Enoblituzumab before Radical Prostatectomy versus Radical Prostatectomy Alone for the Treatment of High-Risk Localized Prostate Cancer

Status: active

This phase II trial compares the effect of enoblituzumab before radical prostatectomy to radical prostatectomy alone in treating patients with high-risk prostate cancer that has not spread to other parts of the body (localized). Enoblituzumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Enoblituzumab may block the activity of the B7 homolog 3 (B7-H3) pathway, which has been linked to aggressive prostate cancer and may drive disease progression. Currently, standard of care (SOC) treatment is a radical prostatectomy, which is surgery to remove the entire prostate. Patients with prostate cancer that has come back after a period of improvement (recurrence) that were treated with local therapies, such as a radical prostatectomy, are at a greater risk of the disease becoming metastatic (spreading to other places in the body). Giving enoblituzumab before undergoing radical prostatectomy may be more effective than surgery alone at delaying or preventing cancer recurrence in patients with high-risk localized prostate cancer.

Inclusion Criteria

Histologically confirmed adenocarcinoma of the prostate (clinical stage T1c–T3b, N0, M0) without involvement of lymph nodes, bone, or visceral organs by CT or nuclear medicine (NM) bone scan. N1 by PSMA allowed with up to 3 lymph nodes (LNs) each ≤ 1 cm. If there is no frank bone disease, but PSMA scan and CT scan are in discordance, then investigators will discuss
Initial prostate biopsy, obtained within 3 months of enrollment, is available for central pathologic review, and is confirmed to show at least 3 positive cores containing at least 1 core with at least 50% disease involvement with ≥ 4+3=7 disease (with at least 1 additional high-risk feature such as PSA > 20 or cT3) or a Gleason sum of ≥ 8
Radical prostatectomy has been scheduled
Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0-1, or Karnofsky score ≥ 70%
White blood cells (WBC) > 3,000 cells/mm^3
Absolute neutrophil count (ANC) > 1,500 cells/mm^3
Hemoglobin > 9.0 g/dL
Platelet count > 100,000 cells/mm^3
Serum creatinine < 1.5 x upper limit of normal (ULN)
Serum bilirubin < 1.5 x ULN
Alanine aminotransferase (ALT) < 3 x ULN
Aspartate aminotransferase (AST) < 3 x ULN
Alkaline phosphatase < 3 x ULN
The etiology of abnormal bilirubin and transaminase levels should be evaluated prior to study entry
Willingness to provide written informed consent and Health Insurance Portability and Accountability Act (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 enoblituzumab (MGA271) until the time of prostatectomy

Exclusion Criteria

Presence of known lymph node involvement on CT (N1 by PSMA allowed with up to 3 LNs each ≤ 1 cm) or distant metastases by CT and NM bone scan
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 chronic obstructive pulmonary disease [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, Sjogren 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, with the exception of patients who have been successfully treated for hepatitis B/C (i.e. documented confirmation of cure at least 6 months after initial treatment).

Additional locations may be listed on ClinicalTrials.gov for NCT06014255.

State:

United States

Illinois

Chicago

Northwestern University

Status: Approved

Contact: Ashley E. Ross

Phone: 312-695-8146

Email: ashley.ross@nm.org

Maryland

Baltimore

Johns Hopkins University/Sidney Kimmel Cancer Center

Status: Active

Contact: Eugene Shenderov

Phone: 410-502-9634

Email: Eugene.Shenderov@jhmi.edu

Minnesota

Minneapolis

University of Minnesota/Masonic Cancer Center

Status: Active

Contact: Emmanuel S. Antonarakis

Phone: 612-625-8287

Email: anton401@umn.edu

Rochester

Mayo Clinic in Rochester

Status: Active

Contact: Paras H. Shah

Email: Shah.Paras@mayo.edu

PRIMARY OBJECTIVE:

I. Recurrence-free survival (RFS).

SECONDARY OBJECTIVES:

I. Time to prostate-specific antigen (PSA) recurrence.

II. Change of PSA levels from baseline to the date of prostatectomy.

III. Overall survival.

IV. Metastasis-free survival.

V. PSA response.

VI. RFS at 36 months since randomization.

VII. Incidence of adverse events.

VIII. To quantify an anti-tumor response to enoblituzumab versus standard of care (SOC).

IX. To assess the immune response to enoblituzumab versus SOC.

X. To assess Gleason grade group before and after neoadjuvant enoblituzumab treatment versus SOC, by comparing prostatectomy Gleason sum to pre-treatment biopsy Gleason sum based on central review.

