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

PRIMARY OBJECTIVES:

I. To evaluate the response rate (RR) in patients with (methylthioadenosine phosphorylase)
MTAP-deficient metastatic urothelial cancer treated sequentially with pemetrexed and
avelumab.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) and overall survival (OS) in patients with
MTAP-deficient metastatic urothelial cancer treated sequentially with pemetrexed and
avelumab.

II. To explore the effect of pemetrexed +/- avelumab on the immune system and tumor
microenvironment.

OUTLINE:

Patients receive pemetrexed intravenously (IV) over 10 minutes on day 1. Starting course 2,
patients also receive avelumab IV over 5-15 minutes. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Patients must have histologic confirmation of MTAP-deficient metastatic urothelial
carcinoma. MTAP-deficiency must be verified by institutional Clinical Laboratory
Improvement Act (CLIA)-certified immunohistochemistry (IHC). Histological variants
such as glandular, squamous, sarcomatoid, micropapillary, plasmacytoid, and small cell
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 immune
checkpoint inhibitor with PD-[L]1 agent) or for third line of therapy (can have
previously received chemotherapy and immune checkpoint inhibitor with PD-[L]1
blockade). Any prior intravesical therapy is allowed and does not count as a prior
line of therapy.

- Patients who received methotrexate-containing chemotherapy (e.g.
methotrexate/vinblastine/adriamycin/cisplatin [MVAC]) as neoadjuvant therapy or
first-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 Solid
Tumors (RECIST) version (v)1.1 and tumors of sufficient sizes for biopsy. In general,
liver and lung lesions should be at least 1.0 cm, and patients with lymph node-only
disease should have lesions of >= 1.5 cm in shortest dimension. Patients with disease
confined to bone may be eligible if a measurable lytic defect is present. The study
principal investigator (PI) is the final arbiter in questions related to
measurability. Patients with a three-dimensional mass or pelvic sidewall fixation on
bladder examination under anesthesia are considered to have measurable disease.

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

- Adequate liver function as defined by aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) =< 2.5 x upper limit 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 liver
metastases, who must have a baseline total bilirubin =< 3.0 mg/dL.

- Adequate bone marrow reserves as define by an absolute neutrophil count (ANC) >= 1.5 x
10^9/L, hemoglobin >= 9 g/dL (may have been transfused), and platelets >= 100 x
10^9/L.

- Adequate renal function as defined by a normal serum creatinine, or a creatinine
clearance >= 40 ml/min [either measured using a 24 hour urine, calculated using
Cockroft-Gault, or estimated using the MDRD method from the National Kidney Disease
Education Program (NKDEP) (the method reported by MD Anderson Cancer Center [MDACC]
laboratories).

- Negative serum or urine pregnancy test at screening for women of child-bearing
potential.

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

- Non-sterilized males who are sexually active with a female partner of childbearing
potential 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 days after
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 of
Pemetrexed.

- The ability to take folic acid, vitamin B12, and dexamethasone according to protocol.

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

Exclusion Criteria:

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

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

- Women who are pregnant or breastfeeding or intend to become pregnant during their
participation in the study.

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

- Known or suspected autoimmune disease. Patients with a history of inflammatory bowel
disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders
such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic
lupus erythematosus or autoimmune vasculitis [e.g., Wegener's granulomatosis] are
excluded from this study.

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

- History of primary immunodeficiency.

- Patients who have prior organ transplantation, including allogeneic stem-cell
transplant.

- Vaccinations within 4 weeks of the first dose of avelumab and while on trials is
prohibited 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 known
acquired immunodeficiency syndrome (AIDS).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, current pneumonitis, symptomatic congestive heart failure, unstable angina
pectoris, symptomatic cardiac arrhythmia, or interstitial lung disease.

- Uncontrolled psychiatric illness/social situations that would limit compliance with
study requirements or compromise the ability of the subject to give written informed
consent.

- Known allergy or hypersensitivity to study drug formulations.

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

- Patient currently on dialysis.