This phase II trial tests how well pemetrexed works in treating patients with urothelial bladder cancer and other solid tumors that have spread from where they first started (primary site) to other places in the body (metastatic) with mutations that result in a loss of function in the MLL4-protein/KMT2D-gene or UTX-protein/KDM6A-gene or MTAP enzyme. Loss of function due to a genetic mutation means a gene's activity may be reduced or eliminated. Mutations that result in a loss of function in the MLL4-protein or KMT2D-gene are found in 9.96% of all cancers including bladder carcinoma patients, esophageal squamous cell carcinoma and esophageal adenocarcinoma patients. In addition, mutations that result in a loss of function in the UTX-protein or KDM6A-gene are found in approximately 5% of all tumors, including bladder cancers, endometrial cancer, and esophagogastric cancer amongst many other tumor types. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make deoxyribonucleic acid and may kill tumor cells. Giving pemetrexed may increase response in patients with metastatic urothelial bladder cancer and other solid tumors with the loss of function in the MLL4-protein/KMT2D-gene or UTX-protein/KDM6A-gene or MTAP enzyme.
Patients must have pathologically or cytologically confirmed metastatic urothelial bladder carcinoma (Arm A) or other metastatic/locally-advanced solid malignancy (Arm B) and MLL4- protein (KMT2D-gene) or UTX-protein (KDM6A-gene) or MTAP loss of function mutation including but not limited to SNVs that cause truncation, CNVs, and indels confirmed by next generation sequencing or immunohistochemistry techniques.
Patients must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), measured preferably by computed tomography (CT) scan.
Patients who have received any prior neoadjuvant or systemic chemotherapy are eligible.
Patients must have progressive disease despite two prior lines of therapy in the metastatic setting or locally advanced setting unless the patient was not suitable for an approved second line regimen due to intolerance or another clinical factor;
Patients who received prior pemetrexed containing chemotherapy.
Patients who have had chemotherapy or radiotherapy ≤ 21 days (prior to planned treatment start date). For palliative radiation, 5 day wash out is sufficient.
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 clinically significant by the treating investigator, adverse events per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v 5.0).
Patients who are receiving any other investigational agents. A 21 day wash out period will be required after discontinuation of an investigational agent prior to first day of study treatment.
Single group
Biospecimen Collection
Procedure/SurgeryUndergo blood and urine sample collection
Computed Tomography
Procedure/SurgeryUndergo CT
Pemetrexed
DrugGiven IV
Overall response rate (ORR)
ORR is defined as the proportion of treated patients who experience an objective response (complete response \[CR\] or partial response \[PR\]). The date of first response for either CR or PR will be used to calculate ORR. Will be measured every 9 weeks +/- 10 days according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). CR and PR need to be confirmed by a subsequent scan. Will compute two-sided 90% confidence intervals (CIs) for ORR using the exact binomial method. The statistical significance of the ORR will be assessed using chi-square tests or Fisher's exact tests, depending on the sample size.
Progression-free survival (PFS)
Progression-free survival will be calculated as the time that elapses between the day of subject registration and the earlier of the day of first documented disease progression by clinical or radiographic evaluation or death from any cause, for all evaluable subjects. PFS will be analyzed using Kaplan-Meier survival analysis to estimate the survival distribution. The median PFS and corresponding 95% confidence intervals will be reported. Log-rank tests will be used to compare PFS between different subgroups. Additionally, Cox proportional hazards models will be used to evaluate the impact of various covariates on PFS, providing hazard ratios (HRs) and 95% CIs. For PFS analysis, disease progression is defined as experiencing progressive disease (PD) per RECIST 1.1 or death due to disease.
Overall survival (OS)
Overall survival time is calculated as the time that elapses between the day of subject registration and death from any cause, for all evaluable subjects. If death from any cause is not observed prior to completing study participation, the OS will be censored at the last known date alive. OS will be analyzed using Kaplan-Meier survival analysis. The median OS and corresponding 95% confidence intervals will be reported. Log-rank tests will be utilized to compare OS between different subgroups. Cox proportional hazards models will also be employed to assess the effect of covariates on OS, with results presented as HRs and 95% CIs.
Duration of response (DOR)
DOR will be assessed by disease progression, defined as experiencing progressive disease per RECIST v1.1, or death due to disease. If disease progression or death from any cause is not observed prior to initiating subsequent anti-cancer therapy the DOR will be censored as the last available disease assessment based on clinical or radiographic evaluation.
Incidence of adverse events
Will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and will be documented by clinical or radiographic evaluation or death from any cause.
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Northwestern University
Lead sponsor
National Cancer Institute (NCI)
Collaborator
