Nivolumab and Ipilimumab in Treating Patients With Metastatic/Recurrent ACC of All Sites and Non-ACC Salivary Gland Cancer

PRIMARY OBJECTIVES:

I. To assess median progression-free survival rate (PFSR) as well as PFSR at 6 and 12 months
in patients with recurrent or metastatic adenoid cystic carcinoma (ACC) treated with a
combination of nivolumab and ipilimumab.

SECONDARY OBJECTIVES:

I. To assess the efficacy of nivolumab and ipilimumab according to response rate (RR),
disease control rate (DCR; complete response [CR], partial response [PR], and stable disease
[SD] at 6 and 12 months), overall survival (OS) and progression free survival (PFS) using
Response Evaluation Criteria in Solid Tumors (RECIST) criteria in patients with recurrent or
metastatic ACC.

II. To assess the efficacy of nivolumab and ipilimumab according to overall response rate
(ORR), DCR, progression free survival (PFS), and OS in patients with recurrent or metastatic
ACC using immune-related response criteria (irRC) criteria.

III. To assess the safety and tolerability profile of nivolumab and ipilimumab therapy in
patients with recurrent or metastatic ACC using Common Terminology Criteria for Adverse
Events (CTCAE) version 4.03.

TERTIARY OBJECTIVES:

I. Assess safety, tolerability and activity of Nivolumab and Ipilimumab in non-ACC malignant
salivary gland tumors (MSGT's) using clinical benefit rate (CBR), ORR, PFS, OS.

II. To assess the predictive value of genomic aberrations observed upon comprehensive genomic
profiling of the tumor deoxyribonucleic acid (DNA) derived from archival tumor tissue, if
available, or blood from patients with recurrent or metastatic ACC and non-ACC MSGTs.

III. Circulating cell free DNA genomic profiling will also be performed at baseline and
during treatment with each imaging to explore the genomic landscape of clonal evolution that
may elucidate mechanisms behind response or resistance with immunotherapy in adenoid cystic
carcinoma and non-ACC MSGTs.

IV. Correlation between expression of PD-L1 and response to treatment will be explored in all
patients enrolled in the study.

V. Correlations between other markers of inflammatory/immune signature will be performed that
may include but not be limited to PD-1, OX40, CD73, CD39, T cell immunoglobulin and mucin
domain containing protein 3 (TIM3), GITRL, CTLA-4, CD3, CD4, CD8, protein tyrosine
phosphatase receptor type C (CD45RO), forkhead box P3 (FOXP3), and granzyme by
immunohistochemistry analysis and/or flow cytometry.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, 29, 43, 57, and
71 of course 1 and on days 1 and 15 of course 2, over 60 minutes on days 29 and 57 of course
2 and on days 1, 29, and 57 of subsequent courses. Patients also receive ipilimumab over 90
minutes on days 1 and 43. Courses repeat every 84 days in the absence of disease progression,
unexpected toxicity, or withdrawal of consent.

After completion of study treatment, patients are followed up for 30 days, every 4 weeks for
12 weeks, and then every 12 weeks for up to 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic/recurrent
adenoid cystic carcinoma (ACC) or non-adenoid cystic carcinomas (non-ACC) of major or
minor salivary glands

- Patients must have evidence of disease progression and cannot be a candidate for
surgical treatment

- NOTE: Disease progression is defined as one of the following occurring within the
6 months prior to study entry:

- At least a 20% increase in radiologically or clinically measurable lesions

- Appearance of any new lesions or

- Symptomatic and/or deterioration in clinical status

- Patients must have received at least one prior line of systemic therapy

- NOTE: There is no limit to the number of prior therapies for stage IV disease

- NOTE: Patients should not be a candidate for surgical treatment

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension in accordance with RECIST criteria v1.1

- Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) status of 0-2

- NOTE: ECOG performance status 3 will be allowed only if thought to be directly
secondary to adenoid cystic carcinoma disease by treating physician

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined by: leukocytes >= 2,000/mcL

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined by: absolute neutrophil count >= 1,500/mcL, regardless of
transfusion or growth factor support

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined by: platelets >= 100,000/mcl, regardless of transfusion or
growth factor support

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined by: total bilirubin total bilirubin =< 1.5 x institutional
upper limit of normal (ULN) (except patients with Gilbert syndrome or liver
metastasis, who can have total bilirubin < 3.0 x ULN)

