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

Primary Purpose

Prostate Cancer

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Enoblituzumab

About this trial

This is an interventional treatment trial for Prostate Cancer focused on measuring enobilituzumab

Eligibility Criteria

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

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

Sites / Locations

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Enoblituzumab

Arm Description

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.

Outcomes

Primary Outcome Measures

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

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

Secondary Outcome Measures

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

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

CD8+ T Cell Infiltration

Number of CD8+ T-cells in harvested prostate glands from treated patients

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).

Regulatory T Cell (Treg) Infiltration

Mean staining percentage of Treg cells in tumor tissue of treated patients, assessed through immunohistochemistry.

CD4+ T Cell Infiltration

Mean staining percentage of CD4+ T-cells in tumor tissue of treated patients, assessed through immunohistochemistry.

Natural Killer (NK) Cell Density

Mean staining percentage of NK cells in harvested prostate glands.

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.

Pathological Complete Responses (pCR)

Number of participants who achieve pCR, defined as absence of tumor identification on standard histological analysis of resected prostate specimens.

PSA Response Rates

Number of participants with undetectable PSA (<0.1 ng/mL) at 3 months after prostatectomy.

Time to PSA Recurrence

Median time from prostatectomy to time when PSA is ≥ 0.2 ng/mL. Estimated using Kaplan-Meier method.

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.

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.

Full Information

NCT ID

NCT02923180

First Posted

September 9, 2016

Last Updated

August 22, 2023

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

MacroGenics

1. Study Identification

Unique Protocol Identification Number

NCT02923180

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

February 14, 2017 (Actual)

Primary Completion Date

August 11, 2020 (Actual)

Study Completion Date

September 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

MacroGenics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Prostate Cancer

Keywords

enobilituzumab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

33 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Enoblituzumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Enoblituzumab

Other Intervention Name(s)

MGA271

Intervention Description

Enoblituzumab 15mg/kg IV (in the vein) weekly for 6 doses beginning 50 days prior to radical prostatectomy.

Primary Outcome Measure Information:

Title

Number of Participants With Treatment-related Adverse Events

Description

Number of participants with treatment-related adverse events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4.0

Time Frame

2 years

Title

Efficacy of Neoadjuvant Enoblituzumab as Assessed by PSA0 Response Rate

Description

Number of participants with undetectable Prostate Specific Antigen (PSA <0.1 ng/mL) at 12 months following radical prostatectomy

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Quantify Markers of Apoptosis in Prostate Tumor Specimens of Treated Patients

Description

Quantify markers of apoptosis in prostate tumor specimens of treated patients using TUNEL staining and expressed as the mean staining percentage in tumor tissue

Time Frame

up to 3 years post-prostatectomy

Title

Markers of Cell Proliferation

Description

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

Time Frame

up to 3 years post-prostatectomy

Title

CD8+ T Cell Infiltration

Description

Number of CD8+ T-cells in harvested prostate glands from treated patients

Time Frame

up to 3 years post-prostatectomy

Title

PD-L1 Expression

Description

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).

Time Frame

up to 3 years post-prostatectomy

Title

Regulatory T Cell (Treg) Infiltration

Description

Mean staining percentage of Treg cells in tumor tissue of treated patients, assessed through immunohistochemistry.

Time Frame

up to 3 years post-prostatectomy

Title

CD4+ T Cell Infiltration

Description

Mean staining percentage of CD4+ T-cells in tumor tissue of treated patients, assessed through immunohistochemistry.

Time Frame

up to 3 years post-prostatectomy

Title

Natural Killer (NK) Cell Density

Description

Mean staining percentage of NK cells in harvested prostate glands.

Time Frame

up to 3 years post-prostatectomy

Title

Enoblituzumab (MGA271) Drug Distribution Evaluated by Detection of MGA271 in Tumor Tissue

Description

Number of participants with positive or negative MGA271 detection in post-treatment prostate tumor specimens, as evaluated by IHC of fresh frozen sections.

Time Frame

3 years

Title

Pathological Complete Responses (pCR)

Description

Number of participants who achieve pCR, defined as absence of tumor identification on standard histological analysis of resected prostate specimens.

Time Frame

3 years

Title

PSA Response Rates

Description

Number of participants with undetectable PSA (<0.1 ng/mL) at 3 months after prostatectomy.

Time Frame

3 months post-prostatectomy

Title

Time to PSA Recurrence

Description

Median time from prostatectomy to time when PSA is ≥ 0.2 ng/mL. Estimated using Kaplan-Meier method.

Time Frame

up to 3 years post-prostatectomy

Title

Gleason Grade Group Change

Description

Time Frame

Day 50

Title

Number of Participants With PSA Percentage Decrease Prior to Radical Prostatectomy.

Description

Time Frame

50 Days

Other Pre-specified Outcome Measures:

Title

Androgen Receptor (AR) Quantification

Description

Mean staining percentage of AR in harvested prostate tissue, assessed by immunohistochemistry (IHC) staining for AR protein.

Time Frame

up to 3 years post-prostatectomy

Title

Tissue Androgen Concentrations

Description

Concentration (picogram/3 mg) of testosterone and 5α-dihydrotestosterone (DHT) in prostate tissue.

Time Frame

up to 3 years post prostatectomy

Title

Global Expression Profiling of Tumor Tissues

Description

Number of participants with changes in cellular composition, upregulation and downregulation of immune checkpoints, and other markers of activity versus exhaustion.

Time Frame

up to 3 years post-prostatectomy

Title

IHC Analyses of CD137, CD16 and/or CD107A

Description

CD137, CD107A, and CD16 expression in prostate tumor specimens will be assessed by immunohistochemistry (IHC) in the prostatectomy surgical specimens (post-treatment). This endpoint will be expressed as the mean staining percentage of each of these in tumor tissue

Time Frame

up to 3 years post-prostatectomy

Title

TCR Repertoire

Description

Number of participants with changes in T-cell receptor (TCR) repertoire, assessed by TCR sequencing.

Time Frame

up to 3 years post-prostatectomy

Title

FC Receptor Genotyping

Description

Number of participants with CD16A, CD32A, and CD32B on Fc receptor.

Time Frame

up to 3 years post-prostatectomy

Title

PBLs

Description

Number of participants with upregulation and downregulation of immune checkpoints and other markers of activity versus exhaustion, as assessed by flow cytometry at treatment day 1 (pre-treatment), treatment day 36 (post-treatment), and 30 days post-prostatectomy.

Time Frame

up to 3 years post-prostatectomy

Title

B7-H3 Expression

Description

B7-H3 expression in prostate tumor specimens will be assessed by IHC (immunohistochemistry) in the primary core specimens (pre-treatment) and in the prostatectomy surgical specimens (post-treatment). This endpoint will be expressed as the mean staining percentage of B7-H3 in tumor tissue.

Time Frame

up to 3 years post-prostatectomy

Title

PD-1, LAG3, and TIM3 Expression

Description

PD-1, LAG3, and TIM3 expression in prostate tumor specimens will be assessed by IHC (immunohistochemistry) in the primary core specimens (pre-treatment) and in the prostatectomy surgical specimens (post-treatment). This endpoint will be expressed as the mean staining percentage in tumor tissue.

Time Frame

up to 3 Years post-prostatectomy

Title

Quantify Antigen-spread

Description

Number of participants with antigen-spread to on-target and off-target antigens.

Time Frame

up to 3 years post-prostatectomy

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Emmanuel Antonarakis, MD

Organizational Affiliation

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21205

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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