A Phase II Trial of Avelumab in Patients With Recurrent or Progressive Osteosarcoma

This is a Phase 2 study using a traditional Simon two-stage design. Patients 12 years or
greater with recurrent/refractory osteosarcoma will be administered avelumab at a dose of 10
mg/kg intravenously (IV) over 60 minutes on days 1 and 15 of each cycle, with a cycle lasting
28 days.

Patients will receive avelumab every 2 weeks in cycles of 28 days for up to 24 months, or 26
cycles. Progression free survival and response to therapy after 4 cycles of treatment will be
assessed. In addition, the toxicity profile of avelumab in this population will be closely
monitored.

Inclusion Criteria:

- Patients must be > 12 years of age but < 50 years of age at the time of enrollment.

- Patients must have histologic verification of osteosarcoma at initial diagnosis or
relapse.

- Patients must have had evidence of having relapsed, progressed or become refractory to
conventional therapy.

- Patients must have measurable disease, documented by clinical, radiographic or
histologic criteria. Disease must be bi-dimensionally measurable by computed
tomography (CT) or magnetic resonance imaging (MRI).

- Patients must have a performance status of ≥ 50 using the Karnofsky scale for patients
> 16 years of age and the Lansky scale for patients ≤ 16 years of age.

- Patients must have a life expectancy of ≥ 6 weeks.

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

1. Myelosuppressive chemotherapy: must not have received within 3 weeks of entry
onto this study.

2. Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy
with a biologic agent.

3. Immunotherapies: at least 42 days must have elapsed since a prior therapy that
included a monoclonal antibody or any other type of immunotherapy (e.g. chimeric
antigen receptor (CAR) T cell therapy).

4. Radiation therapy (RT): ≥ 2 weeks for local palliative RT (small port); ≥ 6
months must have elapsed if prior craniospinal RT or if ≥ 50% radiation of the
pelvis; ≥ 6 weeks must have elapsed if other substantial bone marrow (BM)
radiation.

- Organ Function Requirements:

1. Adequate bone marrow function defined as:

- Peripheral absolute neutrophil count (ANC) ≥ 1500/mm3

- Platelet count ≥ 100,000/mm3 (transfusion independent)

- Hemoglobin ≥ 9.0 g/dL (may receive RBC transfusions)

2. Adequate renal function defined as:

- Creatinine clearance or radioisotope GFR ≥70 mL/min/1.73m2 OR

- Serum creatinine based on age/gender as follows: (threshold creatinine
values were derived from the Schwartz formula for estimating GFR).

- Age is: 12 to <13 years, then maximum creatinine is 1.2 mg/DL for male
and female.

- Age is: 13 to <16 years, then maximum creatinine is 1.5 mg/DL for male
and 1.4 mg/DL for female.

- Age is: ≥16 years, then maximum creatinine is 1.7 mg/DL for male and
1.4 mg/DL for female.

3. Adequate liver function defined as:

- Total Bilirubin ≤ 1.5x the institutional upper limit of normal (IULN) for
age

- ALT (SGPT) and AST (SGOT) < 2.5 x IULN for age (or < 5 x IULN for patients
with documented metastatic disease to the liver)

- Serum albumin > 2 g/dL

4. Serum lipase ≤ upper limit of normal (IULN).

5. Patients must have documented pulse oximetry ≥ 92% on room air.

- Female patients of childbearing potential must have a negative serum or urine
pregnancy test within 7 days of enrollment.

- Male or female patients who are sexually active and of reproductive potential must
agree to use an effective contraceptive method throughout the study and for at least
60 days after last avelumab treatment administration. Abstinence is an acceptable form
of contraception.

- Patients must not currently be using other investigational agents.

- Patients must not currently be using other anti-cancer agent.

- Patients must be able to comply with the safety monitoring of the study in the opinion
of the investigator.

- Written, informed consent and assent following Institutional Review Board, NCI, FDA
and OHRP guidelines.

Exclusion Criteria:

- Central nervous system (CNS) metastases.

- 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).

- 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.

- Active infection requiring systemic therapy.

- Known history of testing positive for HIV or known acquired immunodeficiency syndrome.

- 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).

- Patient who has received vaccination within 4 weeks of the first dose of avelumab and
while on trials is prohibited except for administration of inactivated vaccines.

- 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).

- 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, see Appendix II), or serious cardiac arrhythmia
requiring medication.

- 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 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.

- Patients with active diarrhea > CTCAE v4.03 Grade 2.

- Patients who have previously received a prior organ transplantation, including
allogeneic stem cell transplantation.

- Female patients who are pregnant or actively breastfeeding.

- Patients who have previously received anti-PD1 or anti-PD-L1 therapy. Patients who
have previously received anti-CTLA-4 therapy (e.g. ipilimumab) are eligible for study.