Clinical Trials Register

Summary
EudraCT Number:	2020-001240-25
Sponsor's Protocol Code Number:	MOURO48
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-07-02
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.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-001240-25

A.3

Full title of the trial

Phase 2 INSPIRE trial: Ipilimumab with Nivolumab in molecular-selected patients with castration-resistant prostate cancer

Fase II studie INSPIRE: Ipilimumab met Nivolumab in moleculair geselecteerde patiënten met castratie-resistent prostaatkanker

A.3.1

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

A phase II trial to study the effectivity of combination immunotherapy in patients with prostate cancer (INSPIRE)

Een fase II studie om de effectiviteit van combinatie immuuntherapie te onderzoeken bij patiënten met prostaatkanker (INSPIRE)

A.3.2

Name or abbreviated title of the trial where available

INSPIRE

A.4.1

Sponsor's protocol code number

MOURO48

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	Radboudumc
B.1.3.4	Country	Netherlands
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 International Corporation
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Radboudumc
B.5.2	Functional name of contact point	Trialbureau Hematology-Oncology
B.5.3	Address:
B.5.3.1	Street Address	Geert Grooteplein Zuid 10
B.5.3.2	Town/ city	Nijmegen
B.5.3.3	Post code	6525 GA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00312436 14794
B.5.5	Fax number	00312436 15025
B.5.6	E-mail	studies.onco@radboudumc.nl

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.3.2	Product code	BMS-936558
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.3.11 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.3.2	Product code	EU/1/11/698/001-002
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.3.11 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) castration-resistant prostate cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 efficacy of nivolumab in combination with ipilimumab in molecular pre-selected patients with metastatic castration-resistant prostate cancer. Susceptible patients are selected for MMRd/high mutational burden/tandem duplicator phenotype
-cohort 1 will assess the efficacy of the combination in mCRPC patients naïve for ICB
-cohort 2 will assess the efficacy of the combination in patients with prior progression to monotherapy ICB (CTLA-4 or anti-PD1/PDL1)

Het evalueren van de werkzaamheid van nivolumab in combinatie met ipilimumab bij moleculair voorgeselecteerde patiënten met uitgezaaid castratie-resistente prostaatkanker. Gevoelige patiënten worden geselecteerd op MMRd / hoge mutatie last / tandem duplicator-fenotype
-cohort 1 zal de werkzaamheid van de combinatie beoordelen bij mCRPC-patiënten die niet eerder met ICB zijn behandeld
-cohort 2 zal de werkzaamheid van de combinatie beoordelen bij patiënten met eerdere progressie op monotherapie ICB (CTLA-4 of anti-PD1 / PDL1)

E.2.2

Secondary objectives of the trial

Translational: To further optimize and validate predictive and early response immunogenic signatures from biomarkers in tissue and blood, associating with an objective response and disease control (DCR) of at least 6 months.

Translationeel: het verder optimaliseren en valideren van voorspellende en immunogene vroege respons profielen van biomarkers in weefsel en bloed, geassocieerd met een objectieve respons en DCR van ten minste 6 maanden.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent.
2. Histological diagnosis of adenocarcinoma of the prostate. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma.
3. Metastatic Castration-Resistant Prostate Cancer (mCRPC), metastatic disease defined either by measurable disease by RECIST1.1 criteria and/or presence of bone-metastatic disease evaluable per PCWG3 criteria. For cohort 1, measurable disease is compulsory.
4. An immunogenic phenotype, consisting of one of the next criteria:
1, mismatch repair deficiency and/or a high mutational burden of >10 mutations per Mb (cluster A);
2, BRCA2 inactivation and/or BRCAness signature (cluster B);
3, a tandem duplication signature (cluster C).
5. Age ≥18 years.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 – 1.
7. PSA ≥ 2 ng/ml.
8. Documented willingness to use an effective means of contraception while participating in the study and for 7 months post last dose of treatment (see section 4.5).
9. Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM).
10. Received prior castration by orchiectomy and/or ongoing Luteinizing Hormone-Releasing Hormone (LH-RH) agonist treatment.
11. Progression of disease by PSA utilizing PCWG3 criteria and at least another of the following criteria;
a. Bone scan: disease progression as defined by at least 2 new lesions on bone scan.
b. Soft tissue disease progression defined by modified RECIST 1.1.
c. Clinical progression with worsening pain and the need for palliative radiotherapy for bone metastases.
12. Having a biopsiable metastatic lesion and willingness to undergo a baseline* and on-treatment tumour biopsy for next-generation sequencing and biomarker analyses. *When sufficient FFPE material is available from a biopsy in castrate-state, one may apply for a waiver for a new baseline biopsy.

