Metastatic Prostate Cancer
Conditions
Brief summary
This is a randomized, open-label study designed to assess the effects of sipuleucel-T when administered concurrently or sequentially with enzalutamide.
Detailed description
This is a randomized, open-label study designed to assess the effects of sipuleucel-T when administered concurrently or sequentially with enzalutamide. This study consists of 3 phases. The screening phase will begin at the completion of the informed consent process and continue through registration. The active phase will begin at registration and continue through the post-treatment visit (30 to 37 days following the last study treatment). The long term follow-up (LTFU) phase will begin after the post-treatment visit and will continue until the subject's death or until Dendreon terminates the study.
Interventions
BIOLOGICALsipuleucel-T
Sipuleucel-T is an autologous cell product consisting of antigen presenting cells (APCs) loaded with PA2024, a recombinant fusion protein composed of prostatic acid phosphatase (PAP), linked to granulocyte-macrophage colony-stimulating factor (GM-CSF).
DRUGenzalutamide
Enzalutamide is an androgen receptor inhibitor. It is indicated for the treatment of patients with mCRPC who have previously received docetaxel. The enzalutamide dose used in this study will be 160 mg orally once daily.
Sponsors
Dendreon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent provided prior to the initiation of study procedures. * Age ≥ 18 years. * Histologically documented adenocarcinoma prostate cancer confirmed by a pathology report from prostate biopsy or a radical prostatectomy specimen. * Metastatic disease as evidenced by bone metastasis or lymph node metastasis. * Castrate-resistant prostate cancer as demonstrated by one of the following: * Prostate specific antigen progression. * Progression of measurable disease. * Progression of non-measurable disease by soft tissue disease or bone disease. * Castration levels of testosterone (≤ 50 ng/dL) achieved via medical or surgical castration. * Serum PSA (Prostate specific antigen) ≥ 2.0 ng/mL. * Screening ECOG (The Eastern Cooperative Oncology Group )performance status ≤ 1 * Adequate screening hematologic, renal, and liver function as evidenced by laboratory test results obtained ≤ 28 days prior to registration. * Negative serology test for human immunodeficiency virus 1 and 2. * Resides within driving distance (round trip within 1 day) of the clinical trial site for the duration of the active phase.
Exclusion criteria
* The presence of known lung, liver, or brain metastases, malignant pleural effusions, or malignant ascites. * Spinal cord compression, imminent long bone fracture, or any other condition that is likely to require radiation therapy and/or steroids for pain control during the active phase. * History of stage 3 or greater cancer, excluding prostate cancer. Basal or squamous cell skin cancers must have been adequately treated and the subject must be disease free at the time of registration. Subjects with a history of stage 1 or 2 cancer must have been adequately treated and been disease free for ≥ 3 years at the time of registration. * History of seizures or of predisposing factors for seizures. * Child-Pugh Class C hepatic insufficiency. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to sipuleucel-T, GM-CSF or granulocyte colony stimulating factor (G-CSF). * Previous treatment with sipuleucel-T or enrollment in a sipuleucel-T trial, regardless of whether the subject received sipuleucel-T or control. * Previous treatment with enzalutamide. * Previous treatment with abiraterone acetate. * Previous treatment with ipilimumab. * Previous treatment with ketoconazole other than topical use or for treatment of infections (e.g., oral thrush); most recent use must have been ≥ 7 days prior to registration. * Previous treatment with any immunotherapy or investigational vaccine. * A requirement for ongoing systemic immunosuppressive therapy. Use of inhaled, intranasal, intra-articular, and topical steroids is allowed. Oral or IV steroids to prevent or treat IV contrast reactions are allowed. * Previous treatment with chemotherapy for mCRPC, or chemotherapy for any reason ≤ 2 years prior to registration. * Use of concomitant medications that may lower the seizure threshold or the use of antiseizure medications ≤ 1 year prior to registration. * Received GM-CSF or G-CSF ≤ 90 days prior to registration. * Ongoing non-steroidal antiandrogen withdrawal response. * Any of the following medications or interventions ≤ 28 days prior to registration: * Radiation therapy, either via external beam or brachytherapy. * Any