Neoadjuvant Atezolizumab With or Without Enzalutamide in Localized Prostate Cancer Given Before Radical Prostatectomy

PRIMARY OBJECTIVES:

I. To determine the impact of atezolizumab-based combination therapy on the composition and
function of tumor-infiltrating immune cells (TIICS).

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of atezolizumab-based combination therapy in
localized prostate cancer (PC).

II. To determine the clinical efficacy of atezolizumab-based combination therapy in localized
PC.

EXPLORATORY OBJECTIVES:

I. To characterize changes in the frequency and number of circulating immune cells following
atezolizumab-based combination therapy in localized PC.

II. To determine the impact of atezolizumab-based combination therapy on the composition and
phenotype of the tumor microenvironment.

III. To determine the impact of atezolizumab-based combination therapy on the circulating and
intratumoral T cell repertoire.

IV. To explore the role of novel imaging modalities to understand the immunologic and
clinical impact to immunotherapeutic approaches in localized PC.

V. To characterize changes in the gut microbiome associated with each therapeutic
combination.

OUTLINE: Patients are assigned sequentially to 1 of 3 groups.

COHORT A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1.

COHORT B: Patients receive atezolizumab as in Cohort A and enzalutamide orally (PO) once
daily (QD) on days 1-21.

COHORT C: Patients receive emactuzumab IV over 90 minutes on day 1 and atezolizumab as in
Cohort A.

In all cohorts, treatment repeats every 21 days for up to 2 courses in the absence of disease
progression or unacceptable toxicity. Beginning 28 days after treatment, patients undergo
radical prostatectomy.

After completion of study treatment, patients are followed up at 14 days, 6 and 12 weeks, and
6 and 12 months.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate

- Subjects with small cell or neuroendocrine PC are not eligible

- Eligible for radical prostatectomy as determined by urologic oncology surgeon, and
subject consents to proceeding with radical prostatectomy

- Deemed by urologic oncology surgeon to be appropriate for a
?window-of-opportunity? study

- Only patients with high-risk disease are eligible for the safety lead-in for each
cohort. Patients with intermediate-risk disease will be included after interim
analyses is complete for the corresponding cohort and the principal investigator (PI)
has determined that it is safe to do so

- Availability of a representative tumor specimen that is suitable for the planned study
analyses, as determined by the principal investigator

- A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block
(preferred) or at least 15 slides containing unstained, freshly cut, serial
sections should be submitted along with an associated pathology report prior to
study treatment. If only 10?14 slides are available, the patient may still be
eligible for the study, after principal investigator approval has been obtained

- If archival tumor tissue is unavailable or is determined to be unsuitable for
required testing, tumor tissue must be obtained from a biopsy performed at
screening

- Subjects have not received any prior systemic or locally directed therapy for PC (see
exclusion criteria)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Hemoglobin >= 9 g/dL

- Absolute neutrophil count >= 1,500/uL

- Absolute lymphocyte count >= 500/uL

- Platelets >= 100,000/uL without transfusion

- Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (known Gilbert
disease: < 3 x ULN)

- Alkaline phosphatase < 2 x institutional ULN

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =<
2.5 x institutional ULN

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN

- International normalized ratio (INR) or activated partial thromboplastin time (aPTT) <
1.5 x institutional ULN for subjects not receiving therapeutic anticoagulation

- Creatinine clearance >= 30 mL/min (calculated using the Cockcroft-Gault formula)

- Testosterone level > 150 ng/dL

- Contraception: agreement to remain abstinent or use contraceptive measures, and
agreement to refrain from donating sperm as defined below:

- With female partners of childbearing potential: men must remain abstinent or use
a condom plus an additional contraceptive method that together result in a
failure rate of < 1% per year during the treatment period and for 4 months after
the last dose of study treatment. Men must refrain from donating sperm during the
same period

- With pregnant female partners: men must remain abstinent or use a condom during
the treatment period and for 4 months after the last dose of study treatment to
avoid exposing the embryo

- Abstinence: the reliability of sexual abstinence should be evaluated in relation
to the duration of the clinical trial and the preferred and usual lifestyle of
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception

- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen > 3
months.

