Clinical Trials Register

Summary
EudraCT Number:	2018-003461-34
Sponsor's Protocol Code Number:	UR1840
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-03-14
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

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2018-003461-34

A.3

Full title of the trial

Randomised phase 2 trial of stereotactic body radiation therapy, SBRT, in combination with checkpoint inhibitors in metastatic castration-resistant prostate cancer

A.3.1

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

A phase 2 trial for patients with metastatic prostate cancer to study treatment with nivolumab and ipilimumab with or without radiotherapy

Et fase 2 forsøg for patienter med spredning af prostatakræft som behandles med nivolumab og ipilimumab med eller uden strålebehandling

A.3.2

Name or abbreviated title of the trial where available

CheckPRO

A.4.1

Sponsor's protocol code number

UR1840

A.5.4

Other Identifiers

Name:

BMS study number

Number:

CA209-8TY

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	Department of Oncology, Herlev & Gentofte Hospital
B.1.3.4	Country	Denmark
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	Department of Oncology, Herlev & Gentofte Hospital
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Bristol-Myers Squibb
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Varian
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Oncology, Herlev & Gentofte Hospital
B.5.2	Functional name of contact point	PI Rikke Løvendahl Eefsen
B.5.3	Address:
B.5.3.1	Street Address	Borgmester Ib Juuls Vej 7
B.5.3.2	Town/ city	Herlev
B.5.3.3	Post code	2730
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+453868 9381
B.5.5	Fax number	+453868 3570
B.5.6	E-mail	rikke.helene.loevendahl.eefsen@regionh.dk

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	Opdivo
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.1	Product name	Nivolumab
D.3.4	Pharmaceutical form	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	Nivolumab
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yervoy
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.1	Product name	Ipilimumab
D.3.4	Pharmaceutical form	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.3.9.3	Other descriptive name	Ipilimumab
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

metastatic castration-resistant prostate cancer

E.1.1.1

Medical condition in easily understood language

metastatic prostate cancer for which hormone therapy is no longer effective

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10036909
E.1.2	Term	Prostate cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10036920
E.1.2	Term	Prostate cancer stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10076506
E.1.2	Term	Castration-resistant prostate cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the response rate of immune checkpoint inhibition, ipilimumab and nivolumab in combination with SBRT and compare to combination immunotherapy with ipilimumab and nivolumab.

E.2.2

Secondary objectives of the trial

Secondary objective:
Study safety, quality of life (QoL), and efficacy defined as CBR, rPFS and OS.

Exploratory objective:
To describe changes in tumor tissue and blood before, during and after immunotherapy and investigate immune related biomarkers.
Investigate the association between biomarkers in blood and tumor tissue and outcomes

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have a signed Independent Ethics Committee (IEC)-approved informed consent form prior to any study-specific evaluation. Subjects must be willing and able to comply with scheduled visits, treatment schedule, lab testing and other requirements of the study.
2. Male ≥18 years of age at the time consent form is signed
3. Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the prostate (pure small-cell histology or pure high-grade neuroendocrine histology are excluded; neuroendocrine differentiation is allowed)
4. If possible, metastases accessible for image-guided percutaneous biopsies will be acquired, if assessed as safe for the patient
5. Surgically or medically castrated, with serum testosterone levels <50 ng/dL (1.73 nM). For patients currently being treated with luteinizing hormone-releasing hormone (LHRH) agonists (ie patients who have not undergone an orchiectomy) therapy must be continued throughout the study
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
7. Life expectancy greater than 3 months
8. Evidence of disease progression after prior therapy for mCRPC:
a. Disease progression after treatment with at least 1 but not more than 2 prior next generation androgen receptor (AR)-targeted therapies
(abiraterone acetate, enzalutamide or investigational AR-targeted drug) for castrate-resistant disease AND
b. Disease progression after treatment with first and second line chemotherapy for castration resistant disease. Prior taxane therapy administered
for hormone sensitive disease is permitted and is not counted toward this limit.
c. Disease progression after initiation of most recent therapy is based on any of the following criteria:
i. Rise in PSA: a minimum of 2 consecutive rising levels, with an interval of ≥ 1 week between each determination. The most recent screening
measurement must have been ≥2ng/mL
ii. Transaxial imaging: new or progressive tumor on CT or MRI scans as defined by RECIST 1.1 or new lesions on bone scan per PCWG3.
9. Have adequate organ function confirmed by the following laboratory values obtained within 14 days prior to the first dose of immunotherapy with nivolumab and ipilimumab:
a. Bone marrow function:
i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
ii. Platelets > 100 x 109/L
iii. Hemoglobin≥9 g/dL (5.6 mmol/L) independent of transfusion within 14 days
b. Hepatic function:
i. Asparatate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN. For patients with liver metastases AST and ALT < 5 x ULN.
ii. Bilirubin < 1.5 x ULN
c. Renal function: Serum creatinine < 1.5 x ULN
d. Coagulation status: INR≤1.5
10. Male patients with female partners of childbearing potential may be enrolled if they are:
a. Documented to be surgically sterile (ie, vasectomy): or
b. Committed to practicing true abstinence during treatment and for 4 months after the last dose of immunotherapy; or
c. Committed to using any contraception method with a failure rate of less than 1% per year with their partner during treatment and for 4 months
following last dose of immunotherapy.

