Clinical Trials Register

Summary
EudraCT Number:	2018-004562-33
Sponsor's Protocol Code Number:	CheCUP
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-07-22
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

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2018-004562-33

A.3

Full 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.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

CheCUP

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Heidelberg, Med. Fac. repr. by University Hospital and its Commercial Managing Director
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bristol-Myers-Squibb
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Heidelberg
B.5.2	Functional name of contact point	Department of Internal Medicine V
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 410
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4962215638183
B.5.5	Fax number	+496221421444
B.5.6	E-mail	Alwin.Kraemer@med.uni-heidelberg.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	YERVOY
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers-Squibb
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate and solvent for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IPILIMUMAB
D.3.9.2	Current sponsor code	BMS-734016
D.3.9.4	EV Substance Code	SUB29397
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	OPDIVO
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers-Squibb
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BMS-936558
D.3.9.3	Other descriptive name	NIVOLUMAB
D.3.9.4	EV Substance Code	SUB122750
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Cancer of unknown primary site (CUP-Syndrome), relapsed/refractory to platinum-based chemotherapy

E.1.1.1

Medical condition in easily understood language

Cancer of unknown primary site (CUP-Syndrome), relapsed/refractory to platinum-based chemotherapy

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10007460
E.1.2	Term	Carcinoma of unknown primary
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

E.3

Principal 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, or a re-biobsy has failed or cannot be performed for clinical or technical reasons, 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 start of study treatment 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.4

Principal 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
- 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
- Solid organ Transplantation
Prior allogeneic stem cell transplantation with follow-up < 1 year, need for systemic immunosuppression or active chronic graft-versus host disease (cGVHD)
- 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 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.5.1

Primary end point(s)

Progression-free survival (PFS), defined as the time from treatment start to the first occurrence of disease progression

E.5.1.1

Timepoint(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.5.2

Secondary 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.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

194

F.4.2

For a multinational trial

F.4.2.2

In 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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-12-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-27

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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