Trial Title:
Pemetrexed Response in Relation to Tumor Alterations of Gene Status for the Treatment of Patients With Metastatic Urothelial Bladder Cancer and Other Solid Tumors
NCT ID:
NCT06630416
Condition:
Metastatic Bladder Urothelial Carcinoma
Metastatic Malignant Solid Neoplasm
Stage IV Bladder Cancer AJCC v8
Conditions: Official terms:
Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Pemetrexed
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood and urine sample collection
Arm group label:
Treatment (pemetrexed)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (pemetrexed)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Drug
Intervention name:
Pemetrexed
Description:
Given IV
Arm group label:
Treatment (pemetrexed)
Other name:
MTA
Other name:
Multitargeted Antifolate
Other name:
Pemfexy
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.
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:
I. To determine the progression-free survival (PFS) for patients with metastatic solid
tumors and MLL4-protein (KMT2D-gene) and UTX-protein (KDM6A-gene) or MTAP loss of
function mutations treated with pemetrexed.
II. To determine the overall survival (OS) for patients with metastatic solid tumors and
MLL4-protein (KMT2D-gene) and UTX-protein (KDM6A-gene) or MTAP loss of function mutations
treated with pemetrexed.
III. To determine the duration of response (DOR) for patients with metastatic solid
tumors and MLL4-protein (KMT2D-gene) and UTX-protein (KDM6A-gene) or MTAP loss of
function mutations treated with pemetrexed.
IV. To assess safety and tolerability of pemetrexed in patients with metastatic solid
treated with pemetrexed.
EXPLORATORY OBJECTIVE:
I. To collect plasma and urine samples for future translational studies to determine
mechanisms of resistance to pemetrexed.
OUTLINE:
Patients receive pemetrexed intravenously (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 computed
tomography (CT) throughout the trial.
After completion of study treatment, patients are followed up every 3 months for up to 12
months.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- 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
- 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 ≤ 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
- 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
- Patients of child bearing (POCB) potential who are pregnant or nursing.
- Note: Registration of patients is completed in Northwestern Oncology Trial
Information System (NOTIS)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Northwestern University
Address:
City:
Chicago
Zip:
60611
Country:
United States
Contact:
Last name:
Devalingam Mahalingam
Phone:
210-413-1723
Email:
mahalingam@northwestern.edu
Investigator:
Last name:
Devalingam Mahalingam
Email:
Principal Investigator
Start date:
May 10, 2025
Completion date:
May 10, 2031
Lead sponsor:
Agency:
Northwestern University
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
Northwestern University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06630416
