Pemetrexed Response in Relation to Tumor Alterations of Gene Status for the Treatment of Patients With Metastatic Urothelial Bladder Cancer and Other Solid Tumors

Inclusion Criteria:

• Patients must have pathologically or cytologically confirmed metastatic urothelialbladder carcinoma (Arm A) or other metastatic solid malignancy (Arm B) andMLL4-protein (KMT2D-gene) and UTX-protein (KDM6A-gene) or MTAP loss of functionmutation including but not limited to single nucleotide variant (SNVs) that causetruncation, copy number variations (CNVs), and indels confirmed by next generationsequencing or immunohistochemistry techniques

• Patients must have at least 1 measurable lesion per Response Evaluation Criteria inSolid Tumors version 1.1 (RECIST v1.1), measured preferably by computed tomography (CT) scan

• Patients who have received any prior neoadjuvant or systemic chemotherapy areeligible.

• Notes:

• Patients must have progressive disease despite two prior lines of therapyin the metastatic setting unless the patient was not suitable for anapproved second line regimen due to intolerance or another clinicalfactor;

• Treatment cannot have included prior pemetrexed. Any prior intravesicaltherapy, or immunotherapy is allowed. At least 4 weeks (28 days) wash-outperiod since prior chemotherapy or radiation therapy or targeted agent isrequired

• Patients must be aged ≥ 18 years

• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0-2

• Absolute neutrophil count (ANC) ≥ 1,500/mcL (growth factor allowed and can be addedat the discretion of the treating oncologist)

• Hemoglobin (Hgb) ≥ 8.5 g/dL (without the need for transfusion within the previousone week)

• Platelets (PLT) ≥ 100,000/mL (without the need for platelet transfusion within theprevious one week)

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), except subjectswith Gilbert's syndrome or liver metastases, who must have a baseline totalbilirubin ≤ 3.0 mg/dL

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ≤ 3 x institutional ULN or ≤ 5 x ULN if documented liver metastases are present

• Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 3 xinstitutional ULN or ≤ 5 x ULN if documented liver metastases are present

• Creatinine clearance ≥ 45 mL/min/1.73 m^2 using the standard Cockcroft and Gaultformula

• Patients must have the ability to comply with the administration of supplementaltherapies including folic acid, vitamin B12 and steroids as directed by study teamand as per standard of care and institutional standards and practice for pemetrexeduse

• Patients must be able swallow oral medication or not have problems/diseases thataffect absorption or oral medication

• Patients with a known history of human immunodeficiency virus (HIV), infectedpatients on effective anti-retroviral therapy must have a viral load undetectablefor 6 months prior to registration. Please note this lab is not a requirement foreligibility, however, if it was previously done as part of the patient's healthcare, it should be documented for eligibility

• Patients with a known history of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated. Please notethis lab is not a requirement for eligibility, however, if the lab has beencompleted previously as part of the patient's health care, then it should bedocumented for eligibility

• Patients with a known history of hepatitis C virus (HCV) infection must have beentreated and cured. For patients with a known HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load. Pleasenote this lab is not a requirement for eligibility, however if it was previouslydone as part of the patient's health care, it should be documented for eligibility

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Pemetrexed is known to be teratogenic. For this reason, patients of child-bearingpotential (POCBP) and their partners with sperm-producing reproductive capacity mustagree to use adequate contraception from time of informed consent, for the durationof study participation, and for 180 days following completion of pemetrexed therapy.Should a POCBP become pregnant or suspect they are pregnant while they or theirpartner are participating in this study, they should inform their treating physicianimmediately. Patients with sperm-producing reproductive capacity (PWSPRC) treated orenrolled on this protocol must also agree to use adequate contraception withpartners of childbearing potential from time of informed consent, for the durationof study participation, and 180 days after completion of administration

• Note: A POCBP is any patient (regardless of gender, sexual orientation, havingundergone a tubal ligation, or remaining celibate by choice) with anegg-producing reproductive tract who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy

• Has had menses at any time in the preceding 12 consecutive months (andtherefore has not been naturally postmenopausal for > 12 months)

• POCBP must have a negative pregnancy test prior to registration on study

• The ability to interrupt nonsteroidal anti-inflammatory drugs (NSAIDS) or aspirin athigher dose (> 1.3 g per day) 2 days before (5 days for long-acting NSAIDs), the dayof, and 2 days following administration of pemetrexed

• Patients must be able to understand and voluntarily sign a written informed consentand willing and able to comply with the protocol requirements including scheduledvisits, treatment plan, laboratory tests and other study procedures

Exclusion Criteria:

• Patients who received prior pemetrexed containing chemotherapy

• Patients who have had chemotherapy or radiotherapy ≤ 28 days (prior to plannedtreatment start date)

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia,neuropathy and other non-significant adverse events deemed not clinicallysignificant by the treating investigator, adverse events per National CancerInstitute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v 5.0)

• Patients who are receiving any other investigational agents. A 28 day wash outperiod will be required after discontinuation of an investigational agent prior tofirst day of study treatment

• Patients who have a history of allergic reactions attributed to compounds of similarchemical or biologic composition to pemetrexed

• Patients who have an uncontrolled intercurrent illness including, but not limited toany of the following:

• Ongoing or active infection requiring systemic treatment

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Any other illness or condition that the treating investigator feels wouldinterfere with study compliance or would compromise the patient's safety orstudy endpoints

• Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or efficacy assessment of theinvestigational regimen

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification

• Note: To be eligible for this trial, patients should be class 2B or better

• Patients with presence of third space fluid which cannot be controlled by drainage

• Note: For patients who develop or have baseline clinically significant pleuralor peritoneal effusions (on the basis of symptoms or clinical examination)before or during initiation of pemetrexed therapy, consideration should begiven to draining the effusion prior to dosing. However, if, in theinvestigator's opinion, the effusion represents progression of disease, thepatient should be discontinued from study therapy

• Has received the final dose of any of the following treatments/ procedures with thespecified minimum intervals before first dose of study drug:

• Focal radiation therapy - 7 days

• Surgery with general anesthesia - 7 days

• Surgery with local anesthesia - 3 days

• Patients of child bearing (POCB) potential who are pregnant or nursing.

• Note: Registration of patients is completed in Northwestern Oncology TrialInformation System (NOTIS)