A Pilot Study to Investigate the Safety and Clinical Activity of Avelumab (MSB0010718C) in Thymoma and Thymic Carcinoma After Progression on Platinum-Based Chemotherapy

Background:

Platinum-based chemotherapy is the standard of care for advanced unresectable thymic
epithelial tumors (TETs). However more than half of these patients experience disease
recurrence and require second-line therapy. There are no approved drugs for treatment of
recurrent thymoma and thymic carcinoma and new therapeutic options are needed for patients
who have disease progression on or after platinum-containing therapy. The clinical activity
of checkpoint blockade targeting programmed death 1 (PD-1) and its ligand (PD-L1) has been
demonstrated against various tumor types. We have demonstrated the ability of avelumab to
induce major responses in patients with advanced thymoma in a phase I dose escalation study.
Further investigation of avelumab in patients with TETs is needed to define the clinical
activity and safety of immune checkpoint blockade in patients with TETs.

PRIMARY OBJECTIVES:

- To determine the safety and tolerability of Avelumab in patients with relapsed or
refractory thymoma and thymic carcinoma.

- To determine the objective response rate (ORR) to Avelumab in patients with relapsed or
refractory thymoma and thymic carcinoma.

ELIGIBLITY:

- Patients with histologically confirmed, unresectable thymoma or thymic carcinoma who
have previously been treated with at least one platinum-containing chemotherapy regimen
with progressive disease prior to study entry.

- Prior treatment with immune checkpoint inhibitors is permitted if the reason for
discontinuation was not disease progression or life-threatening adverse events
(laboratory abnormalities alone with prior therapy will not exclude patients from this
trial)

- Measurable disease by RECIST 1.1 criteria

- Adequate renal, hepatic and hematopoietic function

- No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of
avelumab

- No prior thymic tumor-associated autoimmune disease with the exception of pure red cell

aplasia and vitiligo.

Design:

- This will be a single-arm, pilot study to determine the clinical activity and safety of
treatment with avelumab in patients with relapsed or refractory thymoma and thymic
carcinoma.

- Avelumab will be administered at a dose of 10 mg/kg intravenously once every two weeks
until disease progression or development of intolerable adverse events. The two week
period will constitute one cycle.

- Toxicity will be assessed every cycle by CTCAE version 4.0.

- Tumor response will be assessed after completion of every third cycle (6 weeks) using
RECIST criteria, version 1.1.

- When possible, a tumor biopsy will be conducted pre-treatment and on C4D43 to evaluate
treatment-related, intra-tumoral changes.

- INCLUSION CRITERIA:

- Patients must have histologically confirmed thymoma or thymic carcinoma by the
pathology department/CCR/NCI.

- Patients must have had at least one prior line of platinum-based chemotherapy or
patient must have refused cytotoxic chemotherapy. - Progressive disease must be
documented prior to study entry and patients must have advanced, unresectable disease
that is not amenable to surgical resection.

- Prior treatment of PD-1 or PD-L1-directed immune checkpoint blockade is permitted if
treatment was not discontinued due to disease progression or lifethreatening adverse
events per the investigators discretion (laboratory abnormalities alone with prior
therapy will not exclude patients from this trial).

- Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST
1.1.

- Male or female subjects aged greater than or equal to 18 years

-- Because no dosing or adverse event data are currently available on the use of
Avelumab in patients <18 years of age, children are excluded from this study, but will
be eligible for future pediatric trials.

- ECOG performance status less than or equal to 1.

