Pemetrexed and Avelumab in Treating Patients With MTAP-Deficient Metastatic Urothelial Cancer

Inclusion Criteria:

• Patients must have histologic confirmation of MTAP-deficient metastatic urothelialcarcinoma. MTAP-deficiency must be verified by institutional Clinical LaboratoryImprovement Act (CLIA)-certified immunohistochemistry (IHC). Histological variantssuch as glandular, squamous, sarcomatoid, micropapillary, plasmacytoid, and smallcell changes will be allowed for this trial if these tumors are MTAP-deficient.

• Patients can be considered for second line of therapy (after chemotherapy or immunecheckpoint inhibitor with PD-[L]1 agent) or for third line of therapy (can havepreviously received chemotherapy and immune checkpoint inhibitor with PD-[L]1blockade). Any prior intravesical therapy is allowed and does not count as a priorline of therapy.

• Patients who received methotrexate-containing chemotherapy (e.g.methotrexate/vinblastine/adriamycin/cisplatin [MVAC]) as neoadjuvant therapy orfirst-line systemic therapy at least 12 months prior will be allowed for this trial.

• All patients must have measurable disease by Response Evaluation Criteria in SolidTumors (RECIST) version (v)1.1 and tumors of sufficient sizes for biopsy. Ingeneral, liver and lung lesions should be at least 1.0 cm, and patients with lymphnode-only disease should have lesions of >= 1.5 cm in shortest dimension. Patientswith disease confined to bone may be eligible if a measurable lytic defect ispresent. The study principal investigator (PI) is the final arbiter in questionsrelated to measurability. Patients with a three-dimensional mass or pelvic sidewallfixation on bladder examination under anesthesia are considered to have measurabledisease.

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2.

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x upperlimit of normal (ULN), or =< 5 ULN if documented liver metastases are present.

• Total bilirubin =< 1.5 x ULN, except subjects with Gilbert's syndrome or livermetastases, who must have a baseline total bilirubin =< 3.0 mg/dL.

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

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

• Platelets >= 100 x 10^9/L.

• Normal serum creatinine, or a creatinine clearance >= 40 ml/min [either measuredusing a 24 hour urine, calculated using Cockcroft-Gault, or estimated using the MDRDmethod from the National Kidney Disease Education Program (NKDEP) (the methodreported by MD Anderson Cancer Center [MDACC] laboratories).

• Negative serum or urine pregnancy test at screening for women of child-bearingpotential.

• Females of childbearing potential who are sexually active with a non-sterilized malepartner and non-sterilized males must use a highly effective method of contraceptionfor 28 days prior to the first dose of investigational product, and must agree tocontinue using such precautions for 180 days after the final dose of investigationalproduct; cessation of contraception after this point should be discussed with aresponsible physician. They must also refrain from egg cell donation for 180 daysafter the final dose of investigational product.

• Non-sterilized males who are sexually active with a female partner of childbearingpotential must use a highly effective method of contraception from days 1 through 180 post last dose. In addition, they must refrain from sperm donation for 180 daysafter the final dose of investigational product.

• The ability to interrupt nonsteroidal anti-inflammatory drugs (NSAIDS) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration ofpemetrexed.

• The ability to take folic acid, vitamin B12, and dexamethasone according toprotocol.

• Mild autoimmune conditions (such as localized psoriasis) requiring minimal treatmentor systemic autoimmune conditions well controlled by target agents such as ananti-IL-17 that do not affect overall immune system. Patients with a history ofHashimoto's thyroiditis only requiring hormone replacement, type I diabetes, orconditions not expected to recur in the absence of an external trigger are allowedto participate.

Exclusion Criteria:

• Primary central nervous system (CNS) malignancies or CNS metastases, includingleptomeningeal metastases, are not allowed. Subjects with previously treated brainmetastases will be allowed if the brain metastases have been stable for at least 4weeks following prior treatment and no ongoing steroid requirement.

• Any other malignancy from which the patient has been disease-free for less than 2years, except for non-melanomatous skin cancer, controlled localized prostatecancer, in situ carcinoma of any site.

• Women who are pregnant or breastfeeding or intend to become pregnant during theirparticipation in the study.

• Presence of third space fluid which cannot be controlled by drainage. For patientswho develop or have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before or during initiation ofpemetrexed therapy, consideration should be given to draining the effusion prior todosing. However, if, in the investigator's opinion, the effusion representsprogression of disease, the patient should be discontinued from study therapy.

• Known or suspected autoimmune disease. Patients with a history of inflammatory boweldisease (including Crohn's disease and ulcerative colitis) and autoimmune disorderssuch as rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemiclupus erythematosus or autoimmune vasculitis (e.g., Wegener's granulomatosis) areexcluded from this study.

• Any condition requiring systemic treatment with corticosteroids (> 10 mg dailyprednisone equivalents) or other immunosuppressive medications within 14 days priorto first dose of study drug. Inhaled steroids and adrenal replacement steroids doses > 10 mg daily prednisone equivalents are permitted in the absence of activeautoimmune disease.

• History of primary immunodeficiency.

• Patients who have prior organ transplantation, including allogeneic stem-celltransplant.

• Vaccinations within 4 weeks of the first dose of avelumab and while on trials isprohibited except for administration of inactivated vaccines.

• True positive test results for hepatitis A, B, or C during screening.

• Known history of testing positive for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS).

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, current pneumonitis, symptomatic congestive heart failure, unstableangina pectoris, symptomatic cardiac arrhythmia, or interstitial lung disease.

• 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.

• Persisting toxicity related to prior therapy (National Cancer Institute [NCI] CommonTerminology Criteria for Adverse Events [CTCAE] version [v.] 5.0 grade > 1);however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 notconstituting a safety risk based on investigator's judgment are acceptable.

• Uncontrolled psychiatric illness/social situations that would limit compliance withstudy requirements or compromise the ability of the subject to give written informedconsent.

• Known allergy or hypersensitivity to study drug formulations.

• Major surgical procedure (as defined by the PI or co-PIs within 28 days prior to thefirst dose of therapy) or still recovering from prior surgery.

• Patient currently on dialysis.