Nivolumab With or Without Ipilimumab in Treating Patients With Refractory Metastatic Anal Canal Cancer

PRIMARY OBJECTIVES:

I. To evaluate overall response rate (ORR) with nivolumab in patients with previously treated
metastatic squamous cell carcinoma (SCCA) of the anal canal. (Part A) II. To determine an
improvement in progression-free survival (PFS) when nivolumab is combined with ipilimumab
versus (vs.) nivolumab alone in patients with previously treated metastatic SCCA (Part B).

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS) of nivolumab in patients with previously
treated metastatic SCCA of the anal canal. (Part A) II. To evaluate overall survival (OS) in
patients with previously treated metastatic SCCA of the anal canal treated with nivolumab.
(Part A) III. To evaluate the grade 3 and 4 toxicity rate in patients with previously treated
metastatic SCCA of the anal canal when treated with nivolumab. (Part A) IV. To evaluate the
overall response rate (ORR) of nivolumab plus or minus ipilimumab in patients with previously
treated metastatic SCCA of the anal canal. (Part B) V. To evaluate overall survival (OS) in
patients with previously treated metastatic SCCA of the anal canal treated with nivolumab
plus or minus ipilimumab. (Part B) VI. To evaluate the grade 3 and 4 toxicity rate in
patients with previously treated metastatic SCCA of the anal canal when treated with
nivolumab plus or minus ipilimumab. (Part B)

EXPLORATORY OBJECTIVES:

I. To evaluate ORR, PFS, and OS based on expression of programmed cell death 1 ligand 1
(PD-L1), programmed cell death 1 (PD-1), peritumoral cluster of differentiation (CD)8+ tumor
infiltrating lymphocytes (TILs), peritumoral CD4+ TILs, and regulatory T cells as analyzed
from tumor biopsies in previously treated patients with metastatic SCCA of the anal canal
when treated with nivolumab. (Part A) II. To evaluate radiographic responses according to
relative changes in proportions of anti-human papillomavirus (HPV) specific CD8+ and CD4+
TILs and regulatory T cells in patients with previously treated metastatic SCCA of the anal
canal following treatment with nivolumab, analyzed from serial peripheral blood samples.
(Part A) III. To evaluate ORR, PFS, and OS based on expression of PD-L1, PD-1, peritumoral
CD8+ tumor infiltrating lymphocytes (TILs), peritumoral CD4+ TILs, and regulatory T cells as
analyzed from tumor biopsies in previously treated patients with metastatic SCCA of the anal
canal when treated with nivolumab plus or minus ipilimumab. (Part B) IV. To evaluate
radiographic responses according to relative changes in proportions of anti-HPV specific CD8+
and CD4+ TILs and regulatory T cells in patients with previously treated metastatic SCCA of
the anal canal following treatment with nivolumab plus or minus ipilimumab. (Part B)

OUTLINE:

PART A: Patients receive nivolumab intravenously (IV) over 60 minutes once every two weeks.
Treatment continues in the absence of disease progression or unacceptable toxicity.

PART B: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab IV over 30 minutes once every 4 weeks. Treatment continues
in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30
minutes once every 8 weeks. Treatment continues in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 100 days and then every 3
months for 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed previously treated
metastatic squamous cell carcinoma of the anal canal

- Patients must have measurable disease according to the standard Response Evaluation
Criteria in Solid Tumors (RECIST) version 1.1, computed tomography (CT) scans or
magnetic resonance imaging (MRI)s used to assess the measurable disease must have been
completed within 28 days prior to study drug initiation

- Patients must have been treated with at least one prior systemic treatment for
incurable advanced or metastatic SCCA of the anal canal; prior treatment for
metastatic disease is not required for patients who develop new metastatic lesions
during or within 6 months of completion of chemoradiation for limited-stage disease;
patients who receive chemotherapy for incurable advanced or metastatic SCCA of the
anal canal must wait a minimum >= 28 days (6 weeks for nitrosoureas or mitomycin C)
after the date of completion of chemotherapy prior to initiating treatment with
nivolumab on this study; patients who undergo palliative radiotherapy to a site of
tumor must wait a minimum >= 28 days from the date of completion of radiotherapy prior
to initiating treatment with nivolumab (Part A and B) or nivolumab +/- Ipilimumab
(Part B) on this study

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 80%)

- Leukocytes >= 2,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 9.0 gm/dL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x ULN

- Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using
the Cockcroft-Gault formula)

