Prostate Cancer Metastatic
Conditions
Keywords
PROSTVAC, metastatic, prostate cancer, castrate-resistant, vaccine, immunotherapy, Phase 3
Brief summary
The purpose of this study is to determine whether PROSTVAC alone or in combination with GM-CSF is effective in prolonging overall survival in men with few or no symptoms from metastatic, castrate-resistant prostate cancer.
Detailed description
BNIT-PRV-301 is a randomized, placebo-controlled, multi-center, global Phase 3 efficacy trial of PROSTVAC in men with asymptomatic or minimally symptomatic, metastatic, castrate-resistant prostate cancer. It is a 3-arm study and will evaluate overall survival in two separate comparisons, PROSTVAC plus adjuvant dose GM-CSF versus controls, and PROSTVAC without GM-CSF versus controls. Patients will be randomized with equal probability into one of three double-blind arms. The intended interventions for randomized patients are: 1. (Arm V+G) PROSTVAC-V/F plus adjuvant dose GM-CSF 2. (Arm V) PROSTVAC-V/F plus GM-CSF placebo 3. (Arm P) Double placebo
Interventions
BIOLOGICALPROSTVAC-V
BIOLOGICALPROSTVAC-F
DRUGGM-CSF
OTHERGM-CSF Placebo
BIOLOGICALPlacebo
PROSTVAC V/F Placebo
Sponsors
Bavarian Nordic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Men, ≥18years of age with documented asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Documented progressive disease post surgical castration or during androgen suppression therapy, or during complete androgen blockade therapy and withdrawal. Documented by either criterion a (Radiological progression), OR criterion b (PSA progression). 1. Radiological progression defined as any new/enlarging bone metastases or new/enlarging lymph node disease, consistent with prostate cancer. OR 2. PSA progression defined by sequence of rising values separated by \> 1 week (2 separate increasing values) over a threshold minimum of 2.0 ng/ml. (PCWG2 PSA eligibility criteria). Chemotherapy naïve and Vaccinia-experienced (previous smallpox vaccination). Currently using a GnRH agonist or antagonist (unless surgically castrated).
Exclusion criteria
Cancer-related pain requiring scheduled opioid narcotics for control (as needed, ≤ 2x per week is allowed). Metastasis to organ systems other than lymph nodes and/or bone. Estimated PSA doubling time of \<1 month as established within 6 months of the anticipated first dose of vaccine or placebo. Concurrent or prior Provenge (sipuleucel-T) immunotherapy for prostate cancer. Receipt of an investigational agent within 30 days (or 60 days for an antibody-based therapy) of the first planned dose of PROSTVAC-V/F. History of prior malignancies other than prostate cancer within the past 3 years, excluding successfully resected basal or squamous cell carcinoma of the skin. Congestive heart failure (NYHA Class II, III, or IV), unstable angina, ventricular or hemodynamically significant atrial arrhythmia, or cardiovascular disease such as stroke or myocardial infarction (current or within the past 6 months) Confirmed positive for HIV, hepatitis B, and /or hepatitis C. Immunodeficiency or splenectomy. History of or active autoimmune disease, persons with vitiligo are not excluded. Diabetics are not excluded if the condition is well controlled. History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Randomization through the date of death due to any cause. Subjects were followed up for approximately 6 years from the first subject randomized to the completion of the study. | The time between the date of randomization and the date of death due to any cause. Subjects who did not experience death or the competing events of definite loss to follow-up or withdrawal of consent were right censored at the date of last contact. OS was calculated using the formula: OS = Date of death/competing event/censoring - date of randomization + 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Alive Without Event at 6 Months | Randomization through Week 25/End of Treatment visit. | A binary assessment that was performed for the 6-months timepoint for the categories of radiographic progression, pain progression, initiation of chemotherapy or death. Subjects without an event prior to 6-months were evaluated at 6-months. Subjects without event by 6-months and were not evaluated at 6-months were assumed to have had an event and analyzed as such. Progression events were defined as: (1) Two new lesions on bone scan, new metastases on CT scans, or an increased size of nodal lesions per RECIST 1.1. Bone or CT scans occurring prior to calendar month 6 were used to determine radiographic progression. (2) Introduction of scheduled opioid narcotics for cancer-related pain control. (3) Initiation of chemotherapy for prostate cancer was assessed as collected on progression forms as well as in cancer treatment and concomitant medications logs. (4) Death. |
Countries
Australia, Belgium, Canada, Denmark, Estonia, France, Germany, Iceland, Israel, Netherlands, Poland, Puerto Rico, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
Phase 3, randomized, placebo-controlled, multicenter, multi-country efficacy trial of PROSTVAC administered SC to adult males with asymptomatic mCRPC, and was designed to enroll approximately 1200 men. Subjects were randomly assigned with equal probability (1:1:1) to one of three double-blind treatment arms.
