Pemetrexed Disodium in Treating Patients With Previously Treated Metastatic Urothelial Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well pemetrexed disodium works in treating patients with previously treated urothelial cancer that has spread from the primary site (place where it started) to other places in the body. Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: To determine the objective response rates (ORR) to pemetrexed disodium (pemetrexed) in patients with MTAP-deficient metastatic bladder cancer. SECONDARY OBJECTIVES: I. To determine the progression-free survival (PFS) for patients with MTAP-deficient metastatic bladder cancer treated with pemetrexed. II. To determine the overall survival (OS) for patients with MTAP-deficient metastatic bladder cancer treated with pemetrexed. III. Evaluate the toxicity of pemetrexed therapy for patients with MTAP-deficient metastatic bladder cancer. IV. Collect blood, urine, and tissue for future translational studies. OUTLINE: Patients receive pemetrexed disodium intravenously (IV) over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3 weeks and then every 3 months for 5 years.

Official Title
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A Phase II Trial to Evaluate Pemetrexed Clinical Responses in Relation to Tumor MTAP Gene Status in Patients With Previously Treated Metastatic Urothelial Carcinoma

Conditions
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Metastatic Urothelial Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Pemetrexed Disodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histological confirmation of metastatic urothelial carcinoma; patients must have sufficient tumor tissues for future MTAP testing and research; histological variants such as glandular, squamous, sarcomatoid, micropapillary, plasmacytoid, and small cell changes will not be allowed for this trial unless these tumors are MTAP-deficient All patients must have measurable disease 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 who have received any non-anti-folate containing neoadjuvant or systemic chemotherapy are eligible; any prior intravesical therapy, or immunotherapy is allowed Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit normal (ULN), or =< 5 x 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) >= 1500 Platelets >= 100,000 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 Modification of Diet in Renal Disease [MDRD] method from the National Kidney Disease Education Program [NKDEP] [the method reported by M D Anderson Cancer Center (MDACC) laboratories]) 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 Females of childbearing potential must also refrain from egg cell donation for 180 days after the final dose of investigational product; Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause) A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly; the acceptable methods of contraception are: barrier method (e.g. male condom with spermicide, copper T intrauterine device, or levonorgestrel-releasing intrauterine system - Mirena) or hormonal methods (e.g. implants, hormone shot or injection, combined pill, minipill, or patch); non-sterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from days 1-180 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 antiinflammatory drug (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 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 3 months following prior treatment (radiotherapy or surgery) Patients who received previous anti-folate-containing chemotherapy Any other malignancy from which the patient has been disease-free for less than 3 years, except for non-melanoma skin cancer, controlled localized prostate cancer, in situ carcinoma of any site Women who are pregnant or breastfeeding 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pemetrexed disodium)<br>Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates | Will be defined as the number of subjects with complete response or partial response by Response Assessment in Solid Tumors 1.1 criteria divided by the total number of subjects receiving their first dose of trial therapy. Objective response rates will be summarized using descriptive statistics. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival will be estimated and plotted with the methods of Kaplan and Meier. | Time from trial entry to the first documented tumor progression as determined by the investigator using the Response Evaluation Criteria in Solid Tumors 1.1 criteria or death from any cause, assessed at 2 years | 
| Overall Survival | Overall survival will be estimated and plotted with the methods of Kaplan and Meier. | Time from trial entry to death from any cause, assessed at 2 years |