Pemetrexed Response in Relation to Tumor Alterations of Gene Status for the Treatment of Patients With Metastatic Urothelial Bladder Cancer and Other Solid Tumors
- Registration Number
- NCT06630416
- Lead Sponsor
- Northwestern University
- 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 ...
- Detailed Description
PRIMARY OBJECTIVE:
I. To determine the overall response rate (ORR) in patients with metastatic solid tumors and MLL4-protein (KMT2D-gene) and UTX-protein (KDM6A-gene) or MTAP loss of function mutations treated with pemetrexed will assess pemetrexed.
SECONDARY OBJECTIVES:
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Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 64
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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
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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
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Patients who have received any prior neoadjuvant or systemic chemotherapy are eligible.
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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
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Patients must be aged ≥ 18 years
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Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
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Absolute neutrophil count (ANC) ≥ 1,500/mcL (growth factor allowed and can be added at the discretion of the treating oncologist)
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Hemoglobin (Hgb) ≥ 8.5 g/dL (without the need for transfusion within the previous one week)
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Platelets (PLT) ≥ 100,000/mL (without the need for platelet transfusion within the previous one week)
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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
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Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ≤ 3 x institutional ULN or ≤ 5 x ULN if documented liver metastases are present
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Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN or ≤ 5 x ULN if documented liver metastases are present
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Creatinine clearance ≥ 45 mL/min/1.73 m^2 using the standard Cockcroft and Gault formula
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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
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Patients must be able swallow oral medication or not have problems/diseases that affect absorption or oral medication
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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
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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
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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
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Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
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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
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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)
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POCBP must have a negative pregnancy test prior to registration on study
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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
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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
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Patients who received prior pemetrexed containing chemotherapy
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Patients who have had chemotherapy or radiotherapy ≤ 28 days (prior to planned treatment start date)
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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)
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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
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Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pemetrexed
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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
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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
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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
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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
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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
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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
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment (pemetrexed) Biospecimen Collection 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. Treatment (pemetrexed) Computed Tomography 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. Treatment (pemetrexed) 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.
- Primary Outcome Measures
Name Time Method Overall response rate (ORR) 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 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...
- Secondary Outcome Measures
Name Time Method 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 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, pro...
Overall survival (OS) Time from the start of treatment to death from any cause, assessed up to 12 months 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) Time from first response (complete or partial) until progression or death, assessed up to 12 months 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 Up to 12 months 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.
Trial Locations
- Locations (1)
Northwestern University
🇺🇸Chicago, Illinois, United States