Nivolumab Alone or Plus Ipilimumab for Patients With Locally-Advanced Unresectable or Metastatic Basal Cell Carcinoma

This is an open-label, phase 2 signal-seeking study.

Screening will begin by establishing a participant's initial eligibility and signing of the
informed consent document. Eligible, enrolled patients will be assigned to one of 2 cohorts
in a non-randomized fashion according to prior treatment history.

Cohort A: Patients who have not received prior anti-PD-1 therapy, but may have previously
experienced progressive disease or intolerance after up to two other systemic therapies
(e.g., one or more hedgehog signaling pathway inhibitors) will receive nivolumab 480 mg IV
every 4 weeks for up to 48 weeks.

Cohort B: Patients whose disease has progressed after anti-PD-1, either as a part of this
trial or outside of this trial, may receive nivolumab 480mg IV q4weeks x 12 doses +
ipilimumab 1mg/kg IV q4 weeks x 4 doses, then q12weeks x 2 doses.

Patients enrolled on Cohort A who demonstrate PD after nivolumab monotherapy may, if
appropriate in the opinion of the investigator, move to Cohort B.

Discontinuation of nivolumab or ipi+nivo may be at the discretion of the investigator under
circumstances including but not limited to the following:

1. A complete response to therapy.

2. A severe IMAR, defined as Grade 3 or greater.

3. Documented disease progression warranting alternative systemic therapy

4. Intercurrent illness that prevents further administration of study treatment

5. Noncompliance with trial treatment or procedure requirements, or administrative reasons

Inclusion Criteria:

1. Signed Written Informed Consent

1. Subjects must have signed and dated an Institutional Review Board (IRB)-approved
written informed consent form in accordance with regulatory and institutional
guidelines. This must be obtained before the performance of any protocol related
procedures that are not part of normal subject care.

2. Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory tests, and other requirements of the study

2. Type of Participant and Target Disease Characteristics

1. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

2. Participants with histologically confirmed Basal Cell Carcinoma with disease that
is considered by the investigator to be unresectable or metastatic.

i. ARM A: patients may have received up to two prior systemic therapies including
hedgehog pathway inhibitors ii. ARM B: patients may have received up to two prior
systemic therapies including hedgehog pathway inhibitors. In addition, Basal Cell
Carcinoma must have progressed after anti-PD-1 therapy, the most recent dose
administered within 3 months of starting therapy on this trial. No other therapy may
have been received between prior anti-PD-1 therapy and on-study ipi + nivo.

c. Patients may not have received prior T cell modulating agents (e.g., anti-CTLA-4,
anti-PD-L1, anti-LAG-3, anti-KIR, etc.), except anti-PD-1 per ARM B specifications,
above.

d. At least one measurable lesion by the revised Response Evaluation Criteria in Solid
Tumors (RECIST 1.1) e. Participants with Gorlin syndrome will be permitted to enroll
in the study. f. Male or female, aged 18 years or older

3. Laboratory Testing Requirements

Screening laboratory values obtained within -28 +/- 3 days of first dose must meet the
following criteria:

1. White Blood Cells greater than or equal to 2000/μL

2. Neutrophils greater than or equal to 1500/μL

3. Platelets greater than or equal to 100 x 10³/μL

4. Hemoglobin greater than or equal to 9.0 g/dL

5. Serum creatinine less than or equal to 1.5 x Upper Limit of Normal (ULN)or
creatinine clearance (CrCl) greater than or equal to 40 mL/minute (using
Cockcroft/Gault formula)

6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or
equal to 3 x ULN, except in patients with liver metastases whose values may be
less than or equal to 5 x ULN

7. Total Bilirubin less than or equal to 1.5 x ULN (except subjects with Gilbert
Syndrome who may have total bilirubin less than or equal to 3.0 mg/dL)

4. Reproductive Status

1. Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24
hours prior to the initial administration of study drug, then every 4 weeks +/- 1
week thereafter for the duration of treatment with study drug(s).

2. Women must not be breastfeeding.

3. WOCBP must agree to follow instructions for method(s) of contraception from the
time of enrollment for the duration of treatment with study drug(s) plus
approximately 5 half-lives of study drug(s) plus 30 days (duration of ovulatory
cycle) for a total of 5 months post treatment completion.

4. Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug(s) plus
approximately 5 half-lives of study drug(s) plus 90 days (duration of sperm
turnover) for a total of 7 months post-treatment completion.

5. Azoospermic males and those who are continuously not heterosexually active are
exempt from contraceptive requirements.

6. WOCBP who are continuously not heterosexually active are exempt from
contraceptive requirements, however they must still undergo pregnancy testing as
described in this section.

Exclusion Criteria:

1. Medical Conditions

1. Pregnant or nursing women

2. Central nervous system metastases, unless stable for at least 4 weeks and no
longer requiring steroid therapy.

3. Patients with an autoimmune disease or with a condition requiring systemic
treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or
other immunosuppressive medications may be permitted to enroll only after
discussion with the study P.I.

4. Participants with human immunodeficiency virus (HIV) or acquired immunodeficiency
syndrome (AIDS)

5. Viral hepatitis

i. Participants with active hepatitis B (positive hepatitis B surface antigen [HBsAg]
or hepatitis C virus (HCV) (positive HCV RNA) are excluded ii. Patients with past
Hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence
of hepatitis B core antibody [HBcAb] and the absence of HBsAg) are not ineligible, but
HBV DNA quantification must be performed and results discussed with the P.I.

iii. HBV carriers or those participants requiring antiviral therapy are not eligible
to participate.

iv. Patients positive for HCV antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV RNA after discussion with the study P.I.

f. Participants with a prior malignancy active within the previous 2 years may be
permitted to enroll only after discussion with the study P.I. Examples might include
locally curable cancers that have been apparently cured, such as squamous cell skin
cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or
breast.

g. Organ transplant recipients with a functioning allograft will be excluded from this
study.

h. For Cohort B, patients may be excluded from the study if they previously
experienced a toxicity to immunotherapy that, in the opinion of the investigator,
would make it unsafe to restart therapy. Examples may include a Grade 3 or greater
immune mediated adverse event that was considered related to previous immunotherapy
and required immunosuppressive therapy, or an immune mediated adverse event that was
considered related to previous immunotherapy and is still > grade 1 despite
administration of immunosuppressive therapy. Exceptions may include Grade 3
ophthalmologic immune-mediated events that improved to Grade 1 within 2 weeks after
topical therapy only, or Grade 3 endocrine immune-mediated events that did not result
in symptoms lasting >6 weeks and are not requiring >7.5mg prednisone or equivalent per
day.

2. Allergies and Adverse Drug Reaction

1. History of severe allergy or hypersensitivity to study drug components.

2. Patients with a history of a severe toxicity to an immune checkpoint blocking
drug may be permitted to enroll only after discussion with the study P.I.

3. Other Exclusion Criteria

1. Prisoners or participants who are incarcerated may be permitted to enroll only
after discussion with the study P.I.

2. Participants who are detained for treatment of either a psychiatric or physical
(e.g., infectious disease) illness.