor (Com-plete Cytoreduction score = 0).
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of the addition of pembrolizumab to chemotherapy assessed by :
    o The Objective Response Rate at the time of interval debulking surgery (after 4 neo ad-juvant cycles) using RECIST 1.1 criteria
    o The rate of the pCR
    o The Best Overall Response to the global strategy of interval debulking surgery + chemo-therapy +/- Pembrolizumab assessed by CT-Scan (using RECIST 1.1) at the end of treat-ment visit & before interval surgery?.
    o The Progression-Free Survival (PFS) using RECIST 1.1 criteria
    o Biological Progression-Free Interval (PFIBIO), by serum Ca125 measured according to the GCIG criteria
    o The overall survival
    • To assess the safety profile of neo adjuvant and adjuvant pembrolizumab when combined with standard of care, according to NCI CTC-AE v4.03.
    • To assess the Post-operative mortality
    • To assess the Post-operative morbidity according to modified Clavien Dindo scoring.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Be willing and able to provide written informed consent for the trial.
    2.Woman 18 and ≤ 75 years old on day of signing informed consent
    3.Histologically confirmed diagnosis of epithelial ovarian carcinoma or fallopian tube carcinoma or primary peritoneal carcinoma with the exception of clear cell, mucinous histology. Histolo-gy should be obtained by laparoscopy (or by laparotomy).
    4.High grade serous or endometrioid (see appendix 1 bis)
    5.Advanced FIGO stage IIIC to IV patient not able to receive primary debulking surgery for whichneo adjuvant chemotherapy with carboplatin and paclitaxel is recommended. (
    Patients with extra abdominal metastasis (FIGO 2014 Stage IV) can be included in case of completely resectable metastasis.
    6.Primary debulking surgery denied and maximum surgical effort of cytoreduction with the goal of no residual disease planned as interval debulking surgery(i.e. Sugarbaker index less than 30)
    7.Eligible for carboplatin and paclitaxel chemotherapy in accordance with local standards of care following cytoreductive surgery.
    8. Debulking surgery anticipated in a center with excellence.
    9. ECOG performance status (PS) ≤ 2.
    10. Life expectancy of at least 6 months,
    11. Interval between diagnosis and enrolment (informed consent) ≤ 8 weeks,
    12. Be willing to provide blood, and tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 8 weeks (56 days) prior to initiation of treatment on Day 1.
    13. Demonstrate adequate organ function as defined, all screening labs should be performed within 7 days before randomization.
    14. Adequate hematological laboratory value:
    • Absolute neutrophil count (ANC) : ≥1,500/mm3
    • Platelets : ≥100,000/mm3
    15. Hemoglobin : ≥9 g/ Adequate renal laboratory value:
    Serum creatinine OR Measured or calculated creatinine clearance a (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
    (Creatinine clearance is calculated according to Cockcroft formula or to MDRD formula for patients older than 65 years-old. Glomerular filtration rate or creatinine clearance according to MDRD formula is: GFR = 186 x (creatinine (µmol/l) x 0,0113)-1,154 x age- 0,203 x 0.742.)
    16. Adequate hepatic laboratory value:
    • Serum total bilirubin: ≤ 1.5 X ULN OR
    • Direct bilirubin: ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    • AST (SGOT) and ALT (SGPT): ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
    17.Adequate coagulation laboratory value:
    • International Normalized Ratio (INR) or Prothrombin Time (PT) : ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • Activated Partial Thromboplastin Time (aPTT): ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    18.Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    19.Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. (see the contraception requirement)
    20. Patient should be beneficiary of healthcare coverage under the social security system.

    E.4Principal exclusion criteria
    1. Histological diagnosis of malignant tumor of non-epithelial origin (e.g. germ cell tumor, sex cord-stromal tumor) of the ovary, the fallopian tube or peritoneum or borderline tumor of the ovary (tumor of low malignant potential).
    2. Patients with extra abdominal metastasis (FIGO 2014 Stage IV) not completely resectable, as e.g. multiple parenchymal lung metastases (preferably histologically proven), non resectable lymph node metastases, brain metastases.
    3. Prior systemic therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, oral targeted therapy, hormonal therapy),
    4. Prior radiotherapy to the abdomen or prior radiotherapy to an extra-abdominal target volume that would bear the risk of increased toxicity of chemotherapy,
    5. Serious illness or concomitant non-oncological disease such as neurologic, cardiologic (ie. congestive heart failure > NYHA II), psychiatric or infectious disease, active ulcers (gastroin-testinal tract, skin) or a laboratory abnormality that may Increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study,
    6. Any contraindications for therapy with paclitaxel or carboplatin, e.g. a history of severe hy-persensitivity reactions to paclitaxel or platinum-containing compounds and their excipients, or other drugs formulated with Polyoxyl 35Is currently participating and receiving study ther-apy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
    7. Diagnosis of immunodeficiency or receiving prolonged period of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
    8. Known history of active Bacillus Tuberculosis (TB)
    9. Hypersensitivity to pembrolizumab or any of its excipients.
    10. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not re-covery (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
    11. Known additional malignancy that is progressing or requires active treatment. Exceptions in-clude basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has under-gone potentially curative therapy or in situ cervical cancer.
    12. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded re-gardless of clinical stability.
    13. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
    14. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
    15. History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    16. Active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
    17. Vaccination with a live vaccine within 30 days of planned start of study therapy.
    Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
    18. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
    19. Active infection requiring systemic therapy.
    20. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
    21. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule,
    22. Psychiatric or substance abuse disorders that would interfere with cooperation with the re-quirements of the trial.
    23. Active alcohol or drug abuse,
    24. Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective is to evaluate the efficacy of neo adjuvant pembrolizumab and chemotherapy or chemo-therapy alone measured by the complete resection rate after interval debulking surgery. Complete resection will be defined as the removal of all macroscopic residual tumor (CC score = 0).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After interval debulking surgery
    E.5.2Secondary end point(s)
    • The Objective Response Rate assessed by CT-Scan (RECIST 1.1) at the time of interval debulking sur-gery (after 4 neo adjuvant cycles of treatment)
    • The rate of Pathologic Complete Response (pCR) after surgery
    • The best response rate
    • The Progression-Free Survival (PFS)
    • Biological Progression-Free Interval (PFIBIO), measured according to the GCIG criteria (
    • Overall survival (OS)
    • The Best Overall Response to the global strategy of interval debulking surgery + chemotherapy +/- Pembrolizumab (MK-3475) assessed by CT-Scan (using RECIST 1.1) at the end of treatment visit.
    To assess the safety profile of neo adjuvant and adjuvant pembrolizumab when combined with standard of care, according to NCI CTC-AE v4.03.
    • To assess Post-operative mortality
    • To assess Post-operative morbidity according to modified Clavien Dindo scoring
    Radiological responses will be assessed by the investigators, according to RECIST version 1.1.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The Objective Response Rate assessed by CT-Scan (RECIST 1.1)
    • The rate of Pathologic Complete Response (pCR) after surgery
    • The best response rate
    • The Progression-Free Survival (PFS)
    • Biological Progression-Free Interval (PFIBIO), measured according to the GCIG criteria
    • Overall survival (OS)
    • The Best Overall Response assessed by CT-Scan (using RECIST 1.1) at the end of treatment visit.
    To assess the safety profile according to NCI CTC-AE v4.03.
    • To assess Post-operative mortality
    • To assess Post-operative morbidity according to modified Clavien Dindo scoring
    Radiological responses will be assessed by the investigators, according to RECIST version 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) 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 Yes
    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) No
    E.8.2.2Placebo No
    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 concerned20
    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 No
    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 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 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 No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    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 state90
    F.4.2 For a multinational trial
    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)
    standard of care
    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 Decision2017-06-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-30
    P. End of Trial
    P.End of Trial StatusOngoing
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