Avelumab/Gemcitabine in Sarcomatoid RCC

Inclusion Criteria:

- Histologic evidence of metastatic RCC with sarcomatoid features (≥10% sarcomatoid
component) or poor-risk RCC prognostic features (as defined by IMDC criteria). (14) An
outside pathology report is sufficient for study eligibility. However, pathology
should still be obtained as possible for internal institutional pathology review.

- ≥ 18 years of age.

- Phase I dose-escalation portion only:

Patients must have ≤3 prior systemic treatment regimens with recent evidence of disease
progression by RECIST 1.1 criteria. Previous treatment with immune-checkpoint inhibitor
therapy is allowable as a line of systemic therapy for the phase I portion. Prior systemic
therapy in the adjuvant treatment setting is allowable as a prior line of therapy.

Phase Ib dose-expansion portion only:

Patients must have been treated with 0 or 1 prior lines of systemic therapy. Previous
treatment with immune-checkpoint inhibitor therapy is allowable as a line of systemic
therapy for the phase Ib expansion portion.

- No prior therapy with gemcitabine chemotherapy.

- ECOG performance status of 0-1. Patients must have primary or metastatic FFPE tissue
available for histologic confirmation and possible determination of percent
sarcomatoid component (if applicable).

Outside pathology report is sufficient for study eligibility. However, pathology should
still be obtained as possible for internal institutional pathology review.

- Patients with history of treated brain metastases are eligible if off systemic
corticosteroids for at least 2 weeks.

- Patients must have normal organ function, as confirmed by laboratory values obtained ≤
14 days prior to the first day of study therapy:

Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L,
and hemoglobin ≥ 9 g/dL (may have been transfused) Hepatic: Total bilirubin level ≤ 1.5 ×
the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN or AST and ALT
levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).

Renal: Estimated creatinine clearance ≥ 45 mL/min using Cockroft Gault formula.

- Patients must have a projected life expectancy of at least 3 months.

- PREGNANCY AND CONTRACEPTION:

Pregnancy test: Negative serum or urine pregnancy test at screening for women of
childbearing potential.

Contraception: Highly effective contraception for both male and female subjects throughout
the study and for at least 30 days after last avelumab treatment administration if the risk
of conception exists.

In addition, women must not breastfeed while on this study as study drugs may also affect a
breast-feeding child. Pregnant women and women who are breastfeeding are not allowed to
participate in this study.

Exclusion Criteria:

- IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, EXCEPT for the
following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10
mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity
reactions (e.g., CT scan premedication).

- AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when receiving an
immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo-
or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.

- ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell
transplantation.

- INFECTIONS: Active infection requiring systemic therapy.

- HIV/AIDS: Known history of testing positive for HIV or known acquired immunodeficiency
syndrome, or positive HIV test result at screening.

- HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening
(positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

- VACCINATION: Vaccination within 4 weeks of the first dose of avelumab and while on
trials is prohibited except for administration of inactivated vaccines.

- HYPERSENSITIIVTY TO STUDY DRUG: 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).

- CARDIOVASCULAR DISEASE: 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.

- OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI CTCAE
v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤
2 not constituting a safety risk based on investigator's judgment are acceptable.

- Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune 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.