systemic steroid. Use of inhaled, intra-nasal, intra-articular, and topical steroids is allowed. Oral or IV steroids to prevent or treat IV contrast reactions are allowed. * Any systemic therapy for prostate cancer, except for ADT (Androgen deprivation therapy). * Any investigational product for prostate cancer. * Major surgery requiring general anesthesia, with the exception of placement of central venous catheters. * Inducers and inhibitors of cytochrome P450 (CYP) enzyme CYP2C8 (gemfibrozil and rifampin). * Medications that are metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a narrow therapeutic index. * Inducers of CYP3A4 (including but not limited to phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital). * A requirement for treatment with opioid analgesics for cancer-related pain ≤ 21 days prior to registration. * An active infection requiring parenteral antibiotic therapy or causing fever (temperature \> 100.5˚ F or 38.1˚ C) ≤ 1 week prior to registration. * Any medical intervention, any other condition, or any other circumstance which could compromise adherence with study requirements or otherwise compromise the study's objectives.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | Each patient was followed for up to 52 weeks after the first dose of sipuleucel-T. Immune sample draws during the treatment period (Week 0 through Week 4) were to be performed at the patient's pre-leukapheresis visits (Pre-Leuk 2 and Pre-Leuk 3). | PA2024-specific T cell proliferation responses over time will be compared between the concurrent arm and sequential arm using a repeated measurement mixed model analysis. The unit of analysis for the T cell proliferation data is the stimulation index, defined as the median 3H uptake of 3 wells exposed to antigen divided by the median 3H thymidine uptake of 3 wells exposed to media. The stimulation index will be log-transformed prior to analysis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Concurrent Arm Subjects will receive sipuleucel-T concurrently with enzalutamide (160 mg orally once daily). Enzalutamide treatment will start 2 weeks prior to the first leukapheresis and continue for 52 weeks or until disease progression or unacceptable toxicity, whichever occurs first.
sipuleucel-T: Sipuleucel-T is an autologous cell product consisting of antigen presenting cells (APCs) loaded with PA2024, a recombinant fusion protein composed of prostatic acid phosphatase (PAP), linked to granulocyte-macrophage colony-stimulating factor (GM-CSF).
enzalutamide: Enzalutamide is an androgen receptor inhibitor. It is indicated for the treatment of patients with mCRPC who have previously received docetaxel. The enzalutamide dose used in this study will be 160 mg orally once daily. | 25 |
| Sequential Arm Subjects will receive sipuleucel-T followed by enzalutamide (160 mg orally once daily). Enzalutamide treatment will start approximately 10 weeks after the first infusion of sipuleucel-T and continue for 52 weeks or until disease progression or unacceptable toxicity, whichever occurs first.
sipuleucel-T: Sipuleucel-T is an autologous cell product consisting of antigen presenting cells (APCs) loaded with PA2024, a recombinant fusion protein composed of prostatic acid phosphatase (PAP), linked to granulocyte-macrophage colony-stimulating factor (GM-CSF).
enzalutamide: Enzalutamide is an androgen receptor inhibitor. It is indicated for the treatment of patients with mCRPC who have previously received docetaxel. The enzalutamide dose used in this study will be 160 mg orally once daily. | 27 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 14 | 15 |
| Overall Study | Investigator Or Dendreon Discretion | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Concurrent Arm | Sequential Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 23 Participants | 38 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 4 Participants | 14 Participants |
| Age, Continuous | 66.4 Years STANDARD_DEVIATION 10.6 | 73.3 Years STANDARD_DEVIATION 9 | 70.0 Years STANDARD_DEVIATION 10.3 |
| Body Mass Index | 30.3 Kg/m^2 STANDARD_DEVIATION 5.1 | 29.0 Kg/m^2 STANDARD_DEVIATION 4.2 | 29.6 Kg/m^2 STANDARD_DEVIATION 4.6 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG 0=Fully Active; No restrictions | 22 Participants | 19 Participants | 41 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG 1=Restricted Strenuous Activity | 3 Participants | 8 Participants | 11 Participants |
| Gleason Score Gleason Score ≤6 | 1 Participants | 2 Participants | 3 Participants |
| Gleason Score Gleason Score 7 | 4 Participants | 8 Participants | 12 Participants |
