Neoadjuvant Dupilumab in Men With Localized High-Risk Prostate Cancer

Study Overview
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Brief Summary
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This is a single-center, single arm, open-label phase II study evaluating the safety, anti-tumor effect, and immunogenicity of neoadjuvant Dupixent given prior to radical prostatectomy.

Detailed Description
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This is a single-center, single arm, open-label phase II study evaluating the safety, anti-tumor effect, and immunogenicity of neoadjuvant Dupixent given prior to radical prostatectomy in men with high-risk localized prostate cancer (this trial will enroll men with at least high risk prostate cancer defined by NCCN Guidelines Version 2.2017 = clinical stage ≥T3a or PSA >20 ng/mL or Gleason score ≥8). Patients will be recruited from the outpatient Urology clinic. Men will be treated with dupilumab 600 mg subcutaneously (SQ) on day 1, and then 300 mg SQ on days 8,15, 22, 29, 36, 43. They will then undergo surgery on day 57. 14 days after the last dose of Dupixent, prostate glands will be harvested at the time of radical prostatectomy, and prostate tissue will be examined for the secondary endpoints. Follow-up evaluation for adverse events will occur 30 days and 60 days after surgery. Patients will then be followed by their urologists according to standard institutional practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 (±2) months during years 2-3.

Official Title
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Neoadjuvant Dupilumab in Men With Localized High-Risk Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Dupilumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for this study, patients must meet all of the following criteria: Histologically confirmed adenocarcinoma of the prostate (clinical stage T1c-T3b, N0, M0) without involvement of lymph nodes, bone, or visceral organs Initial prostate biopsy is available for central pathologic review, and is confirmed to show at least 2 positive cores and a Gleason sum of ≥7 Radical prostatectomy has been scheduled at Johns Hopkins Hospital Age ≥18 years Eastern Cooperative Oncology Group (ECOG) performance status 0-1, or Karnofsky score ≥ 70% Adequate bone marrow, hepatic, and renal function: WBC >3,000 cells/mm3 ANC >1,500 cells/mm3 Hemoglobin >9.0 g/dL Platelet count >100,000 cells/mm3 Serum creatinine <3 × upper limit of normal (ULN) Serum bilirubin <3 × ULN ALT <5 × ULN AST <5 × ULN Alkaline phosphatase <5 × ULN Willingness to provide written informed consent and HIPAA authorization for the release of personal health information, and the ability to comply with the study requirements (note: HIPAA authorization will be included in the informed consent) Willingness to use barrier contraception from the time of first dose of DUPILUMAB until the time of prostatectomy. Exclusion Criteria: To be eligible for this study, patients should not meet any of the following criteria: Presence of known lymph node involvement or distant metastases Other histologic types of prostate cancers such as ductal, sarcomatous, lymphoma, small cell, and neuroendocrine tumors Prior radiation therapy, hormonal therapy, biologic therapy, or chemotherapy for prostate cancer Prior immunotherapy/vaccine therapy for prostate cancer Concomitant treatment with other hormonal therapy or 5α-reductase inhibitors Current use of systemic corticosteroids or use of corticosteroids within 4 weeks of enrollment (inhaled corticosteroids for asthma or COPD are permitted) Use of experimental agents for prostate cancer within the past 3 months from time of screening History or presence of autoimmune disease requiring systemic immunosuppression (including but not limited to: inflammatory bowel disease, systemic lupus erythematosus, vasculitis, rheumatoid arthritis, scleroderma, multiple sclerosis, hemolytic anemia, Sjögren syndrome, and sarcoidosis) History of malignancy within the last 3 years, with the exception of non-melanoma skin cancers and superficial bladder cancer Uncontrolled major active infectious, cardiovascular, pulmonary, hematologic, or psychiatric illnesses that would make the patient a poor study candidate Known prior or current history of HIV and/or hepatitis B/C Significant eye disease

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
Intervention Model: Single Group Assignment
Interventional Model Description: Men will be treated with dupilumab 600 mg s.q. on day 1, and then 300 mg s.q. on days 8,15, 22, 29, 36, 43. They will then undergo surgery on day 57. Fourteen days after the last dose of Dupixent, prostate glands will be harvested at the time of radical prostatectomy, and prostate tissue will be examined for the secondary endpoints. Follow-up evaluation for adverse events will occur 30 days and 60 days after surgery. Patients will then be followed by their urologists according to standard institutional practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 (±2) months during years 2-3.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupixent Subcutaneous (SQ) Injection<br>Participants will be treated with dupilumab 600 mg SQ on day 1, and then 300 mg SQ on days 8,15, 22, 29, 36, 43. They will then undergo surgery on day 57. 14 days after the last dose of Dupixent, prostate glands will be harvested at the time of radical prostatectomy, and prostate tissue will be examined for the secondary endpoints. | Drug: Dupilumab<br>* dupilumab 600 mg SQ on day 1, and then 300 mg SQ on days 8,15, 22, 29, 36, 43.<br>* Other names: Dupixent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in M2-TAM Infiltration From Baseline | Change in M2-TAM infiltration (number of macrophages / cell nuclei per high power field [hpf]) measured in pre- dupilumab biopsy to M2-TAM infiltration measured in post-dupilumab specimen collected at time of radical prostatectomy (up to 59 days post-intervention). Degree of TAM infiltration will be analyzed using immunohistochemical staining for CD206. It is hypothesized that a positive value will be associated with better outcome and a negative value will reflect a worse outcome. | change from baseline to up to 59 days post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Assessed by Number of Participants Experiencing Adverse Events | Adverse events defined by NCI Common Toxicity Criteria version 4.0 (NCI CTCAE v4.0) | up to 59 days post-intervention | 
| Feasibility as Assessed by Number of Participants Who Have an Average Blood Loss in Excess of 2500 mL During Prostatectomy |  | up to 59 days post-intervention | 
| Feasibility as Assessed by Number of Participants With Average Prostatectomy Operative Time in Excess of 3.5 Hours |  | up to 59 days post-intervention | 
| Feasibility as Assessed by Number of Participants With Average Hospital Stay in Excess of 4 Days Post-prostatectomy |  | up to 59 days post-intervention | 
| CD8+ T-cell Infiltration in Post-treatment Prostate Glands | mean CD4+ T-cell staining percentage and CD4+/Treg ratio in harvested tumor tissue collected from prostatectomy specimen | up to 59 days post-intervention | 
| CD4+ T-cell and Treg Infiltration in Post-treatment Prostate Glands | mean CD4+ T-cell staining percentage and CD4+/Treg ratio in harvested tumor tissue collected from prostatectomy specimen | up to 59 days post-intervention | 
| Expression of Apoptosis Marker (Annexin V) in Post-treatment Prostate Tumor Specimen as Measured by Mean Staining Percentage in Tumor Tissue | Mean staining percentage of Annexin V in tumor tissue, using TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) staining. | up to 59 days post-intervention | 
| Expression of Cell Proliferation in Post-treatment Prostate Tumor Specimen as Measured by Mean Staining Percentage of Ki-67 in Tumor Tissue |  | up to 59 days post-intervention | 
| Proportion of Participants With Pathological Complete Response | Pathological response is defined as the absence of tumor identification by study pathologist on standard histological analysis of resected prostate specimens. | 1 month post-prostatectomy | 
| Proportion of Participants Who Achieve an Undetectable PSA at 2 Months Post-prostatectomy | Proportion of participants with PSA <0.1ng/mL by 2 months after prostatectomy | 2 months post-prostatectomy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high-risk prostate cancer, localized prostate cancer, prior to prostatectomy, neoadjuvant