NCT04989946

Androgen Deprivation, With or Without pTVG-AR, and With or Without T-Cell Checkpoint Blockade, in Patients With Newly Diagnosed, High-Risk Prostate Cancer

Phase I/II Trial of Androgen Deprivation, With or Without pTVG-AR, and With or Without T-Cell Checkpoint Blockade, in Patients With Newly Diagnosed, High-Risk Prostate Cancer

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Sponsor: University of Wisconsin, Madison · Academic / Other
• Sex: Male
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The current protocol will examine the use of a plasmid DNA vaccine encoding AR, alone or with T-cell checkpoint blockade, to induce and/or augment therapeutic T-cells following androgen deprivation in patients with newly diagnosed prostate cancer scheduled to undergo prostatectomy. Patients without evidence of metastatic disease, with tissue remaining from a pre-treatment biopsy, and who are being considered for standard treatment by prostatectomy, will be invited to participate and will be on study for up to 15 months.

Detailed description

The original design of this protocol was to examine the use of a plasmid DNA vaccine encoding Androgen Receptor (AR), alone or with nivolumab, to induce and/or augment therapeutic T-cells following androgen deprivation in participants with newly diagnosed prostate cancer scheduled to undergo prostatectomy in one of three treatment arms. Based on emerging preclinical data that the timing of PD-1 blockade with the first immunization may be critical, and that combining PD-1 and LAG-3 blockade can improve the anti-tumor efficacy of vaccination in murine models of prostate cancer, the trial was amended to include two additional treatment arms testing the timing of PD-1 blockade and the addition of LAG-3 blockade. All participants will receive treatment with degarelix for 8 weeks prior to prostatectomy. In the first part of the study encompassing the first 3 treatment arms, participants will be also be randomized to receive either no additional treatment, a DNA vaccine encoding AR, or a DNA vaccine encoding AR and nivolumab. The additional arms will randomize patients to receive cemiplimab (PD-1 antagonist) with vaccine or cemiplimab with fianlimab (LAG-3 antagonist) and vaccine, with each agent initiated with the first immunization. Participants receiving vaccination will begin that treatment prior to degarelix, based on preclinical findings that this may be a preferred sequence of treatment. The overall goal is to determine whether a DNA vaccine can augment the number of prostate tumor-specific infiltrating CD8+ T cells elicited with androgen deprivation, and whether this might be further augmented by combination with T-cell checkpoint blockade. Because these cells should have cytolytic effector function, the primary clinical endpoint is pathological response (pCR and secondarily MRD) at the time of prostatectomy. This endpoint was chosen based on observations from previous clinical trials evaluating androgen deprivation therapies alone in this setting. Safety will also be a primary objective of the current study, as this vaccine and nivolumab have not been previously used in this early stage population. An additional secondary clinical endpoint will be 1-year PSA progression-free survival, after completion of all therapy, and with evidence of testosterone recovery. Laboratory and correlative endpoints will include whether vaccination, with or without concurrent T-cell checkpoint blockade, elicits greater numbers of CD8+ tumor-infiltrating lymphocytes, and whether AR-specific prostate tissue-infiltrating CD8+ T cells and persistent systemic immunity are detectable after treatment with vaccination. Other correlative studies will evaluate FLT PET/CT (Arms 1-3) as an investigational means of specifically identifying tumor infiltration by proliferating T cells as an early marker of treatment response, and whether uptake in other normal tissues is associated with autoimmune toxicity. While this is a relatively small trial, given a focus on correlative endpoints, a phase 2 expansion design was chosen to further evaluate the safety and clinical efficacy if pathological responses are observed in the initial part of the trial. If pathological responses exceeding 20% are observed, this will be considered significantly different from what has been historically observed, and would justify proceeding with future larger studies evaluating these combination approaches in the neoadjuvant stage of prostate cancer. Primary Objectives: 1. To evaluate the safety of androgen deprivation and pTVG-AR DNA vaccine, alone or in combination with T-cell checkpoint blockade, in patients with newly diagnosed prostate cancer 2. To determine if pathological complete responses or minimal residual disease (MRD) can occur in patients with prostate cancer treated with androgen deprivation and pTVG-AR, alone or in combination with T-cell checkpoint blockade, prior to definitive surgery Secondary Clinical Objective: 1. To estimate 1-year PSA progression-free survival (post-prostatectomy) 2. To determine whether treatment with androgen deprivation and pTVG-AR DNA vaccine, alone or in combination with T-cell checkpoint blockade, leads to residual cancer burden (RCB) \<0.25 cm3 at the time of prostatectomy 3. To determine the median progression-free survival Laboratory / Correlative Objectives: 1. To evaluate whether treatment with pTVG-AR elicits persistent systemic AR-specific Th1-biased T-cell responses 2. To determine whether treatment with androgen deprivation and pTVG-AR elicits greater numbers of prostate tissue-infiltrating CD8+ T cells compared with androgen deprivation alone, and whether this is augmented with nivolumab, cemiplimab, or cemiplimab and fianlimab 3. To determine if vaccination with pTVG-AR elicits AR-specific tumor-infiltrating CD8+ T cells 4. To determine whether PD-1 +/- LAG-3 blockade treatment with androgen deprivation and vaccine increases the frequency of CD8+ T cells with memory and effector function, relative to exhausted phenotype, compared with androgen deprivation and vaccine alone 5. To determine whether treatment elicits changes detectable by FLT PET imaging (Arms 1-3) 6. To determine whether LAG-3 with PD-1 blockade and vaccination (Arm 5) elicits greater CD8 T cell infiltration compared to PD-1 blockade and vaccination alone (Arm 4) 7. To determine whether prostate-tumor infiltrating T cells can be expanded and recognize AR

Conditions

• Prostate Cancer

Interventions

Type	Name	Description
DRUG	Degarelix	standard Gonadotropin-releasing hormone (GnRH) antagonist
BIOLOGICAL	pTVG-AR	DNA vaccine encoding androgen receptor ligand-binding domain
DRUG	Nivolumab	Nivolumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of patients with multiple different types of cancer.
DRUG	Cemiplimab	Cemiplimab is a human PD-1 blocking antibody approved for the treatment of patients with non-small cell lung cancer, cutaneous squamous cell carcinoma, and locally advanced basal cell carcinoma.
DRUG	Fianlimab	Lymphocyte activation gene-3 (LAG-3) is a protein that is upregulated on activated CD4+ and CD8+ T cells following T-cell receptor engagement. Binding of LAG-3 to MHC II on professional antigen-presenting cells suppresses the proliferation, activation, and cytokine secretion of T cells. Fianlimab is a human IgG4 antibody to lymphocyte activation gene-3 (LAG-3) that blocks LAG-3/MHC II-mediated T-cell inhibition.
DRUG	FLT PET/CT	Arms 1-3 only, FLT PET/CT scan at baseline (within 1-6 days of Day 1) and Day 43

Timeline

• Start date: 2021-12-16
• Primary completion: 2026-12-01
• Completion: 2028-12-01
• First posted: 2021-08-04
• Last updated: 2026-01-28

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study