This is an open-label, single-arm phase II study of bipolar androgen therapy (BAT) given in addition with standard of care Sipuleucel-T to determine the interferon (IFN) gamma Enzyme-linked Immunospot (ELISPOT) response rate to PA2024 (an engineered fusion protein of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor which the activated autologous dendritic cells in the Sipuleucel-T vaccine are loaded with) in patients with metastatic castration resistant prostate cancer (mCRPC).
The primary endpoint is the immune response to PA2024 as measured by ELISPOT by week 26. This immunological endpoint was chosen as the primary based on the data showing the Sipuleucel-T immune parameters correlating with overall survival from the pooled analysis phase III trials of Sipuleucel-T (Sheikh NA et al. Cancer Immunol Immunother 2013). Secondary endpoints include other immune parameters related to the Sipuleucel-T, including (1) APC cumulative activation (CD54 upregulation), (2) APC number and (3) total nucleated cells (TNC) count, which also have correlated with survival outcomes and clinical endpoints, and (4) T cell proliferation response to PA2024 and PAP, (5) ex vivo cytokine profile and (6) humoral response to PA2024 and PAP, clinical endpoints including: (7) PSA50 response rate (PSA50 RR), (8) objective response rate (ORR), (9) radiographic progression-free survival (rPFS), and (10) overall survival (OS), (11) safety and tolerability. We hypothesize that BAT potentiates the anti-tumor immune response and enhances clinical outcomes when given before and concurrently with Sipuleucel-T. Secondarily, we also hypothesize that the clinical activity of BAT will increase with concurrent Sipuleucel-T, as measured by PSA50 response rate and objective response rate compared to historical controls. Participants will start with testosterone injection every 4 weeks. The first dose of standard of care Sipuleucel-T will be prepared and infused after two doses of testosterone and will continue every 2 weeks for a total of 3 infusions at a standard schedule. The testosterone injection will continue once every 4 weeks until treatment discontinuation criteria are met. The participants will be assessed with HPE, and PSA every 4 weeks, and radiographic assessment per PCWG3 every 12 weeks. DEPO-Testosterone (testosterone cypionate) IM injection will continue until disease progression, unacceptable toxicity, or withdrawal of consent to treatment. In the event of suspected/radiographic disease progression, tumor biopsy may be performed as a standard of care to confirm progression.
Study Type
INTERVENTIONAL
Testosterone Cypionate is an androgen and anabolic steroid medication which is used mainly in the treatment of low testosterone levels in men.
Sipuleucel-T is the first FDA-approved immunotherapy in treatment of mCRPC. It is a therapeutic cancer vaccine composed of activated autologous dendritic cells loaded with an engineered fusion protein of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor, PAP-GMCSF, also called PA2024. This cellular product is prepared in three steps: (1) leukapheresis to isolate CD54+ dendritic cells, (2) the cells and harvested and cultured with PA2024 ex vivo, and (3) re-infusion of the activated DC into the original patient. The preparation and administration of this autologous cellular product are done every 2 weeks for a total of three infusions and is designed to elicit an immune response to prostatic acid phosphatase.
Yale Cancer Center
New Haven, Connecticut, United States
RECRUITINGTo determine the immune response to PA2024 with BAT and Sipuleucel-T
As measured by ELISPOT from blood samples in pg/ml
Time frame: Through the study completion, average 12 months
To determine antigen presenting cell (APC) cumulative activation
as assessed by flow cytometry staining and defined as the increase in surface CD54 on APCs, expressed as an upregulation ratio of the average number of molecules on after culture versus before culture cells from the sipuleucel-T product from blood samples in pg/ml
Time frame: Through the study completion, average 12 months
To determine APC number
as assessed by flow cytometry staining from each sipuleucel-T product. from blood samples in pg/ml
Time frame: Through the study completion, average 12 months
To determine total nucleated cell count
as assessed by flow cytometry staining from each sipuleucel-T product. from blood samples in pg/ml
Time frame: Through the study completion, average 12 months
To determine T cell proliferation to PA2024
As measured by ELISPOT from blood samples in pg/ml
Time frame: Through the study completion, average 12 months
To determine T cell proliferation to Prostatic Acid Phosphatase (PAP)
As assessed by tritiated thymidine uptake from blood samples
Time frame: Through the study completion, average 12 months
To determine ex vivo cytokine profiles with BAT + Sipuleucel-T
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Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
26
As assessed via Luminex assay from blood samples in pg/ml
Time frame: Through the study completion, average 12 months
To determine humeral response with BAT + Sipuleucel-T
As assessed by ELISA from blood samples in pg/ml
Time frame: Through the study completion, average 12 months
To determine PSA50 response rate to BAT + Sipuleucel-T
As defined by PSA decline \> 50% from baseline at any point
Time frame: Through the study completion, average 12 months
To determine objective response rate (ORR) to BAT + Sipuleucel-T
As defined by RECIST v1.1 criteria
Time frame: Through the study completion, average 12 months
To estimate radiographic progression free survival (rPFS)
Defined as the time interval from registration to the first occurrence of radiographic progression by Tc99 Bone Scan using PCWG3 criteria or radiographic soft tissue progression by RECIST v1.1 or death from any cause, whichever occurs first.
Time frame: From the date of registration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 5 years
To estimate overall survival (OS)
Defined as the time interval from registration to death due to any cause
Time frame: From the date of registration until the date of death from any cause, assessed up to 5 years
To assess safety and tolerability to BAT+ Sipuleucel-T
As assessed by using CTCAE version 5.0
Time frame: Through the study completion, average 12 months
To explore potential blood-based and tissue-based biomarkers of treatments response and resistance
Blood-based biomarkers will be assessed by next-generation sequencing. Tissue-based biomarkers will be assessed by biopsy of metastasis at the time of clinically suspected or radiographic disease progression if deemed safe and recommended by the PI.
Time frame: At screening, at End of Treatment (blood-based biomarker only), and at Disease Progression (tissue-based biomarker only)