Medication Combinations of Dasatinib, Quercetin, Fisetin and Temozolomide for the Treatment of Previously Treated Glioma with Residual Disease

Status: active

This early phase I trial tests the safety, side effects and how well medication combinations of dasatinib, quercetin, fisetin and temozolomide work in treating patients with glioma for which the patient has received treatment in the past (previously treated) and for tumor cells that remain after attempts to treat the tumor have been made (residual disease). Dasatinib is in a class of medications called tyrosine kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply, which may help keep tumor cells from growing. Quercetin and fisetin are compounds found in plants. They have antioxidant and anti-inflammatory properties and help remove senescent cells, older or damaged cells that have stopped dividing but don’t die off as they should and build up in tissues over time. Senescent cells may cause inflammation or damage to nearby healthy cells. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells and slow down or stop tumor growth. Giving medication combinations of dasatinib, quercetin, fisetin and temozolomide may be safe, tolerable and/or effective in treating patients with previously treated glioma with residual disease.

Inclusion Criteria

Age ≥ 18 years
* Prior diagnosis of a glioma treated with chemotherapy and/or radiation with stable disease based on Response Assessment in Neuro-Oncology (RANO) criteria * Must have IDH-mutant OR MGMT-methylated glioma ** NOTE: Patients with any radiographic evidence of residual disease are eligible
Eastern Cooperative Oncology Group (ECOG) of 0, 1, or 2, and Karnofsky performance status >= 50
Hemoglobin ≥ 9.0 g/dL (≤ 15 days prior to registration)
Absolute neutrophil count (ANC) ≥ 1500/mm^3 (≤ 15 days prior to registration)
Platelet count ≥ 100,000/mm^3 (without transfusion ≤ 7 days preceding lab assessment) (≤ 15 days prior to registration)
Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN) (or ≤ 5 x ULN for patients with liver involvement) (≤ 15 days prior to registration)
Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula (≤ 15 days prior to registration)
Average corrected QT interval (QTc) ≤ 450 ms on triplicate 12 lead electrocardiogram (ECG) ≤ 29 days prior to registration * NOTE: QTc intervals will be corrected using Fridericia’s formula (Fridericia 1920)
Negative serum pregnancy test is required for persons of childbearing potential ≤ 8 days prior to registration
Presence of an implanted cranial CSF access device, such as Ommaya reservoir or ventriculoperitoneal shunt
Willingness to provide blood and CSF samples for research
Co-enrollment on the neuro-oncology biorepository (institutional review board [IRB]12-003458) for collection of research blood and CSF samples
Provide written informed consent
Willingness to return to Mayo Clinic for follow-up

Exclusion Criteria

Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects: * Pregnant persons * Nursing persons * Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception
Patients who are not appropriate medical candidates due to current or past medical history or uncontrolled concurrent illness which limits safety of or compliance to study proceedings
Participants who are unable to swallow tablets or who are at risk for impaired absorption of oral medication * NOTE: This includes but not limited to, refractory vomiting, gastric resection/bypass, or duodenal/jejunal resection
Patients with known hypersensitivity or allergy to all of the study drugs on the protocol (known hypersensitivity or allergy to one drug does not preclude participation in this protocol)
Inability to undergo MRI scans

PRIMARY OBJECTIVE:

I. Determine the feasibility of transitioning patients with brain tumors from one candidate senolytic therapy to the next in a response-based adaptive approach.

SECONDARY OBJECTIVES:

I. Assess the safety of this algorithm-based approach to individualized therapeutic drug combinations in patients with pre-recurrent central nervous system (CNS) tumors.

II. Determine the feasibility of serially screening multiple candidate therapies or combinations based on individualized empiric biological feedback from biospecimens and imaging.

CORRELATIVE/TERTIARY OBJECTIVE:

I. Determine the impact of novel senolytic drug combinations on cell-free mitochondrial DNA in cerebrospinal fluid (CSF) as well as candidate biomarkers of residual tumor including, CSF 2-hydroxyglutarate (as applicable), amplified chromosomal junctions (as applicable) in CSF and plasma, and fluorodopa F 18-positron emission tomography (18F-DOPA-PET) scans.

OUTLINE: Patients initiate treatment in regimen 1. Patients then transition through regimens 2 through 6 based on disease response or progression.

REGIMEN 1: Patients receive rest and take no treatment on days 1-35 of cycle 1. Patients at the end of cycle 1 proceed to regimen 2.

REGIMEN 2: Patients receive dasatinib orally (PO) once daily (QD) on days 1-2 and quercetin PO QD on days 1-2 of each cycle. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients without a partial response (PR) or complete response (CR) on imaging at the end of cycle 1 proceed to regimen 3. Patients with a PR or CR may remain on the current regimen.

REGIMEN 3: Patients receive fisetin PO QD on days 1-2 of each cycle. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients without a PR or CR on imaging at the end of cycle 1 proceed to regimen 4. Patients with a PR or CR may remain on the current regimen.

REGIMEN 4: Patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients without a PR or CR on imaging at the end of cycle 1 proceed to regimen 5. Patients with a PR or CR may remain on the current regimen.

REGIMEN 5: Patients receive temozolomide PO QD on days 1-5, quercetin PO QD days 14-15 and dasatinib PO QD on days 14-15 of each cycle. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients without a PR or CR on imaging at the end of cycle 1 proceed to regimen 6. Patients with a PR or CR may remain on the current regimen.

REGIMEN 6: Patients receive temozolomide PO QD on days 1-5 and fisetin PO QD on days 14-15 of each cycle. Cycles repeat every 35 days in the absence of disease progression or unacceptable toxicity. Patients without a PR or CR on imaging at the end of cycle 1 proceed to end of study treatment and study follow up. Patients with a PR or CR may remain on the current regimen.

Additionally, patients undergo magnetic resonance imaging (MRI) throughout the study as well as undergo blood and CSF sample collection on study. Patients may undergo 18F-DOPA-PET scans on study.

After completion of study treatment, patients are followed up at 30 days.

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Medication Combinations of Dasatinib, Quercetin, Fisetin and Temozolomide for the Treatment of Previously Treated Glioma with Residual Disease

Inclusion Criteria

Exclusion Criteria

United States

Minnesota

Rochester

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Medication Combinations of Dasatinib, Quercetin, Fisetin and Temozolomide for the Treatment of Previously Treated Glioma with Residual Disease

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