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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Radboud universitair medisch centrum

Participant type

Patients

Age range

18-64 years

Gender

Male

Therapeutic area

Diseases [C] - Male Urogenital Diseases [C12]

Trial duration

1 Feb 2025 → 18 Dec 2025

Decision date (initial)

2025-01-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513186-39-01

EudraCT number

2020-001240-25

ClinicalTrials.gov

NCT04717154

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety, Pharmacogenomic

To evaluate the efficacy of nivolumab in combination with ipilimumab in molecular pre-selected patients with metastatic castration-resistant prostate cancer

Secondary objectives 1

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

Conditions and MedDRA coding

castration-resistant prostate cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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.

Exclusion criteria 1

1. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 1

1. Safety (first secondary endpoint): - Percentage of Grade 3/4 and 5 treatment-related AE's Efficacy (second secondary endpoint): - Best objective response rate (ORR) per RECIST1 .1 criteria - Biochemica! response rate at week 13 and maxi mal PSA decline according to Prostate Cancer Working Group 3 criteria (PCWG3) - Radiographic progression free survival per irRECIST1 .1 immune-related response criteria

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Radboud universitair medisch centrum

Sponsor organisation

Stichting Radboud universitair medisch centrum

Address

Geert Grooteplein Zuid 10

City

Nijmegen

Postcode

6525 GA

Country

Netherlands

Scientific contact point

Organisation

Stichting Radboud universitair medisch centrum

Contact name

Principal Investigator

Public contact point

Organisation

Stichting Radboud universitair medisch centrum

Contact name

Principal Investigator

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications