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.
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.
Inclusion Criteria:
- Male subjects aged ≥ 18 years.
- Clinical staged unfavorable intermediate, high-risk or very high-risk prostate cancer
per NCCN guidelines.
- Histologically proven prostate adenocarcinoma
- Patient must be a surgical candidate
- ECOG Performance Status ≤ 1.
- Adequate organ function as defined as:
- Hematologic:
- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (without granulocyte colony-stimulation
factor support within 2 weeks of screening blood test)
- Platelet count ≥ 100 × 109/L (without platelet transfusion within 2 weeks of
screening)
- Hemoglobin ≥ 9 g/dL (may not have been transfused within 2 weeks of study treatment
initiation)
- White blood cell count (WBC) ≥ 2.5 × 109/L.
- Hepatic:
- Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) (≤ 3 × ULN for subjects
with Gilbert's disease)
- AST and ALT levels ≤ 2.5 × ULN. Patient with a history of unconjugated
hyperbilirubinemia with otherwise acceptable liver enzyme levels (as per above
criteria) may have higher bilirubin levels.
- Renal:
- Urine protein/creatinine ratio (UPCR) ≤ 2 mg/mg (≤ 113.2 mg/mmol) UPCR can be
calculated with either a random spot urine test or a 24 hour test. The 24-hour urine
collection test is more accurate, so it is the definitive test if there is a
discrepancy between the urnialysis and the UPCR. A 24-hour urine test is not required,
but may be obtained.
- Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5
mL/sec) using the Cockcroft-Gault equation.
- Highly effective contraception for male subjects throughout the study and for at least
6 months after last study treatment administration if the risk of conception exists.
- Patients must have archival prostate biopsy tissue available with identified prostate
cancer. If none is available, a repeat prostate biopsy is mandatory to be eligible for
this study. The repeat biopsy if performed must have documented prostate
adenocarcinoma. The archival tissue must not have been obtained more than 4 months
before enrollment.
- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines.
- Prostate MRI must be performed within the past 8 months.
Exclusion Criteria:
- Prostate cancer histology other than adenocarcinoma.
- Previous treatment for prostate cancer.
- Metastatic disease on imaging (CT, MRI, or NM bone scan) or through tissue biopsy.
This includes nodal metastatic disease. A biopsy is not required to rule out
metastasis.
- Use of immunosuppressive medication within 28 days of study treatment initiation,
EXCEPT for the following:
- Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection);
- Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
equivalent;
- Steroids as premedication for hypersensitivity reactions (e.g. CT scan
premedication).
- Known history of and/or active autoimmune disease requiring systemic treatment.
Patients with diabetes mellitus, thyroid disease, vitiligo, or other diseases
determined to be not clinically meaningful (per the treating physician) will not be
excluded for these conditions.
- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
agent per treating physician's clinical judgment. Subjects with diabetes type I,
vitiligo, psoriasis, hypo- or hyperthyroid diseases, or other conditions are eligible
as per 5.2.5.
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
o Cardiovascular disorders:
- Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
pectoris, serious cardiac arrhythmias within 3 months of study enrollment.
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 180 mm Hg
systolic or > 120 mm Hg diastolic despite optimal antihypertensive treatment within 2
weeks of starting treatment.
- Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or
other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary
embolism) within 3 months before first dose.
- Uncontrolled tumor-related pain.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures (once monthly or more frequently).
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium
> 12 mg/dL or corrected serum calcium >ULN).
- Active Tuberculosis
- Prior allogeneic stem cell or solid organ transplantation.
- Known history of acquired immunodeficiency syndrome.
- Prior or concurrent malignancy whose natural history or treatment, in the opinion of
the enrolling investigator, may have the potential to interfere with the safety or
efficacy assessment of the investigational regimen.
- Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at
screening. Patients with a history of HBV or HCV infection are eligible if the viral
load is documented as undetectable at screening. Screening tests for HBV, HCV or HIV
are not mandatory by the study but will be performed per the discretion of the study
investigators.
- Known history of atopic dermatitis or active skin condition (acute chronic, or
exfoliative) that disrupts the epidermis that is clinically significant less than or
equal to 180 days before study enrollment.
- Known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or
evidence of active pneumonitis on screening chest computed tomography (CT) scan.
- Known history of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins.
- Live, attenuated (e.g., FluMist) and inactive vaccinations within 28 days of study
treatment initiation. Live, attenuated vaccinations are generally discouraged for the
duration of the investigational treatment phase of the study. Inactive vaccinations
are acceptable after the prostatectomy is performed but cannot be given within 1 week
of the study vaccine administration. Live vaccinations require PI approval.
- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v 5.0 Grade ≥ 3).
- Known allergy to eggs, egg products, or aminoglycoside antibiotics (for example
gentamicin or tobramycin).
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation.
- Known allergy or hypersensitivity to any component of the PROSTVAC or MVA-BN-Brachyury
formulation.
- Subjects taking prohibited medications as described in Section 6.6. A washout period
of prohibited medications for a period of at least 14 days or as clinically indicated
should occur prior to the start of treatment.
