A Single Arm Open-label, Phase II Study of Sipuleucel-T With Bipolar Androgen Therapy in Men With Metastatic Castration-resistant Prostate Cancer

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. 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. It is hypothesized that BAT potentiates the anti-tumor immune response and enhances clinical outcomes when given before and concurrently with Sipuleucel-T. Secondarily, it is also hypothesized 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.

Inclusion Criteria:

• Written informed consent obtained prior to the initiation of study procedures.
• Patients who meet the US FDA-approved indication for Sipuleucel-T: for asymptomatic or minimally symptomatic mCRPC at the discretion of the treating investigator.
• Histologically confirmed adenocarcinoma of the prostate.
• Metastatic disease as evidenced by soft tissue and/or bony metastases on baseline bone scan and/or computed tomography (CT) scan or Magnetic Resonance Image (MRI).
• Castration-resistant prostate cancer (CRCP): Participants must have current or historical evidence of disease progression concomitant with surgical or medical castration, as demonstrated by (a) PSA progression, or (b) progression of measurable disease, or (c) progression of non-measurable disease as defined below:
  1. By PSA: two consecutively rising PSA values, at least 7 days apart, each ≥ 1.0 ng/mL and ≥ 50% above the minimum PSA observed during castration therapy or above the pre-treatment value if there was no response.
  2. By measurable disease: Progressive disease by RECIST v1.1 criteria
  3. By non-measurable disease

  i. Soft tissue disease: The appearance of 1 or more new lesions, and/or unequivocal worsening of non-measurable disease when compared to imaging studies acquired during castration therapy or against the pre-castration studies if there was no response.

ii. Bone disease: Appearance of 2 or more new areas of abnormal uptake on bone scan when compared to imaging studies acquired during castration therapy or against the pre-castration studies if there was no response. Increased uptake of pre-existing lesions on bone scan does not constitute progression.

• Progressive disease (as defined in section 9.1.4) during the immediately past therapy must be documented prior to enrollment.
• Castration status confirmed by serum testosterone level <50ng/dL
• ECOG Performance Status of 0 or 1.
• Adequate liver function:
  1. Bilirubin <2.0 x institutional upper limit of normal (UNL)
  2. AST (SGOT) <2.5 x UNL
  3. ALT (SGPT) <2.5 x UNL
• Acceptable renal function

  a) Serum creatinine <2.0 x UNL

• Acceptable hematologic function:
  1. Absolute neutrophil count (ANC) > 1.0 x10^9 cells /L)
  2. Platelet counts > 100 x 10^9 / L)
  3. Hemoglobin >9 g/dL

Exclusion Criteria:

• PSA >20ng/dL within the 4 weeks prior to signing ICF
• Previously treated with three or more FDA-approved androgen/AR signaling inhibitors (ASI) (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). No minimum number of ASI is required.
• Prior chemotherapy for mCRPC. However, prior chemotherapy administered for mCSPC is allowed unless the disease progression to CRPC occurred within 12 months from the last dose of chemotherapy.
• Prior treatment with Sipuleucel-T or supraphysiologic dose of testosterone treatment for prostate cancer.
• Prior systemic treatment with ASI, PARP inhibitor or Radium-223 or other systemic anti-cancer therapy for prostate cancer within 4 weeks prior to eligibility confirmation.
• Prior prednisone >10mg (or its equivalent) within 2 weeks prior to registration.
• Prior immunotherapy or Lu177 PSMA radioligand therapy within 6 weeks prior to registration.
• Prior palliative radiotherapy within 2 weeks prior to registration.
• Radiographic evidence of hepatic metastases
• Use of narcotics including tramadol or stronger for cancer-related pain within 4 weeks prior to signing ICF. Use of NSAIDs or acetaminophen is allowed.
• Active autoimmune disease requiring systemic corticosteroids of prednisone greater than 10mg a day or the equivalent dose of other corticosteroids.
• Known HIV, Hepatitis B or Hepatitis C or Human T cell Lymphotropic virus (HTLV)-1 infection. Testing is not required.
• Active infection requiring parenteral antibiotic therapy or causing fever (temperature >100.5 in Fahrenheit scale) within 1 week prior to registration.
• Life expectancy of less than 6 months prior to signing ICF.
• Any medical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence with study requirements or otherwise compromise the study's objectives.