Perioperative Atezolizumab With MVA-BN-Brachyury and PROSTVAC For Intermediate-Risk And High-Risk Localized Prostate Cancer (AtezoVax)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04020094|
Recruitment Status : Not yet recruiting
First Posted : July 15, 2019
Last Update Posted : July 15, 2019
|Condition or disease||Intervention/treatment||Phase|
|Prostate Adenocarcinoma||Combination Product: MVA-BN-Brachyury||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||22 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||This study is a prospective, open label, single arm phase II trial.|
|Masking:||None (Open Label)|
|Official Title:||Perioperative Atezolizumab With MVA-BN-Brachyury and PROSTVAC For Intermediate-Risk And High-Risk Localized Prostate Cancer|
|Estimated Study Start Date :||November 2019|
|Estimated Primary Completion Date :||March 2023|
|Estimated Study Completion Date :||March 2024|
|Experimental: Treatment: all patients||
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.
- To measure the relative change in the number of infiltrating CD8+ lymphocytes within the prostate tissue between the paired biopsy and radical prostatectomy specimens. [ Time Frame: Within 8 weeks after cycle2 day 1 visit ]CD8+ lymphocytes in diagnostic biopsy and prostatectomy tissue samples will be quantified by immunohistochemistry (IHC) and analyzed using digital quantification. The relative change will be reported.
- To assess the safety of combination immunotherapy in localized prostate cancer through evaluation of Adverse Events (AEs), Adverse Events of Special Interest (AESIs), and Serious Adverse Events (SAEs) [ Time Frame: Lead-in safety evaluation for first 6 subjects is the time from Cycle 1 Day 1 until the start Cycle 3 Day 1(about 63 days) then continuing through completion of the study. From enrollment through completion of the study for the remaining participants ]Adverse Events (AEs), Adverse Events of Special Interest (AESIs), and Serious Adverse Events (SAEs) as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0), timing, seriousness, and relationship to study treatment will be documented.
- To assess the undetectable PSA rate [ Time Frame: 6 and 12 months ]Undetectable PSA rates at 6 months and 12 months post-prostatectomy. This will be compared with Huntsman Cancer Institute (HCI) historical controls. Matching will be based on NCCN risk categories, age and follow up time.
- Assess clinical activity of perioperative combination immunotherapy. [ Time Frame: PSA evaluation will occur every 3 months after completion of the adjuvant treatment period. PSA relapse-free survival will be calculated and compared to HCI matched historical controls. Patients will be followed for 2 years after prostatectomy. ]PSA evaluation will occur every 3 months after completion of the adjuvant treatment period. PSA relapse-free survival will be calculated and compared to HCI matched historical controls. Patients will be followed for 2 years after prostatectomy. PSA progression will be defined based on Prostate Cancer Working Group 3 (PCWG3) criteria.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04020094
|Contact: Sally Fairbairnfirstname.lastname@example.org|
|United States, Utah|
|Huntsman Cancer Institute||Not yet recruiting|
|Salt Lake City, Utah, United States, 84112|
|Contact: Sally Fairbairn 801-587-4765 email@example.com|
|Principal Investigator: Benjamin Maughan, MD, PharmD|