| Gleason Score Gleason Score ≥8 | 19 Participants | 16 Participants | 35 Participants |
| Gleason Score Missing | 1 Participants | 1 Participants | 2 Participants |
| Height | 177.0 Centimeters STANDARD_DEVIATION 8 | 177.2 Centimeters STANDARD_DEVIATION 6 | 177.1 Centimeters STANDARD_DEVIATION 6.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 25 Participants | 50 Participants |
| Region of Enrollment United States | 25 Participants | 27 Participants | 52 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 25 Participants | 27 Participants | 52 Participants |
| Time from Diagnosis to Randomization | 5.1 Years STANDARD_DEVIATION 5.3 | 6.5 Years STANDARD_DEVIATION 5.6 | 5.8 Years STANDARD_DEVIATION 5.5 |
| Time in Years 0-5 | 16 years | 14 years | 30 years |
| Time in Years 11-15 | 3 years | 6 years | 9 years |
| Time in Years 16-20 | 0 years | 1 years | 1 years |
| Time in Years 21-25 | 1 years | 1 years | 2 years |
| Time in Years 6-10 | 5 years | 5 years | 10 years |
| Weight | 94.6 Kg STANDARD_DEVIATION 19.4 | 91.2 Kg STANDARD_DEVIATION 13.9 | 92.8 Kg STANDARD_DEVIATION 16.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 25 | 15 / 27 |
| other Total, other adverse events | 23 / 25 | 27 / 27 |
| serious Total, serious adverse events | 2 / 25 | 9 / 27 |
Outcome results
Primary
To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI).
PA2024-specific T cell proliferation responses over time will be compared between the concurrent arm and sequential arm using a repeated measurement mixed model analysis. The unit of analysis for the T cell proliferation data is the stimulation index, defined as the median 3H uptake of 3 wells exposed to antigen divided by the median 3H thymidine uptake of 3 wells exposed to media. The stimulation index will be log-transformed prior to analysis.
Time frame: Each patient was followed for up to 52 weeks after the first dose of sipuleucel-T. Immune sample draws during the treatment period (Week 0 through Week 4) were to be performed at the patient's pre-leukapheresis visits (Pre-Leuk 2 and Pre-Leuk 3).
Population: Summary of Cellular Proliferation Data Through Week 52. All patients with reported data at a specified time-point were analyzed. Number of patients at each time-point differed across the time-points resulting in patient numbers at each time-point that are not equal to the total number of patients analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 14 | 17.05 10^3 cells/mL | Standard Deviation 18.72 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Pre-leuk 3 | 23.33 10^3 cells/mL | Standard Deviation 16.98 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 20 | 22.33 10^3 cells/mL | Standard Deviation 20.23 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 6 | 17.36 10^3 cells/mL | Standard Deviation 14.39 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 26 | 27.07 10^3 cells/mL | Standard Deviation 18.26 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Pre-leuk 2 | 8.76 10^3 cells/mL | Standard Deviation 13.4 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 40 | 18.64 10^3 cells/mL | Standard Deviation 15.48 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 10 | 15.48 10^3 cells/mL | Standard Deviation 9.53 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 52 | 16.67 10^3 cells/mL | Standard Deviation 13.13 |
| Concurrent Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Baseline | 2.48 10^3 cells/mL | Standard Deviation 4.76 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 52 | 25.43 10^3 cells/mL | Standard Deviation 18.72 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Baseline | 1.48 10^3 cells/mL | Standard Deviation 0.92 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Pre-leuk 2 | 5.08 10^3 cells/mL | Standard Deviation 7.07 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 6 | 12.72 10^3 cells/mL | Standard Deviation 11.83 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 10 | 10.90 10^3 cells/mL | Standard Deviation 9.07 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 14 | 13.05 10^3 cells/mL | Standard Deviation 13.28 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 20 | 17.83 10^3 cells/mL | Standard Deviation 13.8 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 26 | 15.39 10^3 cells/mL | Standard Deviation 10.58 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Week 40 | 13.70 10^3 cells/mL | Standard Deviation 11.28 |
| Sequential Arm | To Evaluate Peripheral PA2024-specific T Cell Proliferation Response to Sipuleucel-T Over Time Via a T Cell Stimulation Index (SI). | PA2024 Pre-leuk 3 | 13.96 10^3 cells/mL | Standard Deviation 11.9 |
p-value: 0.095Mixed Models Analysis