Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst Trial) (ImmunoProst)
Primary Purpose
Prostate Cancer
Status
Unknown status
Phase
Phase 2
Locations
Brazil
Study Type
Interventional
Intervention
Nivolumab
Sponsored by

About this trial
This is an interventional treatment trial for Prostate Cancer focused on measuring prostate cancer
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed adenocarcinoma of the prostate with tumor tissue available for molecular analyses. If archival tissue for biomarker analysis is not available then the patient must be willing to have a further biopsy to obtain tumor tissue for histological diagnosis.
Metastatic Castrate-resistant prostate cancer (mCRPC), defined by:
- Disease progression despite androgen deprivation therapy (ADT) and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.
- Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the patient is being treated with GnRH or LHRH agonists or antagonists (patient who have not undergone orchiectomy), this therapy should be maintained.
Documented prostate cancer progression, during treatment with Docetaxel, as assessed by the investigator with one of the following:
- PSA progression is defined according the PCWG3 criteria: PSA increase, that is ≥ 50% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value ≥ 3 weeks later (confirmed the rising trend).
- Radiographic progression of visceral lesions or soft tissue disease by modified RECIST 1.1 criteria.
- Progression of bone metastasis is defined according the Appendix B: Prostate Cancer Clinical Trials Working Group 3 (Adapted) two or more documented new bone lesions on a bone scan with or without PSA progression. Confirmation of ambiguous results by other imaging modalities (eg, CT or MRI) is obligatory. If Docetaxel chemotherapy is used more than once, this will be considered as one regimen.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 Appendix A: Performance Status Criteria
- Life expectancy > 24 weeks.
- Age ≥ 18 years
- At least 28 days since the completion of any prior anti-cancer therapy (except for LHRH agonists or antagonists), including chemotherapy (taxane-based). Additionally, clinically relevant treatment toxicities should have resolved to grade 1 or less prior to start study treatment.
For hormonal treatment must be followed the guideline below:
- No antiandrogens are allowed during the study period. The use of antiandrogens before study entry is permitted, but at least 28 days since the completion of prior antiandrogen are required (washout period).
- Corticosteroids dose > Prednisolone 10 mg/day (or equivalent) are allowed only if clinically indicated for medical conditions. At least 28 days since the completion of prior corticotherapy are required (washout period).
- Agreeable to have all the biomarker studies including the fresh tumor biopsies if needed.
Patients must have adequate organ function within 1 weeks prior enrollment to and evidenced by:
- Hemoglobin ≥ 9.0 g/dL
- WBC > 2.000/mm3
- Absolute neutrophil count ≥ 1.500/mm3
- Platelet count ≥ 100.000/mm3
- Creatinine Clearance ≥ 30 mL/min. Creatinine Clearance (CrCl) must be calculated at screening using the Cockcroft-Gault formula:
- Bilirubin < 3 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome.
- Aspartate transaminase (AST) (SGOT) < 3.0 x ULN.
- Alanine transaminase (ALT) (SGPT) < 3.0 x ULN.
- No cardiac disease defined by as active angina, symptomatic congestive heart failure, or myocardial infarction within previous six months.
Exclusion Criteria:
- Patients with any active known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring systemic treatment, or other conditions under control are permitted to enroll.
- Patients with conditions that needs systemic corticosteroids dose > Prednisolone 10 mg/day (or equivalent) or other immunosuppressive medications within 28 days prior to the first dose of study drug. Inhaled steroids are permitted if necessary.
- Patients with any known active chronic liver disease.
- Patients who have prior history of malignancy treated with curative intention in the past 2 years with the exception of basal cell carcinoma and squamous cell carcinoma of the skin, which were allowed in any case. Patients with other malignancies that do not fulfill the prior criteria could be considered for recruitment if they do not represent a competitive cause of death and have a low potential to progress to metastatic progression. Patients in this condition may be enrolled in the trial if approved after review by principal investigator.
- Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or hepatitis C virus representing acute or chronic disease.
- Preceding treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- Major surgery less than 28 days prior to the first dose of study drug.
- Radiation therapy less than 14 days prior to the first dose of study drug.
Sites / Locations
- Hospital Moinhos de Vento
- Instituto do Câncer do Estado de São Paulo
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Nivolumab
Arm Description
All patients will receive Nivolumab 240 mg every 14 days until progression or unacceptable toxicity
Outcomes
Primary Outcome Measures
PSA response rate
PSA partial response is defined as a ≥ 50% decline in PSA from cycle 1 day 1 (baseline) PSA value. This PSA decline must be confirmed as sustained by a second PSA value obtained ≥ 3 weeks later.
Secondary Outcome Measures
Time to PSA progression
PSA Response Rate at 6 and 12 months
Radiological progression-free survival (rPFS)
Time to Radiographic Progression
Progression free survival (PFS)
Overall survival
Full Information
NCT ID
NCT03040791
First Posted
January 27, 2017
Last Updated
August 24, 2021
Sponsor
Hospital Moinhos de Vento
Collaborators
Bristol-Myers Squibb
1. Study Identification
Unique Protocol Identification Number
NCT03040791
Brief Title
Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst Trial)
Acronym
ImmunoProst
Official Title
Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst Trial)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Unknown status
Study Start Date
June 1, 2018 (Actual)
Primary Completion Date
January 1, 2022 (Anticipated)
Study Completion Date
March 1, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospital Moinhos de Vento
Collaborators
Bristol-Myers Squibb
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Prostate Cancer (PC) is the most frequent cancer in men, accounting for 21% of new cases of cancer in men in the United States. Among the four most incident tumors (breast, lung and colorectal cancer); prostate cancer is the only that does not have any predictive biomarker to guide the treatment. Even though the molecular heterogeneity of PC is well-documented, treatment has not been molecularly stratified and the need for genetic prognostic and predictive markers is critical.
DNA repair defects (DRD), mainly in the Homologous Recombination (HR) pathway (such as BRCA1, BRCA2, ATM and CHEK2) are emerging as potential biomarkers in prostate cancer. It is well known BRCA1 and BRCA2 carriers have better Progression-Free Survival (PFS) and Overall Survival (OS) than non-carriers in ovarian cancer. Differently than ovarian tumors that BRCA mutations provides a good prognosis, PC patients who harbor HR defects have a higher Gleason score 6, an increased risk of recurrence and poor prognosis. The predictive role of DRD in PC was demonstrated in a recent trial using Olaparib, a PARP inhibitor, in DRD carriers. This trial showed 88% of response rate with Olaparib, a PARP inhibitor that acts in HR pathway by synthetic lethality.
Recent data demonstrated important association between HR deficient high-grade serous ovarian cancer (HGSOC), high neoantigen load and high expression of PD-1/PD-L1 compared with HR proficient HGSOCs 10. This study showed that BRCA1 and BRCA2 mutations increase the number of tumor-infiltrating lymphocytes (TILs) and confer a better prognosis. The unprecedented success of immunotherapy in malignant disorders has provided evidence that the patient's immune system can be improved to attack established tumors, mainly melanoma, non-small cell lung cancer and kidney cancer. A high mutational burden increases the likelihood of the development of specific neoepitopes that would confer clinical benefit from CTLA-4 and PD-1 blockade.
These data showed that specific DNA repair defects increase the mutational burden, the expression of PD-1/PD-L1 and TILs; and could improve the response to immunotherapy in cancer. This rationale was already tested in a trial that evaluated the PD-1 checkpoint inhibitor Pembrolizumab in mismatch-repair deficient patients, a kind of DNA repair defect by definition. This important trial showed that this DRD predicted clinical benefit of immune checkpoint blockade in many types of cancer, especially colorectal cancer.
Detailed Description
This is a Phase II, two-stage, multi-center, single-arm, and open-label trial of Nivolumab (BMS-936558) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed to a taxane-based chemotherapy regimen previously. Eligible patients must have ECOG 0-2 and material for biomarker analysis. Prior enzalutamide, abiraterone and cabazitaxel are permitted but not necessary to enrollment. The germline and somatic DRD (BRCA1, BRCA2, ATM, PTEN, CHEK2, RAD51C, RAD51D, PALB2, MLH1, MSH2, MSH6, PMS2.) will be assessed by T-NGS of metastatic sites or by liquid biopsy. The primary endpoint is PSA 50 response rate (PSA50, following the Prostate Cancer Working Group 3 criteria). The trial will meet its endpoint if ≥ 3/29 men achieve a PSA50 response. The secondary endpoints will include progression-free survival (PFS), overall survival, radiologic PFS, PSA response rate at 6 and 12 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostate Cancer
Keywords
prostate cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This is a Phase II, two-stage, multi-center, single-arm, and open-label trial of Nivolumab (BMS-936558) in patients with mCRPC who have progressed to a taxane-based chemotherapy regimen previously.
Masking
None (Open Label)
Allocation
N/A
Enrollment
38 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Nivolumab
Arm Type
Experimental
Arm Description
All patients will receive Nivolumab 240 mg every 14 days until progression or unacceptable toxicity
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558
Intervention Description
Nivolumab
Primary Outcome Measure Information:
Title
PSA response rate
Description
PSA partial response is defined as a ≥ 50% decline in PSA from cycle 1 day 1 (baseline) PSA value. This PSA decline must be confirmed as sustained by a second PSA value obtained ≥ 3 weeks later.
