CIMAvax Vaccine, Nivolumab, and Pembrolizumab in Treating Patients With Advanced Non-small Cell Lung Cancer or Squamous Head and Neck Cancer

PRIMARY OBJECTIVES:

I. To identify the maximum dose of CIMAvax in combination with nivolumab based on dose
limiting toxicities (DLTs) as assessed by Common Terminology Criteria for Adverse Events
version 4.03 (CTCAE version [v] 4.03). (Phase I) II. To evaluate the 12-month overall
survival of CIMAvax combined with nivolumab in patients with advanced non-small cell lung
cancer (NSCLC). (Phase II-Study A) III. To evaluate the 6-month progression free survival
(PFS) of CIMAvax combined with nivolumab in patients with advanced recurrent squamous cell
carcinoma of the head and neck. (Phase II-Study B) IV. To evaluate the objective response
rate of pembrolizumab in combination with CIMAvax as first-line therapy in patients with
advanced NSCLC (PD-L1 expression >= 50%). (Phase II-Study C)

SECONDARY OBJECTIVES I. To assess the toxicity of CIMAvax combined with nivolumab using the
Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE version 4.03). (Phase I) II. Determine the preliminary
efficacy of the combination of anti-PD1 therapy with CIMAvax. (Phase I) III. To evaluate
progression free survival (PFS) for the combination of CIMAvax and nivolumab in patients with
advanced NSCLC. (Phase II-Study A) IV. To evaluate the 12-month overall survival of patients
with advanced recurrent squamous cell carcinoma of the head and neck who received nivolumab
in combination with CIMAvax. (Phase II-Study B) V. To evaluate the PFS and 12-month overall
survival of CIMAvax in combination with pembrolizumab as first-line therapy in patients with
advanced NSCLC (PD-L1 expression >= 50%). (Phase II-Study C) VI. To assess the toxicity of
CIMAvax combined with nivolumab using the CTEP NCI Common Terminology Criteria for Adverse
Events (CTCAE version 4.03). (Phase II)

TERTIARY OBJECTIVES:

I. To conduct correlative studies comparing blood EGF levels, platelet levels, markers of
immune response and functionality of antibody response. (Phase I) II. To examine the
association of EGFR (total and activated), PD-1 and PD-L1 expression and mutations in tumor
tissue with biomarkers of genetic and immune response. (Phase I and II) III. Comparison of
response assessment criteria for a prospective analysis (immune-related [ir] Response
Evaluation Criteria in Solid Tumors [RECIST] response assessment versus [vs.] immune-related
Response Criteria [irRC] vs. RECIST 1.1). (Phase I and II) IV. To characterize the blood EGF
levels and other blood-based biomarkers of patients censored from the trial because of low
titer response. (Phase II)

OUTLINE: This is a phase I dose escalation study of CIMAvax followed by a phase II study.

LOADING PHASE I: Patients receive CIMAvax intramuscularly (IM) and nivolumab intravenously
(IV) over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 doses in the
absence of disease progression or unacceptable toxicity. Within 4 weeks after the 4th dose,
patients receive CIMAvax IM at the same time as the next nivolumab dose.

MAINTENANCE PHASE I: Patients who do not experience a DLT receive CIMAvax every 4 weeks and
nivolumab every 2 weeks.

PHASE II STUDY A and B: Patients receive CIMAvax IM and nivolumab IV over 60 minutes.
Treatment with CIMAvax repeats every 2 weeks for 4 doses during the loading phase and every 4
weeks during the maintenance phase in the absence of disease progression or unacceptable
toxicity. Courses for nivolumab repeat every 2 weeks in the absence of disease progression or
unacceptable toxicity. Patients in Study A with antibody titer >= 1:4000 at the end of the
loading phase may receive CIMAvax IM every 8 or 12 weeks during the maintenance phase.

PHASE II STUDY C: Patients with PD-L1expression >= 50% receive CIMAvax IM and pembrolizumab
IV over 30 minutes. Treatment with CIMAvax repeats every 2 weeks for 4 doses during the
loading phase and every 4 weeks during the maintenance phase in the absence of disease
progression or unacceptable toxicity. Courses for pembrolizumab repeat every 2 weeks for 2
years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 30 days for 120 days.

Inclusion Criteria:

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1 at the
time of study treatment initiation

- Have pathologically confirmed diagnosis of NSCLC (Phase I, Phase II Studies A, C and
Expansion Cohort AE) or squamous cell head and neck cancer (Phase II Study B)

- Must be eligible for treatment with nivolumab as standard of care (for nivolumab
treatment groups only)

- Phase II Study A and Expansion Cohort AE: Patients with advanced (metastatic) NSCLC,
whose disease progressed during or after platinum based therapy

- Phase II Study B: Patients with advanced recurrent head and neck squamous cell
carcinoma

- Phase II Study C: Patients with advanced unresectable NSCLC, first-line therapy with
PD-L1 expression >= 50%; in the rare event that there is a discrepancy in the results
of PD-L1 testing (i.e. 2 or more specimens were tested, etc.), eligibility status will
be per the discretion of the principal investigator (PI) after review of other
available biomarker testing

- NSCLC patients in study A and expansion cohort AE with EGFR or ALK genomic tumor
aberrations (determined through either tissue- or liquid biopsy-based platform) should
have disease progression on Food and Drug administration (FDA)-approved therapy for
these aberrations prior to receiving nivolumabanti-PD1 therapy; patients with smoking
history being considered for Study C may enroll and be treated pending results of
molecular testing

- Have at least 6 month life expectancy

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Hemoglobin >= 9 g/dL

- Serum creatinine =< 1.5 x institution upper limit of normal (ULN) or estimated
glomerular filtration rate (GFR) (measured or calculated with Cockcroft and Gault
formula) > 45 ml/min

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (ALT
and AST =< 5 x ULN is acceptable if liver metastases are present)

- Total serum bilirubin =< 1.5 x ULN; for patients with well documented Gilbert?s
syndrome, total bilirubin =< 3 x ULN with direct bilirubin within normal range

- Troponin-I, creatine kinase muscle and brain (CK-MB) =< ULN, B-type natriuretic
peptide (BNP) < 200 pg/ml

- Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN)
(institutional limit)

- Patients enrolled onto Phase I dose escalation or Expansion Cohort (AE) must have
presence of evaluable disease; patients enrolled onto Phase II studies A, B, or C must
have measurable disease as defined in RECIST 1.1

- Participants of child-bearing potential must agree to use adequate contraceptive
methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
entry; should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

- Phase II studies: Participant agrees to provide tumor biopsy tissue before treatment,
blood samples at the start of treatment and at multiple times during the study and, a
tumor biopsy at the end of the trial or after disease progression; archival
formalin-fixed paraffin-embedded (FFPE) tissue is permitted for Expansion Cohort AE;
archival FFPE tissue is also permitted for Study C patients provided that tissue is
adequate and no systemic anti-cancer therapy had been administered between the time
specimen was obtained and start of protocol therapy

Exclusion Criteria:

- Receipt of anticancer chemotherapy within 4 weeks before the first administration of
study drug

- Previous anti-PD1 or PD-L1 immunotherapy is not allowed; treatment with other
investigational agents within 6 half-lives of first administration of study drug is
not allowed

- Patients requiring 24-hour continuous oxygen therapy

- Prior radiotherapy or gamma knife within 2 weeks of study treatment for non-brain
metastasis; subjects must have recovered from all radiation related toxicities

- Active/untreated brain metastasis; whole brain radiation or gamma knife radiosurgery
performed less than 4 weeks prior to first administration of study drug; previously
treated brain metastasis allowed as long as not requiring steroids and stable on
imaging at least 4 weeks after completing radiation therapy

- Leptomeningeal involvement regardless of treatment status

- Tumor with mutation that is known to be sensitive to FDA approved targeted therapy but
has not yet received such targeted therapy

- History of autoimmune disorder, with exception of patients with vitiligo or
endocrine-related autoimmune conditions receiving appropriate hormonal supplementation
who are eligible; systemic use of immunosuppressant drugs such as steroids (except as
hormone replacement therapy or short-course supportive medication such as chemotherapy
or drug allergy, etc.), azathioprine, tacrolimus, cyclosporine, etc. within 4 weeks
before recruitment

- Currently receiving or has received systemic corticosteroids within 4 weeks prior to
starting study drug for management of brain metastases, or who have not fully
recovered from side effects of such treatment; steroids for endocrine replacement or
receipt of short-course of steroids during the preceding 4 week period as supportive
medication such as for drug allergy, anti-emetic, etc. is allowed

- Had major surgery within 14 days prior to starting study drug or has not recovered
from major side effects (tumor biopsy is not considered major surgery) resulting from
a prior surgery

- Has known immunosuppressive disease (e.g. human immunodeficiency virus [HIV], acquired
immune deficiency syndrome [AIDS] or other immune depressing disease); testing is not
mandatory

- Active, clinically serious infections or other serious uncontrolled medical conditions

- Patient has known hypersensitivity to the components of the study drugs or any analogs

- History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the study, interfere with the patient?s participation
for the full duration of the study, or is not in the best interest of the patient to
participate, in the opinion of the treating investigator, including, but not limited
to:

- Myocardial infarction or arterial or venous thromboembolic events within 6 months
prior to baseline or severe or unstable angina, New York Heart Association (NYHA)
class III or IV disease

- History of documented congestive heart failure (New York Heart Association
functional classification III or IV)

- Documented history of cardiomyopathy

- Uncontrolled hypertension (systolic blood pressure [SBP] > 160/diastolic blood
pressure [DBP] > 100 despite medical intervention)

- History of myocarditis of any etiology

- History of cardiac surgery

- History of ventricular arrhythmias

- Phase II only: Patients diagnosed with an invasive cancer within 2 years prior to
starting protocol therapy with the following exceptions: non-melanoma skin cancers,
in-situ cancers, and prostate cancer gleason =< to 6 (under surveillance or treated),
early stage node-negative estrogen receptor (ER)+/progesterone receptor (PR)+ breast
cancer with Oncotype Dx score < 25 not taking adjuvant hormonal therapy

- Pregnant or nursing female participants

- Any condition which in the investigator?s opinion deems the participant an unsuitable
candidate to receive study drug

- Unwilling or unable to follow protocol requirements