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A Study of Fludarabine Dosing in Children and Young Adults With B-cell Acute Lymphoblastic Leukemia, INFLUENCE Trial
Trial Status: active
This phase III trial compares the effect of targeted dosing of fludarabine versus standard dosing as part of lymphodepletion in children and young adults with B-cell acute lymphoblastic leukemia (B-ALL) who are undergoing Chimeric Antigen Receptor (CAR) T cell therapy. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving chemotherapy, with fludarabine and cyclophosphamide, before CAR T cell therapy helps kill cancer cells in the body and prepare the body to receive the CAR T cells. Targeted dosing of fludarabine uses a blood test to look at levels of the drug in the blood after the first dose, and following doses are calculated based on those levels. Standard dosing uses the same amount of drug for everyone based on average data. Giving targeted dosing of fludarabine may improve how well CAR T cell therapy works compared to standard dosing for children and young adults with B-ALL.
Inclusion Criteria
Patients with B-ALL and eligible to receive commercial tisagenlecleucel
Patient’s weight > 9 kg at time of lymphodepleting chemotherapy
Serum bilirubin ≤ 2 mg/dL, unless benign congenital hyperbilirubinemia (at time of LD)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x the upper limit of normal for age, unless thought to be leukemic disease-related (at time of LD)
Calculated glomerular filtration rate (GFR) ≥ 70 ml/min/1.73m^2 (at time of LD) (based on Schwartz formula GFR (mL/min/1.73 m^2) = (36.2 × Height in cm) / creatinine in µmol/L
Left ventricular ejection fraction (LVEF) ≥ 50% by multi-gated acquisition scan (MUGA), resting echocardiogram, or cardiac magnetic resonance imaging (MRI) within 6 weeks of screening (at time of LD)
Oxygen saturation as recorded by pulse oximetry of ≥ 90% on room air (at time of LD)
Adequate performance status:
* Age ≥ 16 years: Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky ≥ 60% at treatment
* Age < 16 years: Lansky ≥ 60% at treatment
Willing to participate as research subject and provide written informed consent from parents/legal representative, patient, and age-appropriate assent as appropriate before any study specific screening procedures are conducted, according to local, regional or national law and legislation
Exclusion Criteria
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drugs, or drugs chemically related to study treatment or excipients that contraindicate their participation, including fludarabine, cyclophosphamide and tisagenlecleucel
Patients with tisagenlecleucel that is deemed out of specification (OOS) will be excluded from this protocol
Clinically significant active and uncontrolled infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, polymerase chain reaction [PCR] for deoxyribonucleic acid [DNA]/ribonucleic acid [RNA] etc.)
Patient/parent/guardian unable to give informed consent or unable to comply with the treatment protocol
Pregnant or lactating women
Other uncontrolled, symptomatic, intercurrent illness including but not limited to infection, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the principal investigator (PI) would pose an unacceptable risk to the subject
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07223021.
I. To compare the event free survival (EFS) in patients receiving standard versus targeted fludarabine phosphate (fludarabine) lymphodepletion (LD) prior to CAR T cell infusion in pediatric/young adult patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL).
SECONDARY OBJECTIVES:
I. Estimate the one- and two- year overall survival in both arms and compare overall survival.
II. Estimate and compare the percentage of non-response at day 28 post CAR T cell therapy between the two arms.
III. Estimate and compare the percentage of cumulative incidence of disease relapse.
IV. Estimate and compare the percentage of patients who initiate any anti-leukemia therapy, including allogeneic hematopoietic stem cell transplant (allo-HCT).
V. Characterize and compare the post CAR T cell toxicity in both arms including adverse events of special interest (AESI) (cytokine release syndrome [CRS], immune cell associated neurotoxicity syndrome [ICANS], grade 3-4 cytopenia from day 28 – day 180, and infectious adverse events [grade 3-5] during the first 180 days after CAR T cell infusion).
VI. Compare the persistence of CAR T cells post infusion in both arms.
VII. Compare the duration of peripheral blood b-cell aplasia (BCA) in both arms.
VIII. Estimate and compare the percentage of patients who develop bone marrow B-cell recovery (≥ 1% CD19+ normal B-cells in the bone marrow) within 6 months after CAR-T infusion.
IX. Assess the feasibility of achieving targeted fludarabine exposure (area under the curve [AUC] 18 mg*h/L) by therapeutic drug monitoring (TDM) and compare to standard fludarabine conditioning.
X. Determine the quality of life (QoL) by patient reported outcomes (PROs).
EXPLORATORY OBJECTIVES:
I. Develop a pharmacologic model of fludarabine based on clinical parameters for targeting dosing of fludarabine in CAR T cell patients.
II. Perform mechanistic studies to understand how fludarabine exposure influences CAR T cell expansion and persistence.
III. Determine the cost effectiveness of optimizing fludarabine exposure in a pilot feasibility analysis.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive standard dosing of fludarabine intravenously (IV), over 30 minutes, on days -6 to -3 or -7 to -4 and cyclophosphamide IV, over 1 hour, on days -6 and -5 or -7 and -6. Patients then receive tisagenlecleucel IV on day 0. Patients undergo lumbar puncture during screening and blood sample collection and bone marrow aspiration throughout the study. Patients may also undergo positron emission tomography (PET) scan or magnetic resonance imaging (MRI) throughout the study. In addition, patients may undergo lumbar puncture on study, as well as bone marrow biopsy as clinically indicated.
ARM II: Patients receive standard dosing of fludarabine IV, over 30 minutes, on days -6 and -5 or -7 and -6 and adjusted targeted fludarabine IV, over 30 minutes, on days -4 and -3 or -5 and -4. Patients also receive cyclophosphamide IV, over 1 hour, on days -6 and -5 or -7 and -6. Patients then receive tisagenlecleucel IV on day 0. Patients undergo lumbar puncture during screening and blood sample collection and bone marrow aspiration throughout the study. Patients may also undergo PET scan or MRI throughout the study. In addition, patients may undergo lumbar puncture on study, as well as bone marrow biopsy as clinically indicated.
After completion of study treatment, patients are followed up at day 7, 10, 14, 28, months 2-6, and 9, 12 and 24 months.
Trial PhasePhase III
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
