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    Summary
    EudraCT Number:2016-000706-12
    Sponsor's Protocol Code Number:SUNNIFORECAST
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-11-01
    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 - PEI
    A.2EudraCT number2016-000706-12
    A.3Full title of the trial
    A Phase 2, Randomized, Open-Label Study of Nivolumab Combined with Ipilimumab Versus Standard of Care in Subjects with Previously Untreated and Advanced (unresectable or metastatic) non-clear Cell Renal Cell Carcinoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2, Randomized, Open-Label Study of Nivolumab Combined with Ipilimumab Versus Standard of Care in Subjects with Previously Untreated and Advanced (unresectable or metastatic) non-clear Cell Renal Cell Carcinoma
    A.3.2Name or abbreviated title of the trial where available
    SUNNIFORECAST
    A.4.1Sponsor's protocol code numberSUNNIFORECAST
    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 SponsorGoethe University Frankfurt
    B.1.3.4CountryGermany
    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 supportGoethe University Frankfurt
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportBristol-Myers Squibb
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGoethe Univeristy Frankfurt
    B.5.2Functional name of contact pointDr. Nicola Gökbuget
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Stern-Kai 7
    B.5.3.2Town/ cityFrankfurt
    B.5.3.3Post code60590
    B.5.3.4CountryGermany
    B.5.4Telephone number00496963016366
    B.5.5Fax number00496963017463
    B.5.6E-mailgoekbuget@em.uni-frankfurt.de
    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 AuthorisationEuropean Union
    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 nameNivolumab
    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.3.11 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 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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibodies
    D.IMP: 2
    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 YERVOY
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameIpilimumab
    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.3.11 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 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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibodies
    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
    The primary objective of the study is to compare the of OS rate at 12 months of Nivolumab combined with Ipilimumab to Standard of Care in patients with previously untreated and advanced non-clear cell RCC.
    E.1.1.1Medical condition in easily understood language
    Survival of patients with kidney 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 LLT
    E.1.2Classification code 10038415
    E.1.2Term Renal cell carcinoma stage unspecified
    E.1.2System Organ Class 100000004864
    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 of the study is to compare the of OS rate at 12 months of Nivolumab combined with Ipilimumab to Standard of Care in patients with previously untreated and advanced non-clear cell RCC.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to examine if the following is achieved:
    To compare the OS rate at 12 months of Nivolumab combined with Ipilimumab to Standard of Care in patients with previously untreated and advanced non-clear cell RCC in relation to histological subgroups
     To compare the OS rate at 6 and 18 months of Nivolumab combined with Ipilimumab to Standard of Care in previously untreated and advanced non-clear cell RCC
     Duration of reponse (DOR) for both arms and subgroups
     To compare the PFS of Nivolumab combined with Ipilimumab to Standard of Care with previously untreated metastatic non-clear cell RCC
     To compare the medianOS of Nivolumab combined with Ipilimumab to Standard of Care in subjects with previously untreated metastatic non-clear cell RCC C (based on hazard ratio)
     To estimate the objective response rate (ORR) of Nivolumab combined with Ipilimumab to Standard of Care in subjects with previously untreated mRCC
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed Written Informed Consent
    a) Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
    b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
    2. Target Population
    a) Histological confirmation of non-clear RCC with at least 50% non-clear cell component according to actual WHO classification36
    b) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
    c) Karnofsky > 70% (See Appendix 2, 14.2)
    d) Measurable disease as per RECIST v 1.1 (See Appendix 3, 14.3) documented by an English radiology report
    e) Tumor tissue (FFPE archival or recent acquisition) must be available and sent to the central pathological reviewer (see Table 6) in order to confirm the diagnosis. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission).
    f) Patients with all risk categories will be eligible for the study. Patients will be stratified for papillary or non-papillary non-clear cell histology and IMDC risk score Patients will be categorized according to favorable versus intermediate versus poor risk status at registration according to the International Metastatic RCC Database Consortium (IMDC) criteria:
    i. KPS equal to 70%
    ii. Less than 1 year from diagnosis to randomization
    iii. Hemoglobin less than the lower limit of normal (LLN)
    iv. Corrected calcium concentration greater than the upper limit of normal (ULN)
    v. Absolute neutrophil count greater than the ULN
    vi. Platelet count greater than the ULN
    If none of the above factors are present, subjects are only eligible for the favorable-risk cohort, if
    1-2 factors are present subjects are catogerized as intermediate risk and > 3 factors as poor risk.
