Clinical trial NCT06100705: Sipuleucel-T Combined with Bipolar Androgen Therapy in Men with MCRPC
Official title: A Single Arm Open-label, Phase II Study of Sipuleucel-T with Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: Sipuleucel-T
Bipolar Androgen Therapy
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Dendreon
First posted: 2023-10-25
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: open-label, single-arm phase II study
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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).
* Progressive castration-resistant prostate cancer (CRCP): Participants must have current or historical evidence of disease progression concomitant with surgical or medical castration and during immediate past systemic therapy, 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.

* Castration status confirmed by serum testosterone level \&lt;50ng/dL
* ECOG Performance Status of 0 or 1.
* Adequate liver function:

  1. Bilirubin \&lt;2.0 x institutional upper limit of normal (UNL)
  2. AST (SGOT) \&lt;2.5 x UNL
  3. ALT (SGPT) \&lt;2.5 x UNL
* Acceptable renal function

  a) Serum creatinine \&lt;2.0 x UNL
* Acceptable hematologic function:

  1. Absolute neutrophil count (ANC) \&gt; 1.0 x10\^9 cells /L)
  2. Platelet counts \&gt; 100 x 10\^9 / L)
  3. Hemoglobin \&gt;9 g/dL

Exclusion Criteria:

* PSA \&gt;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 \&gt;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 active HIV, Hepatitis B or Hepatitis C or Human T cell Lymphotropic virus (HTLV)-1 infection. Testing is not required. Note: Participants with resolved, historic HIV, Hepatitis B or Hepatitis C or Human T cell Lymphotropic virus (HTLV)-1 will be assessed by the PI and deemed eligible if their viral infections are in remission: without detectable viruses and secondary immunodeficiency, and without requiring any treatments that affects immune function. Eligibility will be determined after a discussion with the PI and adequate standard clinical tests are acquired to prove that they are in remission.
* Active infection requiring parenteral antibiotic therapy or causing fever (temperature \&gt;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.

Primary outcomes:
measure: To determine the immune response to PA2024 with BAT and Sipuleucel-T
timeFrame: Through the study completion, average 12 months
Secondary outcomes:
measure: To determine antigen presenting cell (APC) cumulative activation
timeFrame: Through the study completion, average 12 months
measure: To determine APC number
timeFrame: Through the study completion, average 12 months
measure: To determine total nucleated cell count
timeFrame: Through the study completion, average 12 months
measure: To determine T cell proliferation to PA2024
timeFrame: Through the study completion, average 12 months
measure: To determine T cell proliferation to Prostatic Acid Phosphatase (PAP)
timeFrame: Through the study completion, average 12 months
measure: To determine ex vivo cytokine profiles with BAT + Sipuleucel-T
timeFrame: Through the study completion, average 12 months
measure: To determine humeral response with BAT + Sipuleucel-T
timeFrame: Through the study completion, average 12 months
measure: To determine PSA50 response rate to BAT + Sipuleucel-T
timeFrame: Through the study completion, average 12 months
measure: To determine objective response rate (ORR) to BAT + Sipuleucel-T
timeFrame: Through the study completion, average 12 months
measure: To estimate radiographic progression free survival (rPFS)
timeFrame: 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
measure: To estimate overall survival (OS)
timeFrame: From the date of registration until the date of death from any cause, assessed up to 5 years
measure: To assess safety and tolerability to BAT+ Sipuleucel-T
timeFrame: Through the study completion, average 12 months
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
Study officials:
affiliation: Yale University
name: Joseph W Kim, MD
role: PRINCIPAL_INVESTIGATOR
References: