Checkpoint Inhibitors and SBRT for mCRPC

Study Overview
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Brief Summary
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The goal of this investigator-initiated, single-center, and randomized phase II trial is to investigate the potential synergistic effect of combining stereotactic body radiotherapy of a single soft tissue- or bone metastasis with ipilimumab and nivolumab in patients with mCRPC and perform translational analyses on tissue and blood, searching for predictive biomarkers of efficacy and toxicity. Participants will be randomized to receive ipilimumab and nivolumab with or without stereotactic body radiotherapy (SBRT).

Detailed Description
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The participants receive treatment for 52 weeks, including four cycles of ipilimumab and nivolumab with or without concomitant SBRT (24 Gray in three fractions) to a single soft tissue or bone metastasis, followed by 10 cycles of nivolumab. Participants are followed until progression, death, or for 12 months after the end of treatment. Biopsies from metastatic sites are collected at baseline, before the third treatment, and at the end of treatment. Blood sampling for immune monitoring and circulating tumor DNA is performed consecutively at baseline and every radiographic assessment.

Official Title
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Randomised Phase 2 Trial of Stereotactic Body Radiation Therapy, SBRT in Combination With Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer

Conditions
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Prostate Cancer Metastatic, Castrate Resistant Prostate Cancer, Metastatic Castration-resistant Prostate Cancer, Prostate Cancer Stage IV

Intervention / Treatment
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* Radiation: Stereotactic body radiotherapy
* Drug: Ipilimumab Injection [Yervoy]
* Drug: Nivolumab Injection [Opdivo]
* Procedure: Biopsies


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Male ≥18 years of age at the time consent form is signed 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) If possible, metastases accessible for image-guided percutaneous biopsy should be performed, if considered safe assessed by the PI. 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 (i.e., patients who have not undergone an orchiectomy) therapy must be continued throughout the study Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Life expectancy greater than 3 months Evidence of disease progression after prior therapy for mCRPC: Disease progression after treatment with 1 androgen-receptor (AR) targeted therapies (abiraterone acetate, enzalutamide or investigational AR-targeted drug) for castrate-resistant disease AND Disease progression after treatment with 1 line of taxane-based chemotherapy for castration resistant disease. Prior taxane therapy administered for hormone sensitive disease is permitted and is not counted toward this limit. 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 j. 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. 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. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (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. Coagulations status: International Normalized Ratio (INR) ≤ 1.5 Male patients with female partners of childbearing potential may be enrolled if they are: Documented to be surgically sterile (ie, vasectomy): or Committed to practicing true abstinence during treatment and for 4 months after the last dose of immunotherapy; or Committed to using any contraception method with a failure rate of less than 1% per year of contraception (refer to protocol) with their partner during treatment and for 4 months following last dose of immunotherapy. Exclusion Criteria: 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 Prior therapy with an anti-programmed cell death protein 1 (anti-PD1), anti-programmed death-ligand 1 (anti-PD-L1), anti-CD137 or anti-CTLA4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with asymptomatic, previously treated CNS metastases are eligible provided they have been clinically stable (i.e., not requiring steroids for at least 4 weeks prior to first dose of ipilimumab and nivolumab and have had appropriate scans screening assessments) Symptomatic or impending spinal cord compression unless appropriately treated, clinically stable and asymptomatic 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 Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or history of chronic hepatitis B or C 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 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 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 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 Presence of auto-immune diseases 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 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 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 Allergies History of allergy to study drug components History of severe hypersensitivity reaction to any monoclonal antibody

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two experimental treatment arms.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A SBRT + ipi/nivo<br>Stereotactic body radiotherapy of 8 Gray (Gy) x 3 on one soft tissue or bone metastasis + Nivolumab 3mg/kg IV every 3 weeks (Q3W) + Ipilimumab 1mg/kg IV Q3W for four doses, then Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks treatment in total | Radiation: Stereotactic body radiotherapy<br>* 8 Gray x 3<br>* Other names: 8 Gray x 3;Drug: Ipilimumab Injection [Yervoy]<br>* 1 mg/kg IV Q3W for four doses,<br>* Other names: ipi;Drug: Nivolumab Injection [Opdivo]<br>* Nivolumab 3mg/kg IV Q3W for four doses, then then Nivolumab 480mg IV Q4W<br>* Other names: nivo;Procedure: Biopsies<br>* From soft tissue metastases.<br>|
| Experimental: B ipi/nivo<br>Nivolumab 3mg/kg IV Q3W + Ipilimumab 1mg/kg IV Q3W for four doses, then Nivolumab 480 mg IV Q4W for up to 52 weeks treatment in total | Drug: Ipilimumab Injection [Yervoy]<br>* 1 mg/kg IV Q3W for four doses,<br>* Other names: ipi;Drug: Nivolumab Injection [Opdivo]<br>* Nivolumab 3mg/kg IV Q3W for four doses, then then Nivolumab 480mg IV Q4W<br>* Other names: nivo;Procedure: Biopsies<br>* From soft tissue metastases.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Co-primary endpoint 1 | Objective response rate (ORR) according to modified Response Evaluation Criteria in Solid Tumours (RECIST1.1) per Prostate Cancer Clinical Trials Working Group (PCWG3) criteria for patients with measurable disease | From baseline until progression (up to 24 months) | 
| Co-primary endpoint 2 | Prostate-specific antigen (PSA) response rate of ≥ 50% decline from baseline at any time from treatment start (confirmed after ≥ 4 weeks, all patients with measurable and non-measurable disease) | Any time after treatment start (confirmed ≥ 3 weeks later, up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (Safety) | Common Terminology Criteria for Adverse Events (CTCAE) v. 5 | From inclusion to 100 days after the last dose of ipilimumab or nivolumab or until the last study visit (up to 24 months) | 
| Radiographic progression-free survival | Per PCWG3 with 2+2 rule and clinical progression (all patients) | From baseline until progression (up to 24 months) | 
| Clinical benefit rate | Per RECIST 1.1 and Immune Response Evaluation Criteria in Solid Tumours (iRECIST) | From baseline until progression (up to 24 months) | 
| Objective response rate (ORR) | Per iRECIST | From baseline until progression (up to 24 months) | 
| PSA progression-free survival | Per PCWG3 | beyond 12 weeks (up to 24 months) | 
| Survival | Overall survival | From randomization until death by any cause or last follow-up (up to 24 months) | 
| European Organization for Research and Treatment of Cancer Quality of life of cancer patients (EORTC QLQ-C30) | Questionaire The EORTC QLQ-C30 is a validated questionnaire to assess the quality of life of cancer patients. It includes 30 questions, divided into three major dimensions of global health status, functional-, and symptoms scale. The scales are calculated into a score ranging from 0-100. A high score on global health status and functional scales represents a better quality of life, but a high score on the symptoms scale represents a high burden of symptoms/low quality of life. | Baseline and then every 8 weeks (up to three times) until end-of-treatment (up to 24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, metastatic castration-resistant prostate cancer, Immunotherapy, Stereotactic body radiotherapy, Translational research, Prostate cancer