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    Summary
    EudraCT Number:2017-002054-37
    Sponsor's Protocol Code Number:1000053649
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-05-15
    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 number2017-002054-37
    A.3Full title of the trial
    Pilot Study of Nivolumab in Pediatric Patients with Hypermutant Cancers
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Early study to evaluate the effect of Nivolumab in children with cancers that grow/arise due to lot of abnormal DNA.
    A.4.1Sponsor's protocol code number1000053649
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02992964
    A.5.4Other Identifiers
    Name:Ozmosis Study numberNumber:OZM-075
    Name:SMS-oncology study numberNumber:SMS-0370
    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 SponsorHospital for Sick Children
    B.1.3.4CountryCanada
    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 supportBristol-Myers Squibb-(BMS)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSMS-oncology
    B.5.2Functional name of contact pointAnuska Mohaboe
    B.5.3 Address:
    B.5.3.1Street AddressWalaardt Sacréstraat 401-403
    B.5.3.2Town/ citySchiphol
    B.5.3.3Post code1117 BM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310204350580
    B.5.5Fax number+310204350589
    B.5.6E-mailregulatory@sms-oncology.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 Yes
    D.2.1.1.1Trade name Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical 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 INNNivolumab
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) No
    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
    HYPERMUTANT CANCERS
    E.1.1.1Medical condition in easily understood language
    cancers with a lot of abnormal DNA
    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 10078672
    E.1.2Term DNA mismatch repair protein gene mutation
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10038111
    E.1.2Term Recurrent cancer
    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 10070308
    E.1.2Term Refractory 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
    To evaluate the objective response rate to Nivolumab in pediatric patients with refractory or recurrent hypermutated malignancies including patients with replication repair deficiencies (RRD), such as constitutional mismatch repair deficiency (CMMRD).
    E.2.2Secondary objectives of the trial
    1. To determine the PFS and OS of paediatric patients with progressive or recurrent hypermutated malignancies, including RRD patients such as CMMRD, treated with nivolumab.
    2. To evaluate safety and tolerability of nivolumab administered as a single agent at the adult recommended dose of 3 mg/kg every 2 weeks. To define and describe the toxicities in paediatric patients with progressive or recurrent hypermutated malignancies including RRD patients, such as CMMRD.

    Companion Biomarker Exploratory Objectives:
    1) To explore associations between tumour mutation burden (TMB) and response to nivolumab.
    2) To discover biomarkers predicting response of hypermutant cancers undergoing PD-1 blockade.
    3) To explore the use of minimally invasive methods to monitor and predict response to immune checkpoint inhibition in hypermutant cancers.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient and LAR must be willing and able to provide written informed consent/assent for the trial as per local requirements
    2. patient must have completed and verified a sufficient TMB level or have proof of RRD diagnosed in the appropriate lab
    3. patients must be ≥ 12 months and < 25 years of age at the time of Part I/II enrollment
    3. Recurrent of relapse pediatric cancer patients suspected to be hypermutant.
    4. patients must have had histologic verification of malignancy at the time of initial diagnosis or at relapse
    5. patients must be able to provide specimen of a tumor lesion.
    5. patients must have either measurable or evaluable disease in accordance with criteria as outlined in Section 10
    6. patient’s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life. Chemotherapy-naïve patients will be eligible in cases where first-line therapy does not include chemotherapy
    7. Karnofsky ≥ 50% for patients > 16 years of age or Lansky ≥ 50 for patients ≤ 16 years of age
    8. patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.
    a. Myelosuppressive chemotherapy: at least 21 days after the last dose (42 days if prior nitrosourea)
    b. Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
    c. Biologic (anti-neoplastic agent): at least 14 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
    d. Monoclonal antibodies: at least three (3) half-lives of the antibody after the last dose of a monoclonal antibody.
    e. Radiation Therapy (XRT): at least 14 days after local palliative XRT (small port). At least 150 days must have elapsed if prior Total Body Irradiation, craniospinal XRT or if ≥ 50% radiation of pelvis. At least 42 days must have elapsed if other substantial BM radiation.
    f. Stem Cell Infusion without Total Body Irradiation (TBI): no evidence of active graft vs. host disease and at least 56 days must have elapsed after transplant or stem cell infusion. Patients with prior allogeneic transplants (including solid organ) are not eligible.
    9. a. Adequate BM Function Defined as
    i. Peripheral ANC ≥0.75 x 109/L or 750/mm3.
    ii. Platelet count ≥75 x 109/L or 75,000/mm3.
    iii. Hemoglobin ≥ 90g/L (transfusion permitted).
    iv. Patients with known BM metastatic disease or haematological malignancies will be eligible for study provided they meet haematological criteria.
    b. Renal Function : serum creatinine based on age/gender as provided in Table 3
    c. Liver Function:
    i. Bilirubin (sum of conjugated + unconjugated or total bilirubin) ≤1.5x institutional ULN for age (except for patients with Gilbert’s Syndrome, when bilirubin of < 51 μmol/L or 3.0 mg/dL is permitted).
    ii. ALT/AST:
    1. ≤ 2.5 x institutional ULN for patients without liver metastases.
