Recruiting

Phase 2

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

Sponsor:

Northwestern University

Code:

NCT06630416

Conditions

Metastatic Bladder Urothelial Carcinoma

Metastatic Malignant Solid Neoplasm

Stage IV Bladder Cancer AJCC v8

MTAP Deletion

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Biospecimen Collection

Computed Tomography

Pemetrexed

Study Details

Brief summary:

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.

Conditions

Metastatic Bladder Urothelial Carcinoma

Metastatic Malignant Solid Neoplasm

Stage IV Bladder Cancer AJCC v8

MTAP Deletion

Study ID

NCT06630416

Start date

Nov 27, 2024

Status verified date

Jun, 2026

Completion date

May 10, 2030

Anticipated

Primary completion date

May 10, 2029

Anticipated

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

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.

Notes:

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;
Treatment cannot have included prior pemetrexed. Any prior intravesical therapy, or immunotherapy is allowed. At least 3 weeks (21 days) wash-out period since prior chemotherapy or radiation therapy or targeted agent is required.
Patients must be aged ≥ 18 years.
Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
Patients must have adequate organ and bone marrow function as defined:
Absolute neutrophil count (ANC) ≥ 1,500/mcL (growth factor allowed and can be added at the discretion of the treating oncologist)
Hemoglobin (Hgb) ≥ 8.5 g/dL (without the need for transfusion within the previous one week)
Platelets (PLT) ≥ 100,000/mL (without the need for platelet transfusion within the previous one week)
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), except subjects with Gilbert's syndrome or liver metastases, who must have a baseline total bilirubin ≤ 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 x institutional 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 Gault formula
Patients must have the ability to comply with the administration of supplemental therapies including folic acid, vitamin B12 and steroids as directed by study team and as per standard of care and institutional standards and practice for pemetrexed use.
Patients must be able swallow oral medication or not have problems/diseases that affect absorption or oral medication.
Patients with a known history of human immunodeficiency virus (HIV), infected patients on effective anti-retroviral therapy must have a viral load undetectable for 6 months prior to registration. Please note this lab is not a requirement for eligibility, however, if it was previously done as part of the patient's health care, it should be documented for eligibility.
Patients with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Please note this lab is not a requirement for eligibility, however, if the lab has been completed previously as part of the patient's health care, then it should be documented for eligibility.
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with a known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Please note this lab is not a requirement for eligibility, however if it was previously done 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 after central nervous system (CNS)-directed therapy shows no evidence of progression.
Pemetrexed is known to be teratogenic. For this reason, patients of child-bearing potential (POCBP) and their partners with sperm-producing reproductive capacity must agree to use adequate contraception from time of informed consent, for the duration of study participation, and for 180 days following completion of pemetrexed therapy. Should a POCBP become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. Patients with sperm-producing reproductive capacity (PWSPRC) treated or enrolled on this protocol must also agree to use adequate contraception with partners of childbearing potential from time of informed consent, for the duration of study participation, and 180 days after completion of administration

Note: A POCBP is any patient (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) with an egg-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 (and therefore 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 at higher dose (> 1.3 g per day) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed.
Patients must be able to understand and voluntarily sign a written informed consent and willing and able to comply with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

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.
Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pemetrexed.
Patients who have an uncontrolled intercurrent illness including, but not limited to any 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 would interfere with study compliance or would compromise the patient's safety or study endpoints
Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function 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 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
Has received the final dose of any of the following treatments/ procedures with the specified 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
For palliative radiation - 5 days
Patients of child bearing (POCB) potential who are pregnant or nursing.

Note: Registration of patients is completed in Northwestern Oncology Trial Information System (NOTIS)

Study Design

Enrollment

64 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (pemetrexed)

Patients receive pemetrexed IV over 10 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and urine sample collection on study as well as CT throughout the trial.

Interventions

Biospecimen Collection

Undergo blood and urine sample collection

Computed Tomography

Undergo CT

Pemetrexed

Given IV

Primary outcome measure

Overall response rate (ORR) [ Time Frame: From baseline until the subject experiences disease progression, the subject initiates subsequent anti-cancer therapy, or the subject completes study participation (whichever occurs first), assessed up to 12 months ]

Central Contacts and Locations

Central contacts

Study Coordinator, MD, PhD

3126951301 cancer@northwestern.edu

Locations

Northwestern University

Recruiting

Chicago, Illinois, United States, 60611

Contacts

Devalingam Mahalingam, MD, PhD

3126951301 mahalingam@northwestern.edu

Principal Investigator:

Devalingam Mahalingam, MD, PhD

Northwestern Medicine Orland Park

Recruiting

Orland Park, Illinois, United States, 60462

Contacts

Study Coordinator

3126951301 cancer@northwestern.edu

Principal Investigator:

Devalingam Mahalingam, MD, PhD

More Information

Sponsor

Northwestern University

Last update posted

Jun 12, 2026

Last verified

Jun, 2026

Keywords

KMT2D (gene)/MLL4 (protein) or KDM6A (gene)/UTX (protein) or MTAP loss of function mutations

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by Northwestern University on 2026-06-12.