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

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ClinicalTrials.gov Identifier: NCT02923180
Recruitment Status : Recruiting
First Posted : October 4, 2016
Last Update Posted : November 22, 2018
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Enoblituzumab Phase 2

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 expended 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer
Actual Study Start Date : October 2016
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Enoblituzumab
15mg/kg IV (in the vein) weekly for 6 weeks
Drug: Enoblituzumab
Other Name: MGA271




Primary Outcome Measures :
  1. Frequency, type, and severity of adverse events [ Time Frame: 2 years ]
    Evaluate the number of participants with treatment-related adverse events as assessed by the CTCAE v4.0

  2. Estimation of PSA0 Response Rate (Undetectable PSA level <0.1 ng/mL) at 12 months following radical prostatectomy [ Time Frame: 12 months ]
    For cohort 2 expansion, Our primary efficacy endpoint will be to estimate the clinical benefit of neoadjuvant Enoblituzumab in terms of undetectable PSA level (<0.1 ng/mL) at 12 months following radical prostatectomy.


Secondary Outcome Measures :
  1. Quantify markers of apoptosis in prostate tumor specimens of treated patients [ Time Frame: 3 years ]
    Quantify markers of apoptosis in prostate tumor specimens of treated patients using TUNEL staining and expressed as the mean staining percentage in tumor tissue

  2. Markers of cell proliferation [ Time Frame: 3 years ]
    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

  3. CD8+ T cell infiltration [ Time Frame: 3 years ]
    Quantify the extent of CD8+ T cell infiltration into the prostate from harvested prostate glands of treated patients

  4. PD-L1 expression [ Time Frame: 3 years ]
    PD-L1 expression in prostate tumor specimens will be assessed by IHC 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 PD-L1 in tumor tissue.

  5. Regulatory T cell (Treg) infiltration [ Time Frame: 3 years ]
    This endpoint will be expressed as the mean staining percentage in tumor tissue.

  6. CD4+ T cell infiltration [ Time Frame: 3 years ]
    This endpoint will be expressed as the mean staining percentage in tumor tissue.

  7. Mean NK cell density in tumor tissue from harvested prostate glands of patients. [ Time Frame: 3 years ]
    This endpoint will be expressed as the mean staining percentage in tumor tissue.

  8. FC Receptor Genotyping [ Time Frame: 3 years ]
    Determination of Fc receptor genotype (CD16A, CD32A, CD32B)

  9. Sera for Immunoassays [ Time Frame: 3 years ]
    Sera for immunoassays will be collected at each time point (Pre-treatment, Radical Prostatectomy, and Follow-up)

  10. PBLs [ Time Frame: 30 days ]
    Whole blood (100cc) will be collected for PBLs at each time point ((Treatment Day 1, Treatment Day 36, and Follow-up day 30),

  11. TCR Repertoire [ Time Frame: 90 days ]
    To assess changes in TCR repertoire in peripheral and tumor T-cells following treatment with MGA271, TCR Deep Sequencing analysis will be performed via Adaptive Biotechnology (Seattle, WA). For tumor T-cell analysis, a tumor sample (10 mg fresh frozen or 25 mg FFPE) will be used. For peripheral T-cell analysis, peripheral whole blood samples (2x10 mL) pre-treatment, at time of surgery, and 30 and 90 days post-op will be used. Note: Adaptive Biotechnology requires a min of 3ug DNA (tissue or blood) for deep sequencing.

  12. B7-H3 expression [ Time Frame: 3 years ]
    B7-H3 expression in prostate tumor specimens will be assessed by IHC 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.

  13. Enoblituzumab (MGA271) drug distribution [ Time Frame: 3 years ]
    To analyze MGA271 drug levels in prostate tumor specimens of treated patients, fresh frozen sections will be evaluated by IHC for evidence of MGA271 drug distribution. Fresh frozen section samples will be shipped to MacroGenics for analysis. This endpoint will be expressed as positive or negative detection of MGA271 in tumor tissue.

  14. Tissue androgen concentrations [ Time Frame: 3 years ]
    Tissue concentrations of testosterone and 5α-dihydrotestosterone (DHT) will be measured using a highly sensitive liquid chromatography-electrospray ionization tandem mass spectrometry method using a high proton affinitive derivatization of the 17β-hydroxyl group of testosterone and DHT with picolinic acid, and a mobile phase consisting of MeCN-MeOH-H2O-formic acid and a conventional octadecylsilica (ODS) column (Yamashita et al 2009). Purification of the derivatives will be carried out using solid-phase extraction with the ODS cartridge. By this method, testosterone and DHT will be determined simultaneously with limits of quantification of 0.5 pg and 1 pg/3 mg of prostate tissue, respectively.

  15. Androgen receptor (AR) quantification [ Time Frame: 3 years ]
    The method for quantifying androgen receptor (AR) density from harvested prostate tissue is similar to that described in Section 8.3.3, and will rely on immunohistochemical staining for the AR protein. This endpoint will be expressed as the mean staining percentage in tumor tissue.

  16. Pathological complete responses (pCR) [ Time Frame: 3 years ]
    This will be defined as the absence of tumor identification by the study pathologist on standard histological analysis of the resected prostate specimens. The endpoint will be expressed as the proportion of men achieving a pCR.

  17. PSA response rates [ Time Frame: 3 years ]
    This will be defined as the proportion of patients who achieve an undetectable PSA (<0.1 ng/mL) by 3 months after prostatectomy. The endpoint will be expressed as the proportion of men achieving a PSA response.

  18. Time to PSA recurrence [ Time Frame: 3 Years ]
    This will be defined as the interval from the time of prostatectomy to the time when the serum PSA is ≥0.2 ng/mL. PSA will be measured approximately 1 month after prostatectomy, and every 3 (±1) months during the first post-operative year and every 6 (±2) months during the second and third post-operative years. For subjects who have not yet demonstrated PSA relapse at the time of censoring, patients will be censored at the date of the last assessment that shows a lack of PSA recurrence. This outcome will be expressed as a median and will be determined using the Kaplan-Meier method.

  19. Assessment of Gleason grade change [ Time Frame: 3 years ]
    This will be defined by comparing highest Gleason grade from pre-treatment biopsy versus highest Gleason grade from post-treatment prostatectomy. This endpoint will be expressed as the proportion of men achieving a Gleason score change.

  20. Global expression profiling of pre and post treatment tumor tissue [ Time Frame: 3 years ]
    using single cell RNA sequencing, the immune NanoString immunopanel and/or microarrays

  21. IHC analyses of CD137, CD16 and/or CD107A [ Time Frame: 3 years ]
    CD137, CD107A, and CD16 expression in prostate tumor specimens will be assessed by IHC in the prostatectomy surgical specimens (post-treatment). This endpoint will be expressed as the mean staining percentage of each of these in in tumor tissue



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02923180


Contacts
Contact: Emmanuel Antonarakis, MD 410-502-7528 eantona1@jhmi.edu
Contact: Rana Harb, MS 443-287-6662 Rharb1@jhmi.edu

Locations
United States, Maryland
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21205
Contact: Emmanuel Antonarakis, MD    410-502-7528    eantona1@jhmi.edu   
Contact: Rana Harb, MS    443-287-6662    rharb1@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Investigators
Principal Investigator: Emmanuel Antonarakis, MD Johns Hopkins University

Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT02923180     History of Changes
Other Study ID Numbers: J1693
First Posted: October 4, 2016    Key Record Dates
Last Update Posted: November 22, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases