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    Summary
    EudraCT Number:2018-004562-33
    Sponsor's Protocol Code Number:CheCUP
    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:2019-07-22
    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 number2018-004562-33
    A.3Full title of the trial
    A phase II, open-label, non-randomized, multi-center study evaluating the efficacy and safety of nivolumab plus ipilimumab in patients with cancer of unknown primary site who are relapsed after or refractory to platinum-based chemotherapy (CheCUP)
    Eine Phase II, offene, nicht-randomisierte multizentrische Studie zur Bewertung der Wirksamkeit und Sicherheit von Nivolumab plus Ipilimumab bei Patienten mit einer Krebserkrankung mit unbekanntem Primärtumor, die nach einer platinbasierten Chemotherapie rückfällig bzw. therapieresistent sind (CheCUP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II, open-label, non-randomized, multi-center study evaluating the efficacy and safety of nivolumab plus ipilimumab in patients with cancer of unknown primary site who are relapsed after or refractory to platinum-based chemotherapy (CheCUP)
    A.4.1Sponsor's protocol code numberCheCUP
    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 SponsorUniversity Heidelberg, Med. Fac. repr. by University Hospital and its Commercial Managing Director
    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 supportBristol-Myers-Squibb
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Heidelberg
    B.5.2Functional name of contact pointDepartment of Internal Medicine V
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 410
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number+4962215638183
    B.5.5Fax number+496221421444
    B.5.6E-mailAlwin.Kraemer@med.uni-heidelberg.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 YERVOY
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers-Squibb
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 and solvent for 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 INNIPILIMUMAB
    D.3.9.2Current sponsor codeBMS-734016
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.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 OPDIVO
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers-Squibb
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 and solvent 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.3.9.2Current sponsor codeBMS-936558
    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 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
    Cancer of unknown primary site (CUP-Syndrome), relapsed/refractory to platinum-based chemotherapy
    E.1.1.1Medical condition in easily understood language
    Cancer of unknown primary site (CUP-Syndrome), relapsed/refractory to platinum-based chemotherapy
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10007460
    E.1.2Term Carcinoma of unknown primary
    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 main purpose of the study is to determine the efficacy and safety of an immunotherapy with nivolumab plus ipilimumab in subjects with poor-prognosis CUP (non-specific subset as defined in the ESMO guidelines (Fizazi et al. 2015)) who are resistant or refractory to platinum-based first-line chemotherapy. Subjects will be stratified according to their tumor mutational burden (TMB).
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of nivolumab plus ipilimumab in subjects with poor-prognosis CUP (non-specific subset) who are relapsed or refractory to platinum-based first-line chemotherapy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed Informed Consent Form
    - Able and willing to comply with the study protocol
    - Age ≥ 18 years at time of signing Informed Consent Form
    - Histologically-confirmed disseminated or advanced unresectable CUP diagnosed according the criteria defined in the 2015 ESMO Clinical Practice Guidelines for CUP. Acceptable disease histology includes:
    • Adenocarcinoma of unknown primary site (ACUP)
    • Poorly differentiated adenocarcinoma of unknown primary site
    • Poorly differentiated carcinoma of unknown primary site
    • Squamous cell carcinoma of unknown primary site (SCUP)
    - At least one lesion that is measurable according to RECIST v1.1 by CT/MRI
    - Availability of a tumor FFPE block either fresh or archival if obtained ≤ 6 months at Screening that is sufficient for generation of a TruSight Oncology 500 (TSO500) panel at the central reference pathology laboratory or pre-existing result of a TMB analysis from routinely performed panel sequencing using the TSO500 panel at the MPZ, Institute of Pathology, University Heidelberg, which must not be older than < 6 months at screening, respectively. In case one attempt to perform TMB analysis on a new specimen has failed due to insufficient tumor cell quantity or insufficient quality in the specimen, resorting to a specimen not older ≤24 months is allowed as an exception.
    - Availability of test reports confirming local CUP diagnosis. If test reports confirming local CUP diagnosis are not available, an FFPE block or a fresh biopsy sample must be submitted that is sufficient to allow for central confirmation of CUP diagnosis.
    - Disease relapse or progression after at least three cycles of a platinum-based standard chemotherapy. There is no upper limit of prior treatments received.