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count: greater than or equal to 1,500/mm^3 OR greater than or
equal to 1.5 x 10^9/L

- platelets greater than or equal to 100,000/mm^3 OR greater than or equal to 100 x
10^9/L

- hemoglobin greater than or equal to 9g/dL (may have been transfused)

- total bilirubin less than or equal to 1.5 x the upper limit of normal range(ULN)

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 x ULN OR less than or equal to 5 x
ULN for subjects with documented metastatic disease to the liver

- creatinine clearance greater than or equal to 30 mL/min according to the
Cockcroft Gault formula (or local institutional standard method)

- Highly effective contraception for both male and female subjects if the risk of
conception exists. (Note: The effects of the study drug on the developing human fetus
are unknown. Thus, women of childbearing potential and men must agree to use highly
effective contraception, defined as 2 barrier methods, or 1 barrier method with a
spermicide, an intrauterine device or use of oral female

contraceptive. Effective contraception must be used 30 days prior to first study drug
administration, for the duration of trial participation, and at least for 30 days after
last avelumab treatment administration if the risk of conception exists. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating in
this trial, the treating physician should be informed immediately.)

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

EXCLUSION CRITERIA:

- Concurrent treatment with a non-permitted drug

- Concurrent anticancer treatment within 28 days before the start of trial treatment
(e.g., cytoreductive therapy, radiotherapy [with the exception of palliative bone
directed radiotherapy], immune therapy, or cytokine therapy except for
erythropoietin); major surgery within 28 days before the start of trial treatment
(excluding prior diagnostic biopsy); concurrent systemic therapy with
immunosuppressive agents within 28 days before the start of trial treatment; use of
hormonal agents within 7 days before the start of trial treatment; or use of any
investigational drug within 28 days before the start of trial treatment.

- History of previous malignant disease within the last 2 years with the following
exceptions: basal or squamous cell carcinoma of the skin, cervical carcinoma in situ,
ductal carcinoma in situ of the breast, papillary or follicular thyroid carcinoma, and
non-muscle invasive bladder cancer.

- Active autoimmune disease that might deteriorate when receiving an immunestimulatory
agent. Patients with diabetes type 1, vitiligo, psoriasis, pure red cell aplasia, Good
s syndrome or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment
are eligible.

- Patients with symptomatic brain metastases will be excluded from trial secondary to
poor prognosis. However, patients who have had treatment for their brain metastasis
and whose brain disease has remained stable for 3 months without steroid therapy may
be enrolled.

- Active infection requiring systemic therapy or significant acute or chronic infections
including, among others:

- 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).

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

- Prior organ transplantation including allogenic stem-cell transplantation.

- 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 greater than or equal to 3).

- Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1) however,
alopecia, sensory neuropathy Grade less than or equal to 2, or other Grade less than
or equal to 2 not constituting a safety risk based on investigator s judgment are
acceptable.

- Pregnancy or lactation period. Note: a negative pregnancy test is required for women
of childbearing potential. Women who are postmenopausal (age-related amenorrhea
greater than or equal to 12 consecutive months or follicle-stimulating hormone (FSH) >
40 milli international units per milliliter [mIU/ml]), or who had undergone
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary
to confirm postmenopausal status a FSH level will be included at screening.

- Pregnant women are excluded from this study because Avelumab is in the class of agents
known as antineoplastics/monoclonal antibodies with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in

nursing infants secondary to treatment of the mother with Avelumab, breastfeeding should be
discontinued if the mother is treated with Avelumab.

- Known alcohol or drug abuse.

- 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 greater than or equal
to New York Heart Association Classification Class II, or serious cardiac arrhythmia
requiring medication.

- All 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.

- Any psychiatric condition that would prohibit the understanding or rendering of
informed consent.

- Legal incapacity or limited legal capacity.

- Non-oncology vaccine therapies for prevention of infection disease (e.g. seasonal flu
vaccine, human papilloma virus vaccine) within 4 weeks of study drug administration.
Vaccination while on study is also prohibited except for administration of inactivated
vaccines (e.g. inactivated influenza vaccines).

- HIV-positive TET patients are ineligible because of the risk of developing
opportunistic infections after treatment with an immune checkpoint inhibitor. Prior
cases of disseminated herpes virus and fungal infections have been documented in this
patient population.