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

• INCLUSION CRITERIA:

• Participants must have histologically confirmed thymoma or thymic carcinoma by thepathology department/CCR/NCI.

• Participants must have had at least one prior line of platinum-based chemotherapy orparticipant must have refused cytotoxic chemotherapy. Progressive disease must bedocumented prior to study entry and participants must have advanced, unresectabledisease that is not amenable to surgical resection.

• Prior treatment of PD-1 or PD-L1-directed immune checkpoint blockade is permitted iftreatment was not discontinued due to disease progression or lifethreatening adverseevents per the investigators discretion (laboratory abnormalities alone with priortherapy will not exclude participants from this trial).

• Disease must be measurable with at least 1 unidimensional measurable lesion byRECIST 1.1.

• Individuals aged greater than or equal to 18 years

-- Because no dosing or adverse event data are currently available on the use ofAvelumab in participants <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.

• Participants must have normal organ and marrow function as defined below:

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

• platelets greater than or equal to 100,000/mm^3 OR greater than or equal to 100x 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 normalrange(ULN)

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

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

• Highly effective contraception for all individuals if the risk of conception exists. (Note: The effects of the study drug on the developing human fetus are unknown.Thus, individuals of childbearing potential and those able to father a child mustagree to use highly effective contraception, defined as 2 barrier methods, or 1barrier 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 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 ofchildbearing potential.

• Ability of individual to understand and the willingness to sign a written informedconsent document.

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 bonedirected radiotherapy], immune therapy, or cytokine therapy except forerythropoietin); major surgery within 28 days before the start of trial treatment (excluding prior diagnostic biopsy); concurrent systemic therapy withimmunosuppressive agents within 28 days before the start of trial treatment; use ofhormonal agents for the treatment of thymic cancer within 7 days before the start oftrial treatment; or use of any investigational drug within 28 days before the startof trial treatment.

--Note: Individuals receiving bisphosphonate or denosumab are eligible providedtreatment was initiated at least 14 days before the first dose of avelumab.

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

• Active autoimmune disease that might deteriorate when receiving animmune-stimulatory agent. Participants with diabetes type 1, vitiligo, psoriasis,pure red cell aplasia, Good s syndrome or hypo- or hyperthyroid diseases notrequiring immunosuppressive treatment are eligible. Anti-acetylcholine receptorantibodies will be checked during screening. Participants will be ineligible ifresults are positive, even if there is no clinical history of autoimmune disease.

• Participants with symptomatic brain metastases will be excluded from trial secondaryto poor prognosis. However, participants who have had treatment for their brainmetastasis and whose brain disease has remained stable for 3 months without steroidtherapy may be enrolled.

• Active infection requiring systemic therapy or significant acute or chronicinfections 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 testpositive).

• Known history of testing positive for HIV or known acquired immunodeficiencysyndrome.

• Prior organ transplantation including allogenic stem-cell transplantation.

• Known prior severe hypersensitivity to investigational product or any component inits formulations, including known severe hypersensitivity reactions to monoclonalantibodies (NCI CTCAE v5 Grade greater than or equal to 3).

• Persisting toxicity related to prior therapy (NCI CTCAE v5Grade > 1) however,alopecia, sensory neuropathy Grade less than or equal to 2, or other Grade less thanor equal to 2 not constituting a safety risk based on investigator s judgment areacceptable.

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

• Pregnant individuals are excluded from this study because Avelumab is in the classof agents known as antineoplastics/monoclonal antibodies with the potential forteratogenic or abortifacient effects. Because there is an unknown but potential riskfor 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 vascularaccident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 monthsprior to enrollment), unstable angina, congestive heart failure (>= New York HeartAssociation Classification Class II), or serious cardiac arrhythmia requiringmedication.

• All other severe acute or chronic medical conditions including immune colitis,inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatricconditions including recent (within the past year) or active suicidal ideation orbehavior; or laboratory abnormalities that may increase the risk associated withstudy participation or study treatment administration or may interfere with theinterpretation of study results and, in the judgment of the investigator, would makethe participants inappropriate for entry into this study.

• Any psychiatric condition that would prohibit the understanding or rendering ofinformed consent.

• Legal incapacity or limited legal capacity.

• Non-oncology vaccine therapies for prevention of infectious disease (e.g. seasonalflu vaccine, human papilloma virus vaccine) within 4 weeks of study drugadministration with the exception of vaccinations against COVID-19. Vaccinationwhile on study is also prohibited except for administration of inactivated vaccines (e.g. inactivated influenza vaccines) and vaccinations against COVID-19.

• HIV-positive TET participants are ineligible because of the risk of developingopportunistic infections after treatment with an immune checkpoint inhibitor. Priorcases of disseminated herpes virus and fungal infections have been documented inthis patient population.