Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer

Study Overview
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Brief Summary
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This study evaluates the safety, anti-tumor effect, and immunogenicity of Enoblituzumab given before radical prostatectomy. All patients will receive Enoblituzumab for 6 weekly doses beginning 50 days 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 MGA271 given prior to radical prostatectomy in men with intermediate and high-risk localized prostate cancer. Eligible patients will receive MGA271 at a dose of 15mg/kg IV given weekly for 6 doses beginning 50 days prior to radical prostatectomy. 14 days after the last dose of MGA271, 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 90 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. In Amendment 1, the study was expanded to enroll an additional 16 patients for a total of 32 patients to continue evaluating safety and better estimate the clinical benefit of Enoblituzumab in terms of undetectable PSA level (<0.1 ng/mL) at 12 months following radical prostatectomy.

Official Title
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A Phase II Trial of Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate- and High-Risk Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Enoblituzumab


Participation Criteria
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Eligibility Criteria
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Inclusion 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 ECOG performance status 0-1, or Karnofsky score ≥ 70% (see Appendix A) 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 <1.5 × upper limit of normal (ULN) Serum bilirubin <1.5 × ULN ALT <3 × ULN AST <3 × ULN Alkaline phosphatase <3 × ULN The etiology of abnormal bilirubin and transaminase levels should be evaluated prior to study entry. 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 MGA271 until the time of prostatectomy. Exclusion 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 Prior use of experimental agents for prostate cancer Concomitant treatment with other hormonal therapy or 5α-reductase inhibitors Current use of systemic corticosteroids or use of systemic corticosteroids within 4 weeks of enrollment (inhaled corticosteroids for asthma or COPD are permitted as are other non-systemic steroids such as topical corticosteroids) 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

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enoblituzumab<br>Men with localized intermediate and high-risk prostate cancer will be given neoadjuvant Enoblituzumab 15mg/kg IV weekly for 6 weeks followed by radical prostatectomy on day 50, with follow-up visits 30 days and 90 days post-prostatectomy. PSA values will be tracked for 3 years post-prostatectomy. | Drug: Enoblituzumab<br>* Enoblituzumab 15mg/kg IV (in the vein) weekly for 6 doses beginning 50 days prior to radical prostatectomy.<br>* Other names: MGA271;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Adverse Events | Number of participants with treatment-related adverse events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4.0 | 2 years | 
| Efficacy of Neoadjuvant Enoblituzumab as Assessed by PSA0 Response Rate | Number of participants with undetectable Prostate Specific Antigen (PSA <0.1 ng/mL) at 12 months following radical prostatectomy | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantify Markers of Apoptosis in Prostate Tumor Specimens of Treated Patients | Quantify markers of apoptosis in prostate tumor specimens of treated patients using TUNEL staining and expressed as the mean staining percentage in tumor tissue | up to 3 years post-prostatectomy | 
| Markers of Cell Proliferation | Quantify markers of cell proliferation in prostate tumor specimens of treated patients using Ki-67 staining and expressed by the mean staining percentage in tumor tissue | up to 3 years post-prostatectomy | 
| CD8+ T Cell Infiltration | Number of CD8+ T-cells in harvested prostate glands from treated patients | up to 3 years post-prostatectomy | 
| PD-L1 Expression | Mean staining percentage of PD-L1 in tumor tissue, assessed by immunohistochemistry (IHC) in the primary core specimens (pre-treatment) and the prostatectomy surgical specimens (post-treatment). | up to 3 years post-prostatectomy | 
| Regulatory T Cell (Treg) Infiltration | Mean staining percentage of Treg cells in tumor tissue of treated patients, assessed through immunohistochemistry. | up to 3 years post-prostatectomy | 
| CD4+ T Cell Infiltration | Mean staining percentage of CD4+ T-cells in tumor tissue of treated patients, assessed through immunohistochemistry. | up to 3 years post-prostatectomy | 
| Natural Killer (NK) Cell Density | Mean staining percentage of NK cells in harvested prostate glands. | up to 3 years post-prostatectomy | 
| Enoblituzumab (MGA271) Drug Distribution Evaluated by Detection of MGA271 in Tumor Tissue | Number of participants with positive or negative MGA271 detection in post-treatment prostate tumor specimens, as evaluated by IHC of fresh frozen sections. | 3 years | 
| Pathological Complete Responses (pCR) | Number of participants who achieve pCR, defined as absence of tumor identification on standard histological analysis of resected prostate specimens. | 3 years | 
| PSA Response Rates | Number of participants with undetectable PSA (<0.1 ng/mL) at 3 months after prostatectomy. | 3 months post-prostatectomy | 
| Time to PSA Recurrence | Median time from prostatectomy to time when PSA is ≥ 0.2 ng/mL. Estimated using Kaplan-Meier method. | up to 3 years post-prostatectomy | 
| Gleason Grade Group Change | Number of participants with change in Gleason grade group from pre-treatment biopsy vs. post-treatment biopsy. Downgrade refers to a net grade group change less than zero, upgrade refers to net grade group change more than zero, and no change refers to stable Gleason grade group. Gleason grade groups are defined as grade group 1 (Gleason score ≤ 6), grade group 2 (Gleason score 3+4=7), grade group 3 (Gleason score 4+3=7), grade group 4 (Gleason score 8), and grade group 5 (Gleason scores 9-10).The lower the grade group, the better the outcome. | Day 50 | 
| Number of Participants With PSA Percentage Decrease Prior to Radical Prostatectomy. | The PSA percentage change is calculated as the difference from the PSA at day 50 prior to prostatectomy and PSA at screening. A negative value of PSA percentage change (PSA percentage < 0) indicates a decrease in PSA from screening, and a positive value (PSA percentage change >= 0) indicates an increase in PSA from screening. | 50 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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enobilituzumab