E.4

Principal exclusion criteria

1. Prior treatment with checkpoint immunotherapy (CTLA-4, or PD-1 and PD-L1 antagonists) for cohort 1. For cohort 2 patients may have prior treatment with monotherapy CTLA-4 or PD-1 or PD-L1.
2. Surgery, chemotherapy within 4 weeks prior to trial entry / randomisation into the study. Any other therapies for prostate cancer, other than GnRH analogue therapy and osteoporosis preventing agents, are not allowed.
3. Radiotherapy within 2 weeks prior to trial entry. Radiation-related side effects higher than grade 1, or above baseline.
4. Participation in another interventional clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry / randomisation.
5. History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism.
6. Untreated or symptomatic brain or leptomeningeal involvement.
7. Inadequate organ and bone marrow function as evidenced by: a. haemoglobin <6.2 mmol/L b. Absolute neutrophil count <1.0 x 109/L c. Platelet count < 75 x 109/L d. Albumin <30 g/dL. e. AST / SGOT and/or ALT / SGPT ≥ 2.5 x ULN (≥ 5 x ULN if liver metastases present) f. Total bilirubin ≥ 1.5 x ULN (except for patient with documented Gilbert’s disease) g. Serum Creatinine > 1.5 x ULN
8. Any of the following cardiac criteria; a. Any clinically significant abnormalities in rhythm, conduction, or morphology of a resting ECG (e.g., complete left bundle branch block, third degree heart block)
c. Experience of any of the following procedures or conditions in the preceding six months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, congestive heart failure NYHA ≥ Grade2
d. Uncontrolled hypotension defined as – systolic blood pressure (BP) <90mmHg and/or diastolic BP <50mmHg
9. Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
10. History of clinically relevant auto-immune disease (including Crohn’s disease or ulcerative colitis). Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of nivolumab or ipilimumab or that may affect the interpretation of the results or renders the patients at high risk from treatment complications.
10. Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5mg of dexamethasone per day or an equivalent dose of other anti-inflammatory corticosteroid, for the use of concomitant steroids on this trial please refer to section 12.1. Patients in which corticosteroids cannot be stopped prior to entering the trial are allowed a maximum of 10mg of prednisolone per day or equivalent. In the case of corticosteroid discontinuation, a 2-week (14 days) washout is required with a mandatory PSA check prior to starting the trial. If the PSA has declined compared to the value obtained prior to stopping corticosteroids, patients will not be eligible for study. Patients can only enter the study with a confirmed PSA increase.
11. Malignancies other than prostate cancer within 3 years prior to trial entry / randomization, except for adequately treated basal or squamous cell skin cancer and non-muscle invasive bladder cancer.
12. Active second malignancy, except basal or squamous cell skin cancer and non-muscle invasive bladder cancer. Other treated malignancies with curative intent, including colorectal cancer, may be included following PI consent.
13. Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy.
14. Inability to comply with study and follow-up procedures.
15. Patients with predominant small cell or neuroendocrine prostate cancer are not eligible.
16. Patients without measurable lesion per RECIST1.1, and with a superscan on bone scintigraphy not evaluable per PCWG3 criteria, are not eligible.

E.5 End points

E.5.1

Primary end point(s)

Efficacy endpoint: disease control rate (DCR) of >6mo; this includes SD, PR or CR by best ORR in evaluable patients, all lasting longer than 6mo

E.5.1.1

Timepoint(s) of evaluation of this end point

At inclusion, Wk 7, Wk 17, Wk 29, Wk 41, and 30 days after last dose

E.5.2

Secondary end point(s)

1) Safety endpoint: percentage of Grade 3/4 and 5 treatment-related AE’s

2) Efficacy endpoint: best objective response rate (ORR) per RECIST1.1 criteria

3) Efficacy endpoint: biochemical response rate at week 13 and maximal PSA decline according to Prostate Cancer Working Group 3 criteria (PCWG3)

4) Efficacy endpoint: radiographic progression free survival per irRECIST1.1 immune-related response criteria

E.5.2.1

Timepoint(s) of evaluation of this end point

1) At inclusion, Wks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and at end of treatment

2) At inclusion, Wk 7, Wk 17, Wk 29, Wk 41, and 30 days after last dose

3) BRR at Wk 13, PSA at inclusion, Wks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and at end of treatment

4) At inclusion, Wk 7, Wk 17, Wk 29, Wk 41, and 30 days after last dose

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

Finding predictive and prognostic biomarkers of disease

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.8.2.4

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

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

last study assessment for the last subject on study or if the sponsor terminates the study, whichever comes first.

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

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)

None

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

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-23

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials