Prostate Cancer
Conditions
Keywords
enobilituzumab
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.
Interventions
DRUGEnoblituzumab
Enoblituzumab 15mg/kg IV (in the vein) weekly for 6 doses beginning 50 days prior to radical prostatectomy.
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
MacroGenics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Neoadjuvant Enoblituzumab as Assessed by PSA0 Response Rate | 12 months | Number of participants with undetectable Prostate Specific Antigen (PSA \<0.1 ng/mL) at 12 months following radical prostatectomy |
| Number of Participants With Treatment-related Adverse Events | 2 years | Number of participants with treatment-related adverse events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v4.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Regulatory T Cell (Treg) Infiltration | 3 years post-prostatectomy | Mean staining percentage of Treg cells in tumor tissue of treated patients, assessed through immunohistochemistry. |
| CD4+ T Cell Infiltration | 3 years post-prostatectomy | Mean staining percentage of CD4+ T-cells in tumor tissue of treated patients, assessed through immunohistochemistry. |
| Natural Killer (NK) Cell Density | 3 years post-prostatectomy | Mean staining percentage of NK cells in harvested prostate glands. |
| Enoblituzumab (MGA271) Drug Distribution Evaluated by Detection of MGA271 in Tumor Tissue | 3 years | 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) | 3 years | Number of participants who achieve pCR, defined as absence of tumor identification on standard histological analysis of resected prostate specimens. |
| PSA Response Rates | 3 months post-prostatectomy | Number of participants with undetectable PSA (\<0.1 ng/mL) at 3 months after prostatectomy. |
| Time to PSA Recurrence | up to 37 months post-prostatectomy | Median time (months) from prostatectomy to time when PSA is ≥ 0.2 ng/mL. Estimated using Kaplan-Meier method. |
| Mean Staining Percentage of Markers of Cell Proliferation | 3 years post-prostatectomy | 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 |
| Quantify Markers of Apoptosis in Prostate Tumor Specimens of Treated Patients | up to 5 years post-prostatectomy | Quantify markers of apoptosis in prostate tumor specimens of treated patients using TUNEL staining and expressed as the mean staining percentage in tumor tissue |
| Gleason Grade Group Change | Day 50 | 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. |
| CD8+ T Cell Infiltration | 3 years post-prostatectomy | Mean staining percentage of CD8+ T-cells in harvested prostate glands from treated patients |
| Number of Participants With PSA Percentage Decrease Prior to Radical Prostatectomy. | 50 Days | 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. |
| PD-L1 Expression | 3 years post-prostatectomy | 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). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATOREugene Shenderov, MD, PhD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Participant flow
Pre-assignment details
33 subjects signed consent to be screened for eligibility. \- 1 subject signed consent, but did not meet the eligibility criteria to start the study (screen failure)
Participants by arm
| Arm | Count |
|---|---|
| Enoblituzumab 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. | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Enoblituzumab |
|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 5.82 |
| Body-mass index (kg/m^2) Normal (BMI 18.5 - 24.9) | 6 Participants |
| Body-mass index (kg/m^2) Obese (BMI ≥ 30.0) | 12 Participants |
| Body-mass index (kg/m^2) Overweight (BMI 25.0 - 29.9) | 14 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 | 31 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Family History of Prostate Cancer No | 25 Participants |
| Family History of Prostate Cancer Yes | 7 Participants |
| Gleason Group / Gleason sum at biopsy Grade Group 3: 4+3 | 5 Participants |
| Gleason Group / Gleason sum at biopsy Grade Group 4: 4+4 | 8 Participants |
| Gleason Group / Gleason sum at biopsy Grade Group 5: 4+5, 5+4, or 5+5 | 19 Participants |
| Previous Therapy | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 32 Participants |
| Smoking History No | 23 Participants |
| Smoking History Yes | 9 Participants |
| Stage T3 at initial diagnosis No | 9 Participants |
| Stage T3 at initial diagnosis Yes | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 32 |
| other Total, other adverse events | 32 / 32 |
| serious Total, serious adverse events | 3 / 32 |
Outcome results
Primary
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
Time frame: 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | Efficacy of Neoadjuvant Enoblituzumab as Assessed by PSA0 Response Rate | PSA < 0.1 ng/mL | 21 Participants |
| Enoblituzumab | Efficacy of Neoadjuvant Enoblituzumab as Assessed by PSA0 Response Rate | PSA ≥ 0.1 ng/mL | 11 Participants |
Primary
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
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | Number of Participants With Treatment-related Adverse Events | Grade 1 | 31 Participants |
| Enoblituzumab | Number of Participants With Treatment-related Adverse Events | Grade 2 | 12 Participants |
| Enoblituzumab | Number of Participants With Treatment-related Adverse Events | Grade 3 | 4 Participants |
| Enoblituzumab | Number of Participants With Treatment-related Adverse Events | Grade 4 | 0 Participants |
Secondary
CD4+ T Cell Infiltration
Mean staining percentage of CD4+ T-cells in tumor tissue of treated patients, assessed through immunohistochemistry.
Time frame: 3 years post-prostatectomy
Population: Only 30 of the 32 participants enrolled in the trial had evaluable tissue samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoblituzumab | CD4+ T Cell Infiltration | 11.68 staining percentage | Standard Deviation 0.71 |
Secondary
CD8+ T Cell Infiltration
Mean staining percentage of CD8+ T-cells in harvested prostate glands from treated patients
Time frame: 3 years post-prostatectomy
Population: Only 30 of the 32 participants enrolled in the trial had evaluable tissue samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoblituzumab | CD8+ T Cell Infiltration | 11.68 staining percentage | Standard Deviation 0.71 |
Secondary
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.