- For patients receiving emactuzumab: given the potential risk of impaired wound
healing with emactuzumab, a dose hold or interruption of anticoagulation, or
bridging regimen, should be considered during the perioperative period (i.e.,
risk and benefits of anticoagulation)

- Ability to understand a written informed consent document, and the willingness to sign
it

- Ability to comply with the study protocol, in the investigator?s judgment

Exclusion Criteria:

- Evidence of metastatic disease as determined by standard staging scans

- Staging scans should be performed per urologic standard of care for patients
undergoing radical prostatectomy (per American Urological Association
[AUA]/National Comprehensive Cancer Network [NCCN] guidelines)

- Not a candidate for radical prostatectomy as determined by treating urologic oncology
surgeon

- Any prior systemic therapy for PC, including antiandrogens, androgen deprivation
therapy (gonadotropin-releasing hormone [GnRH] agonist or antagonist), chemotherapy,
targeted therapy, immunotherapy, OR radiopharmaceuticals

- Subjects who are on finasteride or dutasteride must discontinue therapy and
undergo a washout period of 6 weeks to become eligible for the study. Screening
procedures should begin following the washout period

- Prior radiotherapy for PC

- Any history of prior malignancy, except:

- Non-melanoma skin cancer treated with curative intent

- Carcinoma-in-situ (CIS) treated with curative intent, without evidence of
recurrence or disease progression for 3 years

- All other cancer: treated with curative intent and without evidence of disease on
standard of care follow-up for 5 years

- Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjogren?s syndrome, Guillain-Barre
syndrome, or multiple sclerosis, with the following exceptions:

- Subjects with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement therapy, with a stable dose > 3 months, are eligible for the
study

- Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen,
with a hemoglobin A1C < 7.0 are eligible for the study. All subjects with
controlled type 2 diabetes mellitus are eligible for the study

- Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded from the study) are eligible for the study provided all of the following
conditions are met:

- Rash covers < 10% of body surface area

- Disease is well controlled at baseline and requires only low-potency topical
steroids

- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
within the previous 12 months

- 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

- History of prior positive human immunodeficiency virus (HIV) test

- Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (chronic or acute)

- Subjects with a past or resolved HBV infection are eligible for this study

- HCV positivity is defined as having a positive HCV antibody test followed by a
positive HCV ribonucleic acid (RNA) test at screening; the HCV RNA test will only
be performed for subjects who have a positive HCV antibody test

- Active tuberculosis

- Significant cardiovascular disease, such as New York Heart Association class III or
greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3
months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

- Active chronic obstructive pulmonary disease (COPD) requiring use of home oxygen (O2)
or systemic steroid therapy > 10 mg prednisone (or equivalent) daily

- Asthma requiring systemic corticosteroids > 10 mg prednisone (or equivalent) daily.
Inhaled corticosteroids for the treatment of asthma are permitted

- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
course of the study

- Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia

- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment

- Patients who receive prophylactic antibiotics for transrectal ultrasound guided
prostate biopsy are eligible for the study as long as the last dose of
antibiotics was taken >= 14 days prior to first dose of study treatment

- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from
treatment complications

- Prior allogeneic stem cell or solid organ transplantation

- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine during the course of the study
or within 5 months after the last dose of atezolizumab

- Treatment with investigational therapy within 28 days prior to initiation of study
treatment

- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
anti-CTLA-4, ant-PD-1, and anti-PD-L1 therapeutic antibodies

- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug
(whichever is longer) prior to initiation of study treatment

- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti?TNF- agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during the course of
the study, with the following exceptions:

- Patients who receive acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible for the study

- Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids
for chronic obstructive pulmonary disease (COPD) or asthma (=< 10 mg prednisone
or equivalent), or low-dose corticosteroids for orthostatic hypotension or
adrenal insufficiency (=< 10 mg prednisone or equivalent) are eligible for the
study

- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins

- 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 formulations of
enzalutamide, emactuzumab, and any other drug being combined with atezolizumab in this
study