Phase II Study of Perioperative Immunotherapy in Patients With Advanced Non-Virally Associated Squamous Cell Carcinoma

PRIMARY OBJECTIVES:

I. To determine the effect of neoadjuvant atezolizumab alone or in combination with
emactuzumab and other immune modulating agents on T-cell infiltration in advanced squamous
cell carcinoma of the head and neck (SCCHN). (Translational) II. To determine the impact of
neo-adjuvant immunotherapy on surgical outcomes. (Clinical)

SECONDARY OBJECTIVES:

I. To associate changes in CD3 infiltration with radiographic response in the surgical
window. (Translational) II. To describe the changes in T-cell subtypes and other mediators of
anti-tumor immune response induced by neoadjuvant atezolizumab alone or in combination with
emactuzumab or other immune-modulating agents in advanced SCCHN patients. (Translational)
III. To describe the impact of neoadjuvant, surgical, and adjuvant therapy on peripheral
immune responses. (Translational) IV. To determine whether combined neo-adjuvant and adjuvant
immune therapy improves 2-year relapse-free survival (RFS) in patients with SCCHN. (Clinical)
V. To establish the safety/toxicity profile of each regimen in the perioperative and
postoperative settings for patients with advanced SCCHN. (Clinical)

EXPLORATORY OBJECTIVES:

I. To establish immune-competent tumor xenograft models for future research. II. To
characterize changes in the gut microbiome associated with each therapeutic combination.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes every 3 weeks for
up to 2 courses prior to standard surgery and radiation. 16 weeks post-surgery, patients
receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12 courses in the absence
of disease progression or unacceptable toxicity.

ARM II: Patients receive atezolizumab IV over 30-60 minutes and emactuzumab IV over 90
minutes every 3 weeks for up to 2 courses prior to standard surgery and radiation. 16 weeks
post-surgery, patients receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then
periodically for up to 2 years.

IV. To determine whether combined neo-adjuvant and adjuvant immune therapy improves 2-year
relapse-free survival (RFS) in patients with SCCHN. (Clinical) V. To establish the
safety/toxicity profile of each regimen in the perioperative and postoperative settings for
patients with advanced SCCHN. (Clinical)

EXPLORATORY OBJECTIVES:

I. To establish immune-competent tumor xenograft models for future research. II. To
characterize changes in the gut microbiome associated with each therapeutic combination.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes every 3 weeks for
up to 2 courses prior to standard surgery and radiation. 16 weeks post-surgery, patients
receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12 courses in the absence
of disease progression or unacceptable toxicity.

ARM II: Patients receive atezolizumab IV over 30-60 minutes and emactuzumab IV over 90
minutes every 3 weeks for up to 2 courses prior to standard surgery and radiation. 16 weeks
post-surgery, patients receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then
periodically for up to 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed stage III or stage IV
SCCHN that is amenable to surgical resection with curative intent. Primary tumors in
the oropharynx must test negative for human papillomavirus (HPV). Primary tumors in
the nasopharynx must test negative for Epstein-Barr virus (EBV). Tumors originating
outside of the oropharynx and nasopharynx will be presumed to be virus negative

- Patients must agree to undergo post-surgery adjuvant radiation therapy with or without
concurrent, weekly cisplatin at 40 mg/m2 (as clinically indicated)

- Be willing and able to provide written informed consent/assent for the trial

- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion prior to the initiation of neoadjuvant treatment on protocol

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

- Absolute neutrophil count (ANC) >=1,500 /mcL (performed within 14 days of treatment
initiation)

- Platelets >=100,000 / mcL (performed within 14 days of treatment initiation)

- Hemoglobin >= 9 g/dL (performed within 14 days of treatment initiation)

- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 30 mL/min for subject with creatinine
levels > 1.5 x institutional ULN (performed within 14 days of treatment initiation)

* Creatinine clearance should be calculated per institutional standard

- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (performed within 14 days of treatment initiation)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN OR =< 5 x ULN for subjects with liver metastases (performed within 14 days of
treatment initiation)

- Albumin >= 2.5 mg/dL (performed within 14 days of treatment initiation)

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants (performed
within 14 days of treatment initiation)

- Activated partial thromboplastin rime (aPTT) =< 1.5 x ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants (performed within 14 days of treatment initiation)

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required

- Female subjects of childbearing potential must be willing to use an adequate method of
contraception - Contraception, for the course of the study through 5 months after the
last dose of study medication

- Male subjects must agree to use an adequate method of contraception. Contraception,
starting with the first dose of study therapy through 5 months after the last dose of
study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject

Exclusion Criteria:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

- Contraindication at study enrollment to adjuvant radiation therapy

- Has a known history of active TB (Bacillus tuberculosis)

- Hypersensitivity to atezolizumab, emactuzumab or any of their excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier

- Has had prior targeted small molecule therapy, or radiation therapy within 2 weeks
prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from
adverse events due to a previously administered agent or radiation therapy

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy, in situ cervical cancer,
low-grade thyroid cancer and indolent prostate cancer. Additional malignancies may be
permitted after consultation with the principal investigator Has active autoimmune
disease that has required systemic treatment in the past 2 years (i.e., with use of
disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment

- Has known history of, or any evidence of active, non-infectious pneumonitis requiring
corticosteroids

- Patient has known history of stage 2 or higher chronic obstructive pulmonary disease
(COPD). Stage 2 COPD is defined as forced expiratory volume in one second
(FEV1)/forced vital capacity (FVC) < 70%; 50% < FEV1 < 80% predicted, with dyspnea on
exertion

- Patient has asthma requiring systemic corticosteroids at the time of screening.
Inhaled corticosteroids for the treatment of asthma are permitted

- Has an active infection requiring systemic therapy

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

- Has received prior therapy with an anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2
agent

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] quantitative has
been detected). HBsAg reactive on appropriate antiviral therapy with suppressed
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) less than 100 and eligible liver
function will be allowed

- Current New York Heart Association (NYHA) class III or higher heart failure. Patients
with a prior history of heart failure that has resolved to class II or lower may
participate

- Patient has been treated with a live, attenuated vaccine within 4 weeks prior to
initiation of study treatment, or is anticipated to need such a vaccine during the
course of the study or within 5 months after the last dose of atezolizumab

- Known human immunodeficiency virus positive (HIV+) patients may be included but must
have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based tests