Time frame: 3 years
Population: The Overall Number of Participants Analyzed represents those evaluable for this outcome. Of the 32 participants who received study treatment, data from 2 subjects was not evaluable.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | Enoblituzumab (MGA271) Drug Distribution Evaluated by Detection of MGA271 in Tumor Tissue | Positive | 28 Participants |
| Enoblituzumab | Enoblituzumab (MGA271) Drug Distribution Evaluated by Detection of MGA271 in Tumor Tissue | Negative | 2 Participants |
Secondary
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.
Time frame: Day 50
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | Gleason Grade Group Change | Downgrade (< 0 net grade group change) | 16 Participants |
| Enoblituzumab | Gleason Grade Group Change | No Change (= 0 net grade group change) | 12 Participants |
| Enoblituzumab | Gleason Grade Group Change | Upgrade (> 0 net grade group change) | 4 Participants |
Secondary
Mean Staining Percentage of 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
Time frame: 3 years post-prostatectomy
Population: Only 30 of the 32 participants enrolled in the trial had evaluable tissue samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoblituzumab | Mean Staining Percentage of Markers of Cell Proliferation | 11.92 staining percentage | Standard Deviation 0.82 |
Secondary
Natural Killer (NK) Cell Density
Mean staining percentage of NK cells in harvested prostate glands.
Time frame: 3 years post-prostatectomy
Population: Only 30 of the 32 participants enrolled in the trial had evaluable tissue samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoblituzumab | Natural Killer (NK) Cell Density | 11.92 staining percentage | Standard Deviation 0.82 |
Secondary
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.
Time frame: 50 Days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | Number of Participants With PSA Percentage Decrease Prior to Radical Prostatectomy. | PSA percentage change < 0 | 16 Participants |
| Enoblituzumab | Number of Participants With PSA Percentage Decrease Prior to Radical Prostatectomy. | PSA percentage change >= 0 | 16 Participants |
Secondary
Pathological Complete Responses (pCR)
Number of participants who achieve pCR, defined as absence of tumor identification on standard histological analysis of resected prostate specimens.
Time frame: 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Enoblituzumab | Pathological Complete Responses (pCR) | 0 Participants |
Secondary
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).
Time frame: 3 years post-prostatectomy
Population: Only 30 of the 32 participants enrolled in the trial had evaluable tissue samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoblituzumab | PD-L1 Expression | 10.66 staining percentage | Standard Deviation 0.82 |
Secondary
PSA Response Rates
Number of participants with undetectable PSA (\<0.1 ng/mL) at 3 months after prostatectomy.
Time frame: 3 months post-prostatectomy
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | PSA Response Rates | PSA <0.1 ng/mL | 26 Participants |
| Enoblituzumab | PSA Response Rates | PSA ≥0.1 ng/mL | 6 Participants |
Secondary
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
Time frame: up to 5 years post-prostatectomy
Secondary
Regulatory T Cell (Treg) Infiltration
Mean staining percentage of Treg cells in tumor tissue of treated patients, assessed through immunohistochemistry.
Time frame: 3 years post-prostatectomy
Population: Only 30 of the 32 participants enrolled in the trial had evaluable tissue samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enoblituzumab | Regulatory T Cell (Treg) Infiltration | 9.36 staining percentage | Standard Deviation 0.9 |
Secondary
Time to PSA Recurrence
Median time (months) from prostatectomy to time when PSA is ≥ 0.2 ng/mL. Estimated using Kaplan-Meier method.
Time frame: up to 37 months post-prostatectomy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enoblituzumab | Time to PSA Recurrence | 30 months |
Other Pre-specified
Androgen Receptor (AR) Quantification
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
Other Pre-specified
B7-H3 Expression
Number of participants with 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).
Time frame: 3 years post-prostatectomy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Enoblituzumab | B7-H3 Expression | 28 Participants |
Other Pre-specified
FC Receptor Genotyping
Number of participants with CD16A, CD32A, and CD32B on Fc receptor.
Time frame: up to 3 years post-prostatectomy
Other Pre-specified
Global Expression Profiling of Tumor Tissues
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
Other Pre-specified
IHC Analyses of CD137, CD16 and/or CD107A
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
Other Pre-specified
PBLs
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: 3 years post-prostatectomy
Other Pre-specified
PD-1, LAG3, and TIM3 Expression
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: 3 Years post-prostatectomy
Other Pre-specified
Quantify Antigen-spread
Number of participants with antigen-spread to on-target and off-target antigens.
Time frame: 3 years post-prostatectomy
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | Quantify Antigen-spread | Number of participants with IgG reactivity | 1 Participants |
| Enoblituzumab | Quantify Antigen-spread | Number of participants with IgM reactivity | 1 Participants |
| Enoblituzumab | Quantify Antigen-spread | Number of participants without antigen reactivity | 30 Participants |
Other Pre-specified
TCR Repertoire
Fraction of peripherally expanded clones that are tumor associated for each participant.
Time frame: 3 years post-prostatectomy
Population: Only 30 of the 32 participants enrolled in the trial had evaluable samples.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enoblituzumab | TCR Repertoire | Number of participants with 100% peripheral expanded clones associated with tumor | 7 Participants |
| Enoblituzumab | TCR Repertoire | Number of participants with 99% or less peripheral expanded clones associated with tumor | 23 Participants |
Other Pre-specified
Tissue Androgen Concentrations
Concentration (picogram/3 mg) of testosterone and 5α-dihydrotestosterone (DHT) in prostate tissue.
Time frame: up to 3 years post prostatectomy