- Before study enrollment, women of child bearing potential must be advised of the
importance of avoiding pregnancy during study participation and the potential risk
factors for an unintentional pregnancy; the subject must sign an informed consent form
documenting this discussion; women of child-bearing potential (WOCBP) and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation; women of
childbearing potential MUST have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within
24 hours prior to the start of nivolumab with or without ipilimumab; the minimum
sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG; if the
pregnancy test is positive, the subject must not receive nivolumab with or without
ipilimumab and must not be enrolled in the study

- Women of childbearing potential (WOCBP) is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes

- WOCBP receiving nivolumab (Parts A+B) or nivolumab and ipilimumab (Part B) will be
instructed to adhere to contraception for a period of 5 months after the last dose of
investigational product; men receiving nivolumab (Parts A+B) or nivolumab and
ipilimumab (Part B only) and who are sexually active with WOCBP will be instructed to
adhere to contraception for a period of 7 months after the last dose of
investigational product; these durations have been calculated using the upper limit of
the half-life for nivolumab (25 days) and are based on the protocol requirement that
WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active
with WOCBP use contraception for 5 half-lives plus 90 days

- Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she (or the participating partner) should inform the
treating physician immediately; if, following initiation of the investigational
product, it is subsequently discovered that a study subject is pregnant or may have
been pregnant at the time of investigational product exposure, including during at
least 6 half-lives after product administration, the investigational product will be
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary
for subject safety); the investigator must immediately notify BMS of this event and
record the pregnancy on the Pregnancy Surveillance Form (not an severe adverse event
[SAE] form); initial information on a pregnancy must be reported immediately to BMS,
and the outcome information provided once the outcome is known; completed Pregnancy
Surveillance Forms must be forwarded to BMS according to SAE reporting procedures; any
pregnancy that occurs in a female partner of a male study participant should be
reported to the sponsor. Information on this pregnancy will be collected on the
Pregnancy Surveillance Form; protocol-required procedures for study discontinuation
and follow-up must be performed on the subject unless contraindicated by pregnancy
(e.g., X-ray studies); other appropriate pregnancy follow-up procedures should be
considered if indicated. In addition, the investigator must report and follow-up on
information regarding the course of the pregnancy, including perinatal and neonatal
outcome. Infants should be followed for a minimum of 8 weeks

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

- Brain metastases are allowed if they have been adequately treated with radiotherapy or
surgery and have been stable for at least three months prior to registration; eligible
subjects should be neurologically asymptomatic; there is no magnetic resonance imaging
(MRI) evidence of progression for a minimum of 4 weeks after treatment is complete and
within 28 days prior to the first dose of nivolumab administration; there must also be
no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day
prednisone equivalents) for at least 2 weeks prior to study drug administration

- Willingness for evaluation of cardiac function including electrocardiography (EKG) and
echocardiogram (ECHO) cardiogram for any patients with a history of congestive heart
failure (CHF) or at risk because of underlying cardiovascular disease or exposure to
cardiotoxic drugs as clinically indicated

- All patients must be willing to undergo testing for human immunodeficiency virus (HIV)
testing if not tested within the past 6 months

- If HIV+ positive, all patients infected with human immunodeficiency virus (HIV) may be
eligible for study provided that their CD4+ count >= 300/uL; their viral load is
undetectable; they are currently receiving highly active antiretroviral therapy
(HAART)

- All HIV+ patients will be under the care of an infectious diseases specialist; if a
relationship with an infectious diseases specialist is not established, infectious
disease specialist will be consulted; records of all viral counts and peripheral
T-cell counts must be sent to the study coordinator in order to follow these values
over the course of treatment

- All patients must be willing to be tested for hepatitis screening; patients
co-infected with hepatitis B virus and/or hepatitis C virus may be included in this
study provided that their liver function tests remain within the limits listed above;
patients must be followed by a hepatologist during the course of this study

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (AEs) due to agents administered more than 4 weeks
earlier (i.e., grade >= 2 AE present); palliative (limited-field) radiation therapy is
permitted, as long as the lesion being considered for palliative radiation is not a
target lesion

- Patients who are receiving any other investigational agents

- Patients should be excluded if they have had prior treatment with an anti-PD-1,
anti-PD-L1, anti-programmed cell death ligand 2 (PD-L2), anti-cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or immune checkpoint pathways

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab (Parts A+ B) and/or ipilimumab (Part B)

- History of severe hypersensitivity reaction to any monoclonal antibody

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- 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 systemic lupus erythematosus (SLE), connective
tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative
colitis, and patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or anti-phospholipid syndrome should be excluded

- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration; inhaled or
topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption); physiologic replacement doses of systemic
corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief
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 contact allergen) is permitted

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for at least three years