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Checkpoint Inhibitors and SBRT for mCRPC (CheckPRO)

Primary Purpose

Prostate Cancer Metastatic, Castrate Resistant Prostate Cancer, Metastatic Castration-resistant Prostate Cancer

Status
Recruiting
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Stereotactic body radiotherapy
Ipilimumab Injection [Yervoy]
Nivolumab Injection [Opdivo]
Biopsies
Sponsored by
Herlev and Gentofte Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prostate Cancer Metastatic focused on measuring Oncology, metastatic castration-resistant prostate cancer, Immunotherapy, Stereotactic body radiotherapy, Translational research, Prostate cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Department of Oncology, Copenhagen University Hospital Herlev and Gentofte HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

A SBRT + ipi/nivo

B ipi/nivo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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
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)

Secondary Outcome Measures

Adverse events (Safety)
Common Terminology Criteria for Adverse Events (CTCAE) v. 5
Radiographic progression-free survival
Per PCWG3 with 2+2 rule and clinical progression (all patients)
Clinical benefit rate
Per RECIST 1.1 and Immune Response Evaluation Criteria in Solid Tumours (iRECIST)
Objective response rate (ORR)
Per iRECIST
PSA progression-free survival
Per PCWG3
Survival
Overall survival
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.

Full Information

First Posted
December 7, 2022
Last Updated
December 16, 2022
Sponsor
Herlev and Gentofte Hospital
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT05655715
Brief Title
Checkpoint Inhibitors and SBRT for mCRPC
Acronym
CheckPRO
Official Title
Randomised Phase 2 Trial of Stereotactic Body Radiation Therapy, SBRT in Combination With Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 25, 2019 (Actual)
Primary Completion Date
January 12, 2024 (Anticipated)
Study Completion Date
January 11, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Herlev and Gentofte Hospital
Collaborators
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostate Cancer Metastatic, Castrate Resistant Prostate Cancer, Metastatic Castration-resistant Prostate Cancer, Prostate Cancer Stage IV
Keywords
Oncology, metastatic castration-resistant prostate cancer, Immunotherapy, Stereotactic body radiotherapy, Translational research, Prostate cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Two experimental treatment arms.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
A SBRT + ipi/nivo
Arm Type
Experimental
Arm Description
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
Arm Title
B ipi/nivo
Arm Type
Experimental
Arm Description
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
Intervention Type
Radiation
Intervention Name(s)
Stereotactic body radiotherapy
Other Intervention Name(s)
8 Gray x 3
Intervention Description
8 Gray x 3
Intervention Type
Drug
Intervention Name(s)
Ipilimumab Injection [Yervoy]
Other Intervention Name(s)
ipi
Intervention Description
1 mg/kg IV Q3W for four doses,
Intervention Type
Drug
Intervention Name(s)
Nivolumab Injection [Opdivo]
Other Intervention Name(s)
nivo
Intervention Description
Nivolumab 3mg/kg IV Q3W for four doses, then then Nivolumab 480mg IV Q4W
Intervention Type
Procedure
Intervention Name(s)
Biopsies
Intervention Description
From soft tissue metastases.
Primary Outcome Measure Information:
Title
Co-primary endpoint 1
Description
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
Time Frame
From baseline until progression (up to 24 months)
Title
Co-primary endpoint 2
Description
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)
Time Frame
Any time after treatment start (confirmed ≥ 3 weeks later, up to 24 months)
Secondary Outcome Measure Information:
Title
Adverse events (Safety)
Description
Common Terminology Criteria for Adverse Events (CTCAE) v. 5
Time Frame
From inclusion to 100 days after the last dose of ipilimumab or nivolumab or until the last study visit (up to 24 months)
Title
Radiographic progression-free survival
Description
Per PCWG3 with 2+2 rule and clinical progression (all patients)
Time Frame
From baseline until progression (up to 24 months)
Title
Clinical benefit rate
Description
Per RECIST 1.1 and Immune Response Evaluation Criteria in Solid Tumours (iRECIST)
Time Frame
From baseline until progression (up to 24 months)
Title
Objective response rate (ORR)
Description
Per iRECIST
Time Frame
From baseline until progression (up to 24 months)
Title
PSA progression-free survival
Description
Per PCWG3
Time Frame
beyond 12 weeks (up to 24 months)
Title
Survival
Description
Overall survival
Time Frame
From randomization until death by any cause or last follow-up (up to 24 months)
Title
European Organization for Research and Treatment of Cancer Quality of life of cancer patients (EORTC QLQ-C30)
Description
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.
Time Frame
Baseline and then every 8 weeks (up to three times) until end-of-treatment (up to 24 months)

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Rikke HL Eefsen, MD, PhD
Phone
38689381
Ext
0045
Email
rikke.helene.loevendahl.eefsen@regionh.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Nicklas J Spindler, MD
Phone
38686519
Ext
0045
Email
nicklas.juel.spindler@regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rikke HL Eefsen, MD, PhD
Organizational Affiliation
Department of Oncology, Herlev and Gentofte Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Oncology, Copenhagen University Hospital Herlev and Gentofte Hospital
City
Herlev
State/Province
Capital Region
ZIP/Postal Code
2730
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rikke HL Eefsen, MD, PhD
Phone
38689381
Ext
0045
Email
rikke.helene.loevendahl.eefsen@regionh.dk
First Name & Middle Initial & Last Name & Degree
Nicklas J Spindler, MD
Phone
38686519
Ext
0045
Email
nicklas.juel.spindler@regionh.dk
First Name & Middle Initial & Last Name & Degree
Nicklas J Spindler, MD
First Name & Middle Initial & Last Name & Degree
Rikke HL Eefsen, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
According to International Committee of Medical Journal Editors (ICMJE) guideline: Will individual participant data be available (including data dictionaries)? No. What data in particular will be shared? None. What other documents will be available? Study Protocol, Statistical Analysis Plan, analytic software code. When will data be available (start and end dates)? The study protocol is available from the beginning of the trial. Statistical analysis plan and analytic code will be available beginning 3 months and ending 5 years following the article publication of the primary endpoint. With whom? Investigators who state their purpose. For what types of analyses? Any By what mechanism will data be made available? Proposals should be directed to the PI.

Learn more about this trial

Checkpoint Inhibitors and SBRT for mCRPC

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