Adjuvant Avelumab in Merkel Cell Cancer

PRIMARY OBJECTIVES:

I. To compare the clinical activity of adjuvant avelumab to that of placebo, as determined by
relapse-free survival in subjects with clinically detected nodal metastases from Merkel cell
carcinoma (MCC) after definitive therapy (surgery with/without adjuvant radiation therapy
[RT]).

SECONDARY OBJECTIVES:

I. To examine whether post-operative adjuvant therapy with avelumab improves overall survival
(OS) as compared to placebo.

II. To examine whether post-operative adjuvant therapy with avelumab improves distant
metastases-free survival (DMFS) as compared to placebo.

III. To assess whether post-operative adjuvant therapy with avelumab improves
disease-specific survival (DSS) as compared to placebo.

IV. To assess the safety and tolerability of avelumab in the adjuvant setting.

TERTIARY OBJECTIVES:

I. To explore predictive biomarkers in tissue and peripheral blood for immunogenicity of
avelumab.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive avelumab intravenously (IV) over 1 hour once every 15 days for the
first 120 days (Induction Phase 1), once every 30 days for the next 120 days (Induction Phase
2), and then once every 120 days (Maintenance Phase) for a maximum of 720 days (approximately
24 months or 2 years total) in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo IV over 1 hour once every 15 days for the first 120 days
(Induction Phase 1), once every 30 days for the next 120 days (Induction Phase 2), and then
once every 120 days (Maintenance Phase) for a maximum of 720 days (approximately 24 months or
2 years total) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years for
a minimum of 5 years from study treatment initiation.

Inclusion Criteria:

- Histologically confirmed MCC metastases in clinically detected lymph node(s)

- Confirmation of the MCC diagnosis in the clinically suspicious lymph node(s) is
mandatory for trial participation

- Subjects must have had clinically-detected (i.e. either palpable or
radiologically abnormal) lymph nodal metastasis

- (NOTE: In-transit metastases without regional nodal involvement could be allowed,
but only after written approval of the medical monitor)

- Must have completed definitive treatment that included surgical removal of the
clinically detected MCC metastases (with/without adjuvant radiation therapy as
determined by the treating investigator)

- Estimated life expectancy greater than 3 years

- Must start the study treatment no more than 60 days from the last dose of RT (if
administered) and no more than 120 days from the date of surgical removal of nodal
metastases

- Eastern Co-Operative Group (Eastern Cooperative Oncology Group [ECOG]) performance
score of 0 or 1

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

- Platelet count >= 100 x 10^9/L

- Hemoglobin >= 9 g/dL (may have been transfused)

- Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 2.5 x
ULN

- Estimated creatinine clearance >= 30 mL/min according to the Cockcroft-Gault formula
or by 24-hour urine collection for creatinine clearance or according to local
institutional standard

- Women of childbearing potential must have a negative serum or urine pregnancy test at
screening

- Both male and female subjects must be willing to use highly effective contraception
(that is, methods with a failure rate of less than 1% per year) throughout the study
and for at least 30 days after last avelumab treatment administration if the risk of
conception exists

- (NOTE: Women of childbearing potential and men must agree to use highly effective
contraception, as stipulated in national or local guidelines; should a woman
become pregnant or suspect she is pregnant while she or her partner is
participating in this study, the treating physician should be informed
immediately)

- Must have an ability to understand and the willingness to sign a written informed
consent document

- Must consent to allow the acquisition of existing formalin-fixed paraffin-embedded
(FFPE) tumor tissue, either a block or unstained slides, for performance of
correlative studies

Exclusion Criteria:

- Clinical or radiologic suspicion of residual MCC at the time of enrollment

- Suspicion or known history of distant metastatic MCC, which is not classifiable as
local recurrence or regional metastasis

- (NOTE: Patients presenting with nodal metastases in one lymph node basin and no
known primary tumor are allowed to enroll)

- Any prior systemic therapy (e.g. adjuvant, neo-adjuvant or concurrent use of
chemotherapy, immunotherapy or an investigational agent) for MCC at any time

- Any prior intra-lesional MCC therapy within 180 days from day 1 of study treatment

- Residual toxicity from prior therapy grade > 1 (National Cancer Institute [NCI]-Common
Terminology Criteria for Adverse Events [CTCAE] version [v] 4.0) that could interfere
with study endpoints or put patient safety at risk

- Previous malignant disease (other than Merkel cell carcinoma) diagnosed within 3 years
from day 1 of study treatment that could interfere with study endpoints or put patient
safety at risk

- (NOTE: Exception will be made for adequately treated basal or squamous cell
carcinoma of the skin or carcinoma in situ [skin, bladder, cervical, colorectal,
breast] or low grade prostatic intraepithelial neoplasia or grade 1 prostate
cancer; any other neoplasm, which is adjudged by the treating investigator to
have a low risk of recurrence during the study, could be enrolled only after
written approval from the medical monitor)

- Use of any systemic immunosuppressive treatments including corticosteroids,
cyclosporine, mycophenolate mofetil et cetera, ongoing or within the last 3 months
prior to day 1 of treatment

- (NOTE: Patients on physiologic dose of corticosteroids [=< 10 mg/day of
prednisone or equivalent] for long-term hormone-replacement therapy or those
requiring short, intermittent courses of corticosteroids for hypersensitivity
prophylaxis [such as for iodinated computed tomography (CT) contrast prophylaxis]
or those using intranasal, inhaled, topical steroids, or local steroid injection
[e.g., intra-articular injection] can be allowed)

- Immunosuppressed status due to known human immunodeficiency virus (HIV) infection,
severe uncontrolled diabetes, concurrent hematological malignancy, or other
comorbidities

- Uncontrolled intercurrent illness including, but not limited to, active serious
infection, active hepatitis B or hepatitis C infection, uncontrolled seizure disorder,
substance abuse disorder, or psychiatric illness/social situations that would limit
compliance with study requirements or would put the patient at increased risk of
complications during the study period

- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
prior to enrollment), unstable angina, congestive heart failure (>= New York Heart
Association Classification Class II), or serious cardiac arrhythmia requiring
medication

- Active or history of any serious autoimmune disease, prior organ transplantation,
including allogeneic stem-cell transplantation or immune-deficiencies that required
treatment with systemic immunosuppressive drugs and could flare-up during study
treatment

- (NOTE: Patients with diabetes type I, vitiligo, psoriasis, or hypo- or
hyperthyroid diseases not requiring immunosuppressive treatment are eligible)

- Other severe acute or chronic medical conditions including immune-mediated colitis,
inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions
including recent (within the past year) or active suicidal ideation or behavior; or
laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study

- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v4.03 grade >= 3) that could interfere with study endpoints or
put patient safety at risk

- Pregnant or breast-feeding women