Pemetrexed and Avelumab in Treating Patients With MTAP-Deficient Metastatic Urothelial Cancer
Pemetrexed and Avelumab in Treating Patients With MTAP-Deficient Metastatic Urothelial Cancer
This phase II trial studies how well pemetrexed and avelumab work in treating patients with
 MTAP-deficient urothelial cancer that has spread to other places in the body. Pemetrexed may
 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
 Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system
 attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
 Giving pemetrexed and avelumab may work better in treating patients with MTAP-deficient
 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 including peripheral T-cells, tumor-infiltrating T-cells, macrophages, and
 myeloid-derived suppressor cells (MDSCs).

 OUTLINE:

 Patients receive pemetrexed intravenously (IV) over 10 minutes on day 1. Starting cycle 2,
 patients also receive avelumab IV over 60 minutes. Cycles repeat every 21 days in the absence
 of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 and 120 days, and then
 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.

 -  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.

 -  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 measured using
 a 24 hour urine, calculated using Cockcroft-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.

 -  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), or serious cardiac arrhythmia requiring
 medication.

 -  Persisting toxicity related to prior therapy (National Cancer Institute [NCI] Common
 Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0 grade > 1); however,
 alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety
 risk based on investigator's judgment are acceptable.

 -  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.