Androgen Deprivation, With or Without pTVG-AR, and With or Without Nivolumab, in Patients With Newly Diagnosed, High-Risk Prostate Cancer

Description

The current protocol will 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. All participants will receive treatment with degarelix for 8 weeks prior to prostatectomy. 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.

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 PD-1 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 PD-1 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 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 nivolumab, 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 nivolumab, prior to definitive surgery

Secondary Clinical Objective:

1. To determine 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 nivolumab, leads to residual cancer burden (RCB) <0.25 cm3 at the time of prostatectomy

Laboratory / Correlative Objectives:

1. To determine 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
3. To determine if vaccination with pTVG-AR elicits AR-specific tumor-infiltrating CD8+ T cells
4. To determine whether PD-1 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

Details