Time Frame
through study completion, an average of 1 year
Secondary Outcome Measure Information:
Title
Time to PSA progression
Time Frame
through study completion, an average of 1 year
Title
PSA Response Rate at 6 and 12 months
Time Frame
through study completion, an average of 1 year
Title
Radiological progression-free survival (rPFS)
Time Frame
through study completion, an average of 1 year
Title
Time to Radiographic Progression
Time Frame
through study completion, an average of 1 year
Title
Progression free survival (PFS)
Time Frame
through study completion, an average of 1 year
Title
Overall survival
Time Frame
through study completion, an average of 1 year
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed adenocarcinoma of the prostate with tumor tissue available for molecular analyses. If archival tissue for biomarker analysis is not available then the patient must be willing to have a further biopsy to obtain tumor tissue for histological diagnosis.
Metastatic Castrate-resistant prostate cancer (mCRPC), defined by:
Disease progression despite androgen deprivation therapy (ADT) and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.
Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the patient is being treated with GnRH or LHRH agonists or antagonists (patient who have not undergone orchiectomy), this therapy should be maintained.
Documented prostate cancer progression, during treatment with Docetaxel, as assessed by the investigator with one of the following:
PSA progression is defined according the PCWG3 criteria: PSA increase, that is ≥ 50% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value ≥ 3 weeks later (confirmed the rising trend).
Radiographic progression of visceral lesions or soft tissue disease by modified RECIST 1.1 criteria.
Progression of bone metastasis is defined according the Appendix B: Prostate Cancer Clinical Trials Working Group 3 (Adapted) two or more documented new bone lesions on a bone scan with or without PSA progression. Confirmation of ambiguous results by other imaging modalities (eg, CT or MRI) is obligatory. If Docetaxel chemotherapy is used more than once, this will be considered as one regimen.
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 Appendix A: Performance Status Criteria
Life expectancy > 24 weeks.
Age ≥ 18 years
At least 28 days since the completion of any prior anti-cancer therapy (except for LHRH agonists or antagonists), including chemotherapy (taxane-based). Additionally, clinically relevant treatment toxicities should have resolved to grade 1 or less prior to start study treatment.
For hormonal treatment must be followed the guideline below:
No antiandrogens are allowed during the study period. The use of antiandrogens before study entry is permitted, but at least 28 days since the completion of prior antiandrogen are required (washout period).
Corticosteroids dose > Prednisolone 10 mg/day (or equivalent) are allowed only if clinically indicated for medical conditions. At least 28 days since the completion of prior corticotherapy are required (washout period).
Agreeable to have all the biomarker studies including the fresh tumor biopsies if needed.
Patients must have adequate organ function within 1 weeks prior enrollment to and evidenced by:
Hemoglobin ≥ 9.0 g/dL
WBC > 2.000/mm3
Absolute neutrophil count ≥ 1.500/mm3
Platelet count ≥ 100.000/mm3
Creatinine Clearance ≥ 30 mL/min. Creatinine Clearance (CrCl) must be calculated at screening using the Cockcroft-Gault formula:
Bilirubin < 3 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome.
Aspartate transaminase (AST) (SGOT) < 3.0 x ULN.
Alanine transaminase (ALT) (SGPT) < 3.0 x ULN.
No cardiac disease defined by as active angina, symptomatic congestive heart failure, or myocardial infarction within previous six months.
Exclusion Criteria:
Patients with any active known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring systemic treatment, or other conditions under control are permitted to enroll.
Patients with conditions that needs systemic corticosteroids dose > Prednisolone 10 mg/day (or equivalent) or other immunosuppressive medications within 28 days prior to the first dose of study drug. Inhaled steroids are permitted if necessary.
Patients with any known active chronic liver disease.
Patients who have prior history of malignancy treated with curative intention in the past 2 years with the exception of basal cell carcinoma and squamous cell carcinoma of the skin, which were allowed in any case. Patients with other malignancies that do not fulfill the prior criteria could be considered for recruitment if they do not represent a competitive cause of death and have a low potential to progress to metastatic progression. Patients in this condition may be enrolled in the trial if approved after review by principal investigator.
Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or hepatitis C virus representing acute or chronic disease.
Preceding treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
Major surgery less than 28 days prior to the first dose of study drug.
Radiation therapy less than 14 days prior to the first dose of study drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pedro Isaacsson, MD
Organizational Affiliation
Hospital Moinhos de Vento
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Moinhos de Vento
City
Porto Alegre
State/Province
Rio Grande Do Sul
ZIP/Postal Code
90035000
Country
Brazil
Facility Name
Instituto do Câncer do Estado de São Paulo
City
Sao Paulo
State/Province
São Paulo
ZIP/Postal Code
01246000
Country
Brazil
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Time Frame
At the end of study For 1 year
IPD Sharing Access Criteria
RedCap / Excel
Learn more about this trial
Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst Trial)
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