Pre-assignment details
Screening activities were completed within 28 days prior to the first dose of any medication and were completed prior to dosing. Subjects who required anti-androgen wash-out specifically for this protocol were consented prior to beginning withdrawal of therapy, however, no other screening procedures were performed the subject was deemed eligible.
Participants by arm
| Arm | Count |
|---|---|
| PROSTVAC-V/F-TRICOM + GM-CSF Placebo PROSTVAC V/F + Placebo GM-CSF, where PROSTVAC V is given SC at 2x10\^8 Inf.U/0.5mL (Day 1) and PROSTVAC F is given SC at 1x10\^9 Inf.U/0.5mL (Weeks 3, 5, 9, 13, 17, 21). Placebo GM-CSF was saline for injection (on days of PROSTVAC injection and three subsequent days). | 432 |
| PROSTVAC-V/F-TRICOM + GM-CSF PROSTVAC V/F + GM-CSF, where PROSTVAC V is given SC at 2x10\^8 Inf.U/0.5mL (Day 1) and PROSTVAC F is given SC at 1x10\^9 Inf.U/0.5mL (Weeks 3, 5, 9, 13, 17, 21). GM-CSF is given SC at 100ug (on days of PROSTVAC injection and three subsequent days). | 432 |
| Placebo Control Placebo PROSTVAC V/F + Placebo GM-CSF, where Placebo PROSTVAC V/F is an empty fowlpox vector (Day 1, Weeks 3, 5, 9, 13, 17, 21). Placebo GM-CSF was saline for injection (on days of PROSTVAC injection and three subsequent days). | 433 |
| Total | 1,297 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Long Term Follow-up Period | Death | 235 | 239 | 236 |
| Long Term Follow-up Period | Lost to Follow-up | 2 | 2 | 3 |
| Long Term Follow-up Period | Other per report | 3 | 2 | 2 |
| Long Term Follow-up Period | Study Terminated by Sponsor | 160 | 158 | 165 |
| Long Term Follow-up Period | Unknown/Missing | 0 | 1 | 1 |
| Long Term Follow-up Period | Withdrawal by Subject | 9 | 6 | 6 |
| Treatment Period | Adverse Event | 12 | 18 | 15 |
| Treatment Period | Death | 5 | 7 | 3 |
| Treatment Period | Lack of Efficacy | 89 | 100 | 112 |
| Treatment Period | Non-compliance with study drug | 0 | 0 | 1 |
| Treatment Period | Other per report | 2 | 2 | 1 |
| Treatment Period | Physician Decision | 0 | 2 | 1 |
| Treatment Period | Protocol Violation | 7 | 5 | 4 |
| Treatment Period | Randomized but Not Treated | 3 | 3 | 5 |
| Treatment Period | Withdrawal by Subject | 14 | 16 | 11 |
Baseline characteristics
| Characteristic | PROSTVAC-V/F-TRICOM + GM-CSF Placebo | PROSTVAC-V/F-TRICOM + GM-CSF | Placebo Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 328 Participants | 311 Participants | 324 Participants | 963 Participants |
| Age, Categorical Between 18 and 65 years | 104 Participants | 121 Participants | 109 Participants | 334 Participants |
| Age, Continuous | 71.3 years STANDARD_DEVIATION 8 | 70.6 years STANDARD_DEVIATION 8.42 | 71.4 years STANDARD_DEVIATION 8.33 | 71.1 years STANDARD_DEVIATION 8.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 11 Participants | 18 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 418 Participants | 421 Participants | 415 Participants | 1254 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 6 Participants | 7 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 25 Participants | 23 Participants | 65 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 404 Participants | 400 Participants | 403 Participants | 1207 Participants |
| Randomization Stratum PSA < 50 ng/mL and LDH < 200 U/L | 168 Participants | 168 Participants | 168 Participants | 504 Participants |
| Randomization Stratum PSA < 50 ng/mL and LDH >= 200 U/L | 135 Participants | 135 Participants | 135 Participants | 405 Participants |
| Randomization Stratum PSA >= 50 ng/mL and LDH < 200 U/L | 65 Participants | 64 Participants | 64 Participants | 193 Participants |
| Randomization Stratum PSA >= 50 ng/mL and LDH >= 200 U/L | 64 Participants | 65 Participants | 66 Participants | 195 Participants |
| Region of Enrollment Australia | 36 Participants | 38 Participants | 27 Participants | 101 Participants |
| Region of Enrollment Belgium | 12 Participants | 8 Participants | 10 Participants | 30 Participants |
| Region of Enrollment Canada | 30 Participants | 13 Participants | 26 Participants | 69 Participants |