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined by: aspartate aminotransferase (AST) (serum
glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum
glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
(ULN) (or =< 5 times ULN in case of liver metastasis)

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined by: serum creatinine of < 3.0 X ULN (upper limit of normal)
or creatinine clearance > 30 mL/minute (using Cockcroft/Gault formula)

- Patients with history of central nervous system (CNS) metastases are eligible if CNS
disease has been stable for at least 6 weeks prior to study registration in the
opinion of the investigator and does not require corticosteroids (of any dose) for
symptomatic management

- NOTE: Only patients with a known history or indication of CNS disease are
required to have CNS imaging prior to study entry

- Females of childbearing potential (FOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72
hours of registration

- NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a
tubal ligation, or remaining celibate by choice) who meets the following
criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy

- Has had menses at any time in the preceding 12 consecutive months (and
therefore has not been naturally postmenopausal for > 12 months)

- FOCBP and men who are sexually active with FOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment and the designated
post-treatment period

- Patients must have the ability to understand and the willingness to sign a written
informed consent prior to registration on study

Exclusion Criteria:

- Patients must not have had chemotherapy or radiotherapy =< 28 days prior to study
registration

- Patients who have not recovered to =< grade 1 or tolerable grade 2 from adverse events
due to agents administered >= 28 days earlier are not eligible

- Patient must not be a candidate for surgical treatment or radiation

- Patients may not be receiving any other investigational agents =< 28 days prior to
registration

- Patients who have had prior exposure to immune checkpoint inhibitors are not eligible;
please contact principal investigator, 312-926-4248 for specific questions on
potential interactions

- NOTE: Immune checkpoint inhibitors working through OX40 are an exception (for
example, MEDI6383, MEDI6469, MEDI0562, oxelumab, and PF-04518600) and are
permitted >= 28 days prior to study registration

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including chronic prolonged systemic corticosteroids (defined as corticosteroid use of
duration one month or greater), should be excluded; these include but are not limited
to patients with a history of:

- Immune related neurologic disease

- Multiple sclerosis

- Autoimmune (demyelinating) neuropathy

- Guillain-Barre syndrome

- Myasthenia gravis

- Systemic autoimmune disease such as SLE

- Connective tissue diseases

- Scleroderma

- Inflammatory bowel disease (IBD)

- Crohn's

- Ulcerative colitis

- Patients with a history of toxic epidermal necrolysis (TEN)

- Stevens-Johnson syndrome

- Anti-phospholipid syndrome

- NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism
due to autoimmune condition only requiring hormone replacement, psoriasis not
requiring systemic treatment, or conditions not expected to recur in the absence
of an external trigger are permitted to enroll

- Patients who have an uncontrolled intercurrent illness including, but not limited to
any of the following, are not eligible:

- Ongoing or active infection (including minor localized infections) requiring oral
or IV treatment

- Symptomatic class 3 or 4 congestive heart failure, defined as a clinical syndrome
resulting from any structural or functional cardiac disorder that impairs the
ability of the ventricle to fill with or eject blood

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Any other illness or condition that the treating investigator feels would
interfere with study compliance or would compromise the patient's safety or study
endpoints

- Patients should not have any condition requiring systemic treatment with
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days prior to first dose of study drug

- NOTE: Inhaled or topical steroids and adrenal replacement steroids at any dose
are permitted in the absence of active autoimmune disease; a brief (less than 3
weeks) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or
for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity
reaction caused by a contact allergen) is permitted

- Female patients who are pregnant or nursing are not eligible

- No other prior malignancy is allowed except for the following:

- Adequately treated basal cell or squamous cell skin cancer,

- In situ cervical cancer,

- Or any other cancer from which the patient has been disease free for at least
three years

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS) is not permitted

- Any known positive test for hepatitis B or hepatitis C virus indicating acute or
chronic infection is not permitted

- Patients who received a live, attenuated vaccine =< 30 days before study registration
or are anticipated to require such a live attenuated vaccine are not eligible

- NOTE: Influenza vaccination should be given during influenza season only
(approximately October to March); patients must not receive live, attenuated
influenza vaccine (e.g., FluMist) =< 30 days prior to study registration or at
any time during the study