    3. Age and Reproductive Status
    a) Males and Females, ≥ 18 years of age
    b) 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 study drug.
    c) Women must not be breastfeeding
    d) WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. The terminal half-lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours. The terminal half-life of other standard of care agents has to be derived from the product information.
    i. WOCBP randomized to receive Nivolumab + Ipilimumab should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
    ii. WOCBP randomized to receive a standard of care agent should use an adequate method to avoid pregnancy for at least 8 weeks (30 days plus the time required for the active metabolite of the standard of care agent to undergo five half-lives)
    e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives. The terminal half-lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours.
    i. Males randomized to receive Nivolumab combined with Ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
    ii. Males randomized to receive standard of care who are sexually active with WOCBP must continue contraception for at least16 weeks (90 days plus the time required for the active metabolite of the standard of care agent to undergo five half-lives) after the last dose of investigational drug.
    f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy
    testing as described in this section.
    E.4Principal exclusion criteria
    1) Any active brain metastases requiring systemic corticosteroids.
    2) Tumors with a clear-cell component of > 50% Medical History and Concurrent Diseases
    3) Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, Sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) or prior treatment with an mTOR inhibitor or cytokines.
    4) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
    5) Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone
    replacement are permitted to enroll.
    6) Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
    7) Uncontrolled adrenal insufficiency.
    8) Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3√RR
    9) Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥ 150 mmHg or diastolic blood pressure (DBP) of ≥ 90 mmHg), despite antihypertensive therapy.
    10) History of any of the following cardiovascular conditions within 12 months of enrollment:
    cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association.
    11) History of cerebrovascular accident including transient ischemic attack within the past 12 months.
    12) History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin
    13) History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
    14) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
    15) Serious, non-healing wound or ulcer.
    16) Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
    17) Any requirement for anti-coagulation, except for low molecular weight heparin.
    18) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
    19) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    20) Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
    21) Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
    22) Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
    23) Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.
    24) Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
    25) Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Sunitinib
    26) Left ventricular ejection fraction (LVEF) less than the LLN as assessed by echocardiography or multigated acquisition (MUGA) scan.
    27) Any of the following laboratory test findings:
    i. WBC < 2,000/mm3
    ii. Neutrophils < 1,500/mm3
    iii. Platelets < 100,000/mm3
    iv. AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
    v. Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
    vi. Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula):
    28) History of severe hypersensitivity reaction to any monoclonal antibody.
    29) Subjects who are incompetent to understand and sign the informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is the overall survival rate at 12 months (OS12) (landmark).
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months after start of treatment of patient.
    E.5.2Secondary end point(s)
    Secondary endpoints were:
     OS rate at 6 and 18 months in overall population and histological and prognostic subgroups.
     Overall survival (OS)
     Progression-free survival (PFS)
     Objective response rate (ORR)
     Safety/tolerability
     Quality of Life (QoL) as assessed by FKSI-DRS questionnaire
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints were:
     OS rate at 6 and 18 months in overall population and histological and prognostic subgroups.
     Overall survival (OS)
     Progression-free survival (PFS)
     Objective response rate (ORR)
     Safety/tolerability
     Quality of Life (QoL) as assessed by FKSI-DRS questionnaire
    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 No
    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 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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard of care
    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 concerned17
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    The study will end 18 months after the last patient is in.
    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 months6
    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 months6
    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: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 306
    F.4.2.2In the whole clinical trial 306
    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)
    The study drug (ipilimumab and nivolumab) is supplied by Bristol-Myers-Squibb (BMS). After the end of the study, subjects who continue to demonstrate clinical benefit will be eligible to receive BMS supplied study drug. Study drug will be provided through another mechanism at the discretion of BMS.
    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 Decision2017-01-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-29
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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