E.4

Principal exclusion criteria

1.Active malignancy, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ, or superficial bladder cancer - Patients with a history of malignancy that has been completely treated, and currently with no evidence of that cancer, are permitted to be enrolled in the trial provided all chemotherapy was completed > 6 months prior and/or bone marrow transplant >2years prior to first dose of ipilimumab and nivolumab
2.Prior therapy with an anti-PD1, anti-PD-L1, anti-CD137 or anti-CTLA4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
3. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with asymptomatic, previously treated CNS metastases are eligible provided they have been clinically stable, ie not requiring steroids for at least 4 weeks prior to first dose of ipilimumab and nivolumab and have had appropriate scans screening assessments
4. Symptomatic or impending spinal cord compression unless appropriately treated, clinically stable and asymptomatic
5. If patient have an active known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger
6. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or history of chronic hepatitis B or C.
7. Received treatment with chemotherapy, hormonal therapy (with the exception of LHRH analog), radiation, antibody therapy or immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors or experimental drugs within 4 weeks prior to first dose of ipilimumab and nivolumab
8. Adverse effect of prior therapy not resolved to CTCAE Grade 1 or below with the exception of alopecia. Ongoing Grade 2 non-hematologic toxicity related to most recent treatment regimen may be permitted with prior advanced approval from the sponsor
9. Initiated denosumab or bisphosphonate therapy or adjusted denosumab or bisphosphonate dose/regimen within 4 weeks prior to first dose of ipilimumab and nivolumab. Patients on stable denosumab or bisphosphonate regimen are eligible and may continue treatment
10. Non-study related minor surgery procedure <5 days or major surgery < 21 days prior to first dose of ipilimumab and nivolumab; in all cases the patient must be sufficiently recovered and stable before treatment administration
11. Presence of auto-immune diseases
12. Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and in the opinion of the investigator would make the patient inappropriate for entry into the study
13. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses>10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
14. As there is a potential risk for hepatic toxicity with nivolumab/ipilimumab combinations, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab/ipilimumab containing regimen
15. Allergies
a. History of allergy to study drug components
b. History of severe hypersensitivity reaction to any monoclonal antibody

E.5 End points

E.5.1

Primary end point(s)

Coprimary endpoints:
-Objective response-rate according to RECIST1.1 per PCWG3 criteria (for patients with measurable disease)
-Prostate-specific antigen (PSA) response-rate of ≥ 50% decline from baseline at any time from treatment start (confirmed after ≥ 3 weeks, all patients with measurable and non-measurable disease)

E.5.1.1

Timepoint(s) of evaluation of this end point

Due to the two-stage design of trial, the first analysis of CBR is done after first 40 patients (20 in each arm) are randomised and at least 6 months have elapsed since randomisation. Final analysis will be done at least 6 months have elapsed from the completion of enrollment

E.5.2

Secondary end point(s)

Safety per CTCAE v5.0, radiographic progression-free survival (rPFS) defined as per PCWG3 and clinical progression (all patients), rPFS per iRECIST, CBR as defined by RECIST 1.1 and iRECIST (stable disease (SD) for  6 months, partial response (PR), complete response (CR), ORR by iRECIST, duration of response (DoR), PSA-PFS beyond 12 weeks per PCWG3, rPFS rate and OS rate at 6 months and 1 year, OS, quality of life using EORTC QLQ-C30

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints will be analysed after LVLS. However, safety will be evaluated continously during the trial.

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

Yes

E.6.13.1

Other scope of the trial description

Translational research

Other information:
Data sharing statement:
Individual participant data will not be shared.
Study Protocol is available from the beginning of the trial
Statistical Analysis Plan, analytic software code will be available beginning 3 months and ending 5 years following the article publication of the primary endpoint with any investigators who state their purpose. Request documents from rikke.helene.loevendahl.eefsen@regionh.dk

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

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)

Patients who receive 52 weeks of treatment without PD will receive follow-up CT scans every 8 weeks for up to 52 additional weeks. At PD a re-induction therapy with nivolumab 3 mg/kg IV q3w and ipilimumab 1 mg/kg IV q3w for four doses, then nivolumab 480 IV q4w for a maximum of 52 weeks will be given.

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

2019-05-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-09

P. End of Trial
P.	End of Trial Status	Ongoing

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