    - Subjects who have received prior surgery and/or radiotherapy and/or stereotactic brain metastasis radiosurgery are eligible. In case of prior radiotherapy, the measurable lesion(s) must not have been irradiated, radiotherapy has to be finished at least 7 days before inclusion into the study and the patient must have recovered to grade 1 or less from any toxicity of radiotherapy.
    - ECOG performance status of 0 - 2
    - Life expectancy ≥ 12 weeks
    - Eligible for immune checkpoint inhibitor
    - Adequate hematologic and end-organ function as detailed in the protocol (see section 4.4)
    - For women of childbearing potential and men capable of reproduction: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 5 months for women and 7 months for men, respectively after the last dose of study treatment.
    - Recovery from significant toxicity from platinum-doublet therapy to Grade ≤ 1, except for alopecia and for neurosensory toxicity, which must be ≤ 2
    - Recovery from active infections requiring intravenous antibiotics, with antibiotic therapy ceased for ≥ 7 days prior to planned start of therapy
    E.4Principal exclusion criteria
    - Subjects with any of the specific non-CUP neoplasms identified in the ESMO CUP guidelines (Fizazi et al. 2015)
    - Subjects belonging to any of the following subsets of CUP with favorable prognoses
    - Known presence of brain or spinal cord metastasis, as determined by CT or magnetic resonance imaging (MRI) evaluation during screening. As an exception, patients with brain metastases are allowed to be included if all of the following five criteria are met:
    (i) the total number of brain metastases is 3 or less,
    (ii) brain metastases were / are asymptomatic,
    (iii) brain metastases have been completely surgically resected or completely treated with stereotactic radiosurgery
    (iv) there was / is no indication for whole-brain irradiation,
    (v) a brain MRI or high-resolution CT-scan at screening shows no evidence of residual disease
    - Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
    - Human immunodeficiency virus (HIV) infection
    - Positive for hepatitis C virus (HCV) infection at screening
    - Positive for hepatitis B surface antigen (HBsAg) at screening
    - Active tuberculosis at Screening
    - Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia (including active ventricular arrhythmia requiring medication), or unstable angina
    - Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
    - History of malignancy other than CUP within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%)
    - Prior allogeneic stem cell or solid organ transplantation
    - Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
    - Known allergy or hypersensitivity to any component of the immunotherapy, including history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins and to Chinese hamster ovary cell products or other recombinant human or humanized antibodies for nivolumab and ipilimumab.
    - Subjects with an active, known or suspected autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, myocarditis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents), or other immuno-suppressive medications within 14 days of study treatment. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents in the absence of active autoimmune disease are permitted.
    - Subjects who received 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
    - All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 5) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum-based therapy, are permitted to enroll.
    - Systemic treatment for cancer (any chemotherapy, biologics for cancer or investigational therapy) within 21 days of first administration of study treatment
    - Radiotherapy or stereotactic brain metastasis radiosurgery has to be finished at least 7 days before inclusion into the study and the subject must have recovered to grade 1 or less from any toxicity of radiotherapy / stereotactic brain metastasis radiosurgery.
    - Subjects must not have received a live / attenuated vaccine within 30 days of first treatment.
    - Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the last dose of study treatment or intention of fathering a child within 7 months after the last dose of study treatment.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS), defined as the time from treatment start to the first occurrence of disease progression
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 3 months tumors are staged by CT/MRI Imaging and assessed by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first.
    E.5.2Secondary end point(s)
    - Overall survival (OS), defined as the time from treatment start to death from any cause
    - Overall response rate (ORR), defined as the proportion of subjects who exhibit a CR or PR to study treatment on two consecutive occasions ≥ 4 weeks apart
    - Duration of clinical benefit (DCB), defined as the time from the first occurrence of a CR, PR or SD after treatment start until disease progression or death from any cause, whichever occurs first
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 3 months tumors are staged by CT/MRI Imaging and assessed by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first.
    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 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 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 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 concerned15
    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 years3
    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: 97
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 97
    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 state194
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 194
    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)
    Subjects have beein diagnosed with prognostically unfavorable CUP syndrome according to ESMO criteria who are refractory to or progressive to platinum-containing first-line standard combination chemotherapy. Approved or established second-line therapies do not exist for this patient population. After the study completion no approved or established second-line standard therapy exists so that many patients no longer receive tumour-specific therapy but will be treated with best supportive 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 Decision2019-12-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-27
    P. End of Trial
    P.End of Trial StatusOngoing
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