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

NCT06630416 | Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: NU 24MH03NCI-2024-07862STU00222531P30CA060553
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 2

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

Outcome Measures

Primary Outcomes (1)

• 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.

  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

Secondary Outcomes (4)

• Progression-free survival (PFS)

  Time from the start of treatment to the first documented progression or death from any cause, whichever comes first, assessed up to 12 months

• Overall survival (OS)

  Time from the start of treatment to death from any cause, assessed up to 12 months

• Duration of response (DOR)

  Time from first response (complete or partial) until progression or death, assessed up to 12 months

• Incidence of adverse events

  Up to 12 months

Study Arms (1)

Treatment (pemetrexed)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Pemetrexed

Interventions

Biospecimen Collection PROCEDURE

Undergo blood and urine sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (pemetrexed)

Pemetrexed DRUG

Given IV

Also known as: MTA, Multitargeted Antifolate, Pemfexy

Treatment (pemetrexed)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (pemetrexed)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have pathologically or cytologically confirmed metastatic urothelial bladder carcinoma (Arm A) or other metastatic solid malignancy (Arm B) and MLL4-protein (KMT2D-gene) and UTX-protein (KDM6A-gene) or MTAP loss of function mutation including but not limited to single nucleotide variant (SNVs) that cause truncation, copy number variations (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 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 4 weeks (28 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
• 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

You may not qualify if:

• Patients who received prior pemetrexed containing chemotherapy
• Patients who have had chemotherapy or radiotherapy ≤ 28 days (prior to planned treatment 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 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 28 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

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Northwestern University

Chicago, Illinois, 60611, United States

RECRUITING

Northwestern Medicine Orland Park

Orland Park, Illinois, 60462, United States

RECRUITING

MeSH Terms

Conditions

Neoplasm Metastasis; Urinary Bladder Neoplasms

Interventions

Specimen Handling; Pemetrexed

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• Devalingam Mahalingam

  Northwestern University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Study Coordinator, MD, PhD

CONTACT

3126951301; cancer@northwestern.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 4, 2024
• First Posted: October 8, 2024
• Study Start: November 27, 2024
• Primary Completion (Estimated): May 10, 2029
• Study Completion (Estimated): May 10, 2030
• Last Updated: February 24, 2026

Record last verified: 2026-02

Locations

US (2)