Clinical Trials /

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

NCT02923180

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer
  • Official Title: Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: J1693
  • NCT ID: NCT02923180

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
EnoblituzumabMGA271Enoblituzumab

Purpose

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
EnoblituzumabExperimental15mg/kg IV (in the vein) weekly for 6 weeks
  • Enoblituzumab

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Frequency, type, and severity of adverse events
Time Frame:2 years
Safety Issue:
Description:Evaluate the number of participants with treatment-related adverse events as assessed by the CTCAE v4.0

Secondary Outcome Measures

Measure:Quantify markers of apoptosis in prostate tumor specimens of treated patients
Time Frame:3 years
Safety Issue:
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
Measure:Markers of cell proliferation
Time Frame:3 years
Safety Issue:
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
Measure:CD8+ T cell infiltration
Time Frame:3 years
Safety Issue:
Description:Quantify the extent of CD8+ T cell infiltration into the prostate from harvested prostate glands of treated patients
Measure:PD-L1 expression
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Regulatory T cell (Treg) infiltration
Time Frame:3 years
Safety Issue:
Description:This endpoint will be expressed as the mean staining percentage in tumor tissue.
Measure:CD4+ T cell infiltration
Time Frame:3 years
Safety Issue:
Description:This endpoint will be expressed as the mean staining percentage in tumor tissue.
Measure:Mean NK cell density in tumor tissue from harvested prostate glands of patients.
Time Frame:3 years
Safety Issue:
Description:This endpoint will be expressed as the mean staining percentage in tumor tissue.
Measure:FC Receptor Genotyping
Time Frame:3 years
Safety Issue:
Description:Determination of Fc receptor genotype (CD16A, CD32A, CD32B)
Measure:Sera for Immunoassays
Time Frame:3 years
Safety Issue:
Description:Sera for immunoassays will be collected at each time point (Pre-treatment, Radical Prostatectomy, and Follow-up)
Measure:PBLs
Time Frame:30 days
Safety Issue:
Description:Whole blood (100cc) will be collected for PBLs at each time point ((Treatment Day 1, Treatment Day 36, and Follow-up day 30),
Measure:TCR Repertoire
Time Frame:90 days
Safety Issue:
Description: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.
Measure:B7-H3 expression
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Enoblituzumab (MGA271) drug distribution
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Tissue androgen concentrations
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Androgen receptor (AR) quantification
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Pathological complete responses (pCR)
Time Frame:3 years
Safety Issue:
Description: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.
Measure:PSA response rates
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Time to PSA recurrence
Time Frame:3 Years
Safety Issue:
Description: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.
Measure:Assessment of Gleason grade change
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Global expression profiling of pre and post treatment tumor tissue
Time Frame:3 years
Safety Issue:
Description:using single cell RNA sequencing, the immune NanoString immunopanel and/or microarrays
Measure:IHC analyses of CD137, CD16 and/or CD107A
Time Frame:3 years
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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