NCT04020094

Perioperative Atezolizumab With MVA-BN-Brachyury and PROSTVAC For Intermediate-Risk And High-Risk Localized Prostate Cancer

• Status: Withdrawn
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: University of Utah · Academic / Other
• Sex: Male
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This study is a prospective, open label, single arm phase II trial. A total of 22 patients will be treated with atezolizumab, PROSTVAC, and pre-operative MVA-BN-Brachyury to confirm the efficacy of prostatic combination immunotherapy and to measure the relative change in the number of tumor infiltrating CD8+ lymphocytes within the prostate tissue between the paired biopsy and radical prostatectomy specimens.

Detailed description

Here we propose to use a combination of both checkpoint therapy with dual vaccine therapy. Patients will be treated with an intraprostatic injection of MVA-BN-Brachyury and subcutaneous PROSTVAC therapy. MVA-BN-Brachyury is a replication-deficient, attenuated vaccinia virus (Ankara strain) expressing both a CD8+ T-cell epitope from the brachyury protein and a triad of T-cell co-stimulatory molecules (B7.1, ICAM-1 and LFA-3). MVA-brachury-TRICOM, upon infection of cells, causes innate and then adaptive immune responses, antigen cascade, and improved T cell trafficking to the tumor. Vaccine therapy is one strategy that might increase immune infiltration into the tumor microenvironment. Prostate cancer is known to have minimal lymphocyte infiltration within the microenvironment. This vaccine strategy of direct injection into the tumor in combination with checkpoint inhibitors has previously been performed in early phase clinical trials.6 Furthermore, this approach of potent vaccine vector use can induce systemic effects as seen in a recent clinical trial of 12 patients with metastatic melanoma.12 In that study, responses were also observed in non-target lesions. In this case, MVA-BN-Brachyury is preferred as in intralesional injection agent over other vaccines due to the increased immunogenicity of MVA compared with fowlpox and improved safety profile for direct injection when compared with vaccinia, due to replication incompetence. In the prior study with MVA-BN-Brachyury no patients were observed to have replication of the virus. T cell mediated tumor cell killing is dependent on specific T cell recognition of a tumor target antigen, localization of those specific T cells to the tumor, and those T cells properly functioning within the tumor microenvironment. We hypothesize that these three primary issues comprise the major causes of most patients receiving no benefit from checkpoint inhibitor therapy or with vaccine monotherapy. We hypothesize that these issues can be addressed with an active intratumoral virus administration approach combined with the use of a subcutaneously administered vaccine (PROSTVAC) to induce PSA-specific T cell activation in combination with a checkpoint inhibitor. Combination viral based vaccine plus immune checkpoint inhibitor therapy will result in exposure of cancer specific antigens and induce inflammation at the site of the cancer ultimately resulting in significant clinical antitumor effect. Additionally, we hypothesize that the concurrent administration of anti-PD-1 moncolonal antibody therapy is necessary to allow those active T cells to achieve tumor cell killing, and significant overall clinical efficacy. The addition of atezolizumab is likely to provide additional efficacy over vaccine therapy alone. This is suggested by the induction of PD-1+ T-cells with vaccines.17 Additionally, PD-1 inhibition with nivolumab18 and pembrolizumab19 have shown clinical activity in metastatic prostate cancer. We suggest that the combination will provide even greater efficacy. Multiple studies have demonstrated a strong correlation between density of lymphocytes and prognosis, including overall survival.13-16 Given the very low density of infiltrating lymphocytes historically in prostate cancer, (Kaur HB, Hum Path 2019) we suggest that the primary endpoint of the change in CD8+ density is a reasonable pharmacodynamic endpoint for this exploratory, hypothesis generating study. However, as this study will be the first to date of the treatment combination, safety will also serve as a co-primary endpoint. The secondary objectives of PSA responses will help confirm the clinical utility of this approach in this target population.

Conditions

• Prostate Adenocarcinoma

Interventions

Type	Name	Description
COMBINATION_PRODUCT	MVA-BN-Brachyury	Cycle= 21 days. Neoadjuvant Therapy: Treatment will be given for 2 neoadjuvant cycles. MVA-BN-Brachyury will be administered as intratumoral injection on Day 1 of each of 2 neoadjuvant cycles. PROSTVAC-V will be administered as a subq injection on Day 1 of Cycle 1 (the first neoadjuvant cycle) and PROSTVAC-F will be administered as a subq injection on Day 1 of Cycle 2 (the second neoadjuvant cycle). Atezolizumab will be given as an infusion on Day 1 of each 2 neoadjuvant cycles. MVA-BN-Brachyury will be injected intratumorally into the prostate. Injections will target PI-RADS 4 and 5 lesions. Surgery: Patients will undergo SOC radical prostatectomy Adjuvant Therapy: Systemic treatment with atezolizumab and PROSTVAC-F will be reinitiated between 3 to 8 weeks after surgery and will continue for an additional 6 cycles. PROSTVAC-F will be given as a subq injection on Day 1 of each cycle. Atezolizumab will be given as an infusion on Day 1 of each cycle.

Timeline

• Start date: 2019-11-20
• Primary completion: 2021-04-09
• Completion: 2021-04-09
• First posted: 2019-07-15
• Last updated: 2021-09-22

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study