    2. ≤ 5 x institutional ULN for patients with liver metastases.
    d. Adequate Pulmonary Function: No history of chronic pulmonary disease and no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency and a pulse oximetry > 92% on room air.
    e. Adequate Pancreatic Function:
    Serum lipase ≤ ULN. Patients with glucose intolerance should be on a stable regiment and be monitored.
    10. For patients with brain tumors, debulking surgery prior to treatment with nivolumab should be considered when appropriate to reduce the risk of pseudoprogression-associated toxicities.
    E.4Principal exclusion criteria
    1. Women who are pregnant or breastfeeding and men who are sexually active with women of childbearing potential (WOCBP)* who are not willing to use effective contraception, or to practice abstinence if this is the usual lifestyle and preferred contraception for the patient. **
     Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as there is yet no available information regarding human fetal or teratogenic toxicities.
     WOCBP must have a negative pregnancy test every 4 weeks. During Part II screening, WOCBP must have a negative serum pregnancy test. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab administration. WOCBP who are sexually active, must be willing to adhere to effective contraception during treatment and for 5 months after the last dose of nivolumab.
     Men who are sexually active with WOCBP must be willing to adhere to effective contraception during treatment and for 7 months after the last dose of nivolumab.
     Women who are surgically sterile, as well as azoospermic men do not require contraception.
    *“Women of childbearing potential” is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
    ** List of contraception methods is provided in the Appendix II
    2. Concomitant Medications
    a. Corticosteroids: Patients requiring systemic steroid therapy or any other form of immunosuppressive therapy within seven (7) days prior to first dose of trial therapy or while on trial are not eligible. The use of physiologic doses of corticosteroids (up to 5mg/m2/day prednisone equivalent) is permitted following discussion with the Study Chair or Co-Chair.
    Note: Use of topical, ocular, intra-articular, intra-nasal or inhaled corticosteroids will not render a patient ineligible. A brief course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergen) is permitted if completed at least 7 days prior to initiation of therapy.
    b. Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
    c. Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
    3. Patients with a History of Autoimmune Disease
     Patients with a history of autoimmune disorder that has required systemic treatment in the previous two (2) years are not eligible. Asymptomatic laboratory abnormalities (e.g. ANA, rheumatoid factor, altered thyroid function studies) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder. Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy) is not considered a form of systemic treatment.
    4. Infection: Patients who have an uncontrolled infection are not eligible.
    5. HIV and/or Hepatitis B/C patients: Patients with known HIV/AIDS or acute/chronic Hepatitis B or C are excluded.
    6. Transplant patients: Patients who have received prior allogeneic Bone Marrow (BM) transplants or prior solid organ transplantation are not eligible.
    7. Non-Compliance: Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
    8. Previous anti-PD-1 and/or anti-PD-L1 therapy: Patients who have received prior anti-PD-1 and/or anti-PD-L1 directed therapy (mAb or small molecule) are not eligible.
    9. Live vaccines: Patients who have received a live vaccine within 30 days of start of study treatment are not eligible.
    E.5 End points
    E.5.1Primary end point(s)
    Tumour disease evaluation, includes objective response rate (ORR = complete response [CR] and partial response [PR]) as defined by iRECIST response criteria for solid tumours (revised for neuroblastoma using the revised INRC), iRANO response criteria for CNS malignancies, RECIL 2017 response criteria for lymphomas, revised criteria according to Creutzig, et al. (2012) for acute myeloid leukemia (AML), and response criteria as specified for acute lymphoblastic leukemia (ALL).
    Patients with response of ‘stable disease’ (SD) will also be reported as part of the final analysis of clinical benefit, but will not contribute to the primary efficacy outcome measure.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After enrollment of 10 subjects and at the end of the study. The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.
    E.5.2Secondary end point(s)
    - PFS is defined as the time from the first dose of the study drug administration to the occurrence of disease progression or death from any cause during the study.
    - OS is defined as time from first dose of study drug to death from any cause.
    - A safety evaluation by the Safety Committee will be performed after Patient 1-Cycle 1, Patient 4-Cycle 1, Patient 7-Cycle 1, and Patient 10-Cycle 1. Enrollment will be held after each time point until a safety evaluation of adverse events (AE) and serious adverse events (SAE) confirms it is safe to resume enrollment.
    - Toxicities will be described and defined in paediatric patients, focusing on SAEs, using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Toxicities (drug-related AEs) of any grade, plus all Grade ≥ 3 AEs, all Grade ≥ 3 laboratory toxicities and all SAEs will be collected for this study.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of the study. The end of the study is defined as the date when the last patient, last visit (LPLV) occurs
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Noninvasive methods (circulating tumour DNA in plasma) to monitor and predict response to immune checkpoint inhibition
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    PILOT STUDY
    E.7.2Therapeutic exploratory (Phase II) No
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA1
    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
    Israel
    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 years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 44
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 24
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6
    F.1.3Elderly (>=65 years) No
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 4
    F.4.2.2In the whole clinical trial 50
    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)
    None
    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 Decision2019-06-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-09
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