| Region of Enrollment Denmark | 34 Participants | 42 Participants | 32 Participants | 108 Participants |
| Region of Enrollment Estonia | 7 Participants | 7 Participants | 6 Participants | 20 Participants |
| Region of Enrollment France | 29 Participants | 28 Participants | 28 Participants | 85 Participants |
| Region of Enrollment Germany | 3 Participants | 13 Participants | 6 Participants | 22 Participants |
| Region of Enrollment Iceland | 4 Participants | 3 Participants | 3 Participants | 10 Participants |
| Region of Enrollment Israel | 13 Participants | 11 Participants | 5 Participants | 29 Participants |
| Region of Enrollment Netherlands | 6 Participants | 4 Participants | 6 Participants | 16 Participants |
| Region of Enrollment Poland | 6 Participants | 9 Participants | 5 Participants | 20 Participants |
| Region of Enrollment Puerto Rico | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Russia | 50 Participants | 52 Participants | 61 Participants | 163 Participants |
| Region of Enrollment Spain | 45 Participants | 33 Participants | 48 Participants | 126 Participants |
| Region of Enrollment United Kingdom | 31 Participants | 29 Participants | 39 Participants | 99 Participants |
| Region of Enrollment United States | 124 Participants | 141 Participants | 129 Participants | 394 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 432 Participants | 432 Participants | 433 Participants | 1297 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 252 / 432 | 254 / 432 | 248 / 433 |
| other Total, other adverse events | 351 / 429 | 367 / 429 | 346 / 428 |
| serious Total, serious adverse events | 56 / 429 | 56 / 429 | 53 / 428 |
Outcome results
Primary
Overall Survival
The time between the date of randomization and the date of death due to any cause. Subjects who did not experience death or the competing events of definite loss to follow-up or withdrawal of consent were right censored at the date of last contact. OS was calculated using the formula: OS = Date of death/competing event/censoring - date of randomization + 1.
Time frame: Randomization through the date of death due to any cause. Subjects were followed up for approximately 6 years from the first subject randomized to the completion of the study.
Population: Intent to treat, including all randomized subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PROSTVAC-V/F-TRICOM + GM-CSF Placebo | Overall Survival | 34.4 Months |
| PROSTVAC-V/F-TRICOM + GM-CSF | Overall Survival | 33.2 Months |
| Placebo Control | Overall Survival | 34.3 Months |
p-value: 0.4742Log Rank
p-value: 0.5885Log Rank
Secondary
Number of Subjects Alive Without Event at 6 Months
A binary assessment that was performed for the 6-months timepoint for the categories of radiographic progression, pain progression, initiation of chemotherapy or death. Subjects without an event prior to 6-months were evaluated at 6-months. Subjects without event by 6-months and were not evaluated at 6-months were assumed to have had an event and analyzed as such. Progression events were defined as: (1) Two new lesions on bone scan, new metastases on CT scans, or an increased size of nodal lesions per RECIST 1.1. Bone or CT scans occurring prior to calendar month 6 were used to determine radiographic progression. (2) Introduction of scheduled opioid narcotics for cancer-related pain control. (3) Initiation of chemotherapy for prostate cancer was assessed as collected on progression forms as well as in cancer treatment and concomitant medications logs. (4) Death.
Time frame: Randomization through Week 25/End of Treatment visit.
Population: Intent to treat, including all randomized subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PROSTVAC-V/F-TRICOM + GM-CSF Placebo | Number of Subjects Alive Without Event at 6 Months | 127 Participants |
| PROSTVAC-V/F-TRICOM + GM-CSF | Number of Subjects Alive Without Event at 6 Months | 121 Participants |
| Placebo Control | Number of Subjects Alive Without Event at 6 Months | 131 Participants |
95% CI: [0.7144, 1.2867]
95% CI: [0.6647, 1.2026]