XI. To evaluate the proportion of pathological complete responses (pCR) in prostate tumor specimens of treated patients.

EXPLORATORY OBJECTIVES:

I. Quality of life: Functional Assessment of Cancer Therapy (FACT).

II. To quantify B7-H3 immunohistochemistry (IHC) expression in pre-treatment and post-treatment tumor tissue and correlate with tumor cell apoptosis and time to recurrence.

III. To quantify checkpoint IHC expression (e.g., PD-1, PD-L1, LAG3 and TIM3) in intrapatient pre and post treatment tumor tissue, and interpatient prostates from harvested prostate glands of enoblituzumab versus SOC patients.

IV. Determination of the prevalence of tumor cell free deoxyribonucleic acid (cfDNA), circulating tumor DNA (ctDNA), and tumor vesicle associated DNA/ribonucleic acid (RNA) in this patient population as a biomarker of longitudinal response or resistance when compared to progression-free survival (PFS), metastases-free survival (MFS), and overall survival (OS).

V. IHC analyses of CD137, CD16 and/or CD107A across potential immune infiltrate following enoblituzumab (based on proposed mechanism of action [MoA]).

VI. Global expression profiling of pre and post treatment tumor tissue in treated and untreated prostatectomies using spatial transcriptomics and proteomics.

VII. Global metabolomic profiling of tumor tissue in treated and untreated prostatectomies.

VIII. T-cell receptor (TCR) deep sequencing (Adaptive Biotech) testing hypothesis that successful anti-tumor response modulates TCR repertoire in peripheral and tumor infiltrating lymphocytes.

IX. Whole genome sequencing of tumor tissue in treated and untreated prostatectomies.

X. Long-read whole-genome sequencing analysis of DNA methylation of tumor tissue in treated and untreated prostatectomies.

XI. Single cell RNA sequencing of tumor tissue in treated and untreated prostatectomies.

XII. Flow cytometric analysis of peripheral blood cell population compositions pre-treatment, on-treatment, and post-treatment.

XIII. Quantification of baseline and pre-prostatectomy blood cytokines and chemokines.

XIV. Assessment of congruence between conventional (computed tomography [CT] and bone scans) imaging and prostate-specific membrane antigen (PSMA) imaging.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive enoblituzumab intravenously (IV) over 120 minutes on days 1, 15, 29, 43, 57 and 71 in the absence of disease progression or unacceptable toxicity. Patients undergo radical prostatectomy on day 84. Patients undergo urine, stool, and blood sample collection, CT or magnetic resonance imaging (MRI) and bone scan. Patients also undergo prostatic MRI and optional digital rectal examination at screening and PSMA positron emission tomography (PET) scan at screening and optionally throughout the study. Additionally, patients may optionally undergo bone marrow aspiration on study.

ARM II: Patients undergo radical prostatectomy 4-8 weeks after day 1. Patients undergo urine, stool, and blood sample collection, CT or MRI and bone scan. Patients also undergo prostatic MRI and optional digital rectal examination at screening and PSMA PET scan at screening and optionally throughout the study. Additionally, patients may optionally undergo bone marrow aspiration on study.

After completion of surgery, patients are followed up at 30 and 90 days, then every 3 months during year 1 followed by every 6 months during years 2-5.

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Enoblituzumab before Radical Prostatectomy versus Radical Prostatectomy Alone for the Treatment of High-Risk Localized Prostate Cancer

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