FH-FOLR1 Chimeric Antigen Receptor T Cell Therapy for Treating Pediatric Patients With Relapsed or Refractory Acute Myeloid Leukemia

OUTLINE: This is a dose-escalation study of FH-FOLR1 CAR T.

Patients undergo apheresis to obtain T cells for product manufacturing, receive lymphodepleting chemotherapy with fludarabine intravenously (IV) on days -4 to -1, cyclophosphamide IV on days -4 and -3 and receive FH-FOLR1 CAR T IV on day 0. Patients undergo echocardiography (ECHO) at screening, undergo collection of cerebrospinal fluid (CSF), blood samples and bone marrow aspiration/biopsy throughout the study, and may undergo imaging (such as positron emission tomography (PET) scan).

After completion of study treatment, patients are followed up for 15 years.

Inclusion criteria

• Subject age ≤ 6 years.
• Weight ≥ 7 kilograms.
• AML that expresses FOLR1 by flow cytometry as assessed by Hematologics, Inc.

Laboratory and meets one of the below definitions:

• For subjects who have previously received an allogeneic hematopoietic cell transplantation (HCT), any evidence of AML re-emergence post HCT detectable by flow cytometry.
• First relapse of AML ≤ 6 months from initial diagnosis.
• First relapse of AML > 6 months from initial diagnosis with minimal residual disease (MRD) ≥ 0.05% by flow cytometry after at least one re-induction attempt (one cycle of therapy).
• Second or greater relapse of AML.
• Refractory AML, defined as ≥ 0.1% leukemic cells determined by flow cytometry or > 1% on biopsy after 2 cycles of chemotherapy.

• Able to tolerate apheresis.
• Life expectancy ≥ 8 weeks.
• Has an appropriate stem cell donor source identified.
• Lansky performance status score of ≥ 50. Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for purposes of assessing performance status.
• The subject must discontinue all anticancer agents and radiotherapy and, in the opinion of the investigator, have fully recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy:
• Chemotherapy and biologic agents: All chemotherapy and biologic therapy not specifically mentioned below must be discontinued ≥ 14 days prior to enrollment, with the exception of intrathecal chemotherapy for which there is not a required washout period.
• Steroid use: All corticosteroid therapy (unless physiologic replacement dosing) must be discontinued ≥ 7 days prior to enrollment, unless being used to treat graft-versus-host disease (GVHD) (if being used to treat GVHD see requirements).
• Tyrosine kinase inhibitor (TKI) use: All TKIs must be discontinued ≥ 3 days prior to enrollment.
• Hydroxyurea: must be discontinued ≥ 1 day prior to enrollment.
• FOLR1 targeting therapy must be discontinued within 30 days prior to enrollment.

• Gene modified cellular therapy:
• Must be at least 30 days from most recent gene modified cell therapy infusion and document no evidence of modified cells in the peripheral blood OR
• Must be at least 60 days from most recent gene modified cell therapy.

• Serum creatinine ≤ 1.5 x the upper limit of normal (ULN) based on the following:
• Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for male and 0.6 mg/dL for female.
• Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for male and 0.8 mg/dL for female.
• Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for male and 1 mg/dL for female.

• Total bilirubin ≤ 3 times ULN for age OR conjugated bilirubin ≤ 2 mg/dL.
• Alanine aminotransferase (ALT)(serum glutamic-pyruvic transaminase [SGPT]) ≤ 5 times ULN.
• Shortening fraction ≥ 28% OR ejection fraction (EF) ≥ 50% as measured by echocardiogram.
• Oxygen saturation ≥ 92% on room air without supplemental oxygen or mechanical ventilation.
• Absolute lymphocyte count (ALC) ≥ 100 cells/uL.
• Virology testing negative within 3 months prior to enrollment, to include:
• HIV antigen & antibody.
• Hepatitis B surface antigen.
• Hepatitis C antibody OR if positive, hepatitis C polymerase chain reaction (PCR) is negative.

• Subject and/or legally authorized representative has signed the informed consent form for this study.

Exclusion criteria

• Active malignancy other than acute myeloid leukemia.
• History of symptomatic non-AML central nervous system (CNS) disease or ongoing symptomatic CNS disease requiring medical intervention, including paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder (subjects with non-febrile seizure disorder controlled on anti-epileptic medication and without seizure activity within 1 month are eligible).
• CNS AML involvement that is symptomatic and in the opinion of the investigator, cannot be controlled during the interval between enrollment and T cell infusion.
• If history of allogeneic stem cell transplant: active GVHD or receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to enrollment.
• If history of allogeneic stem cell transplant and patient has received donor lymphocyte infusion (DLI) the subject is < 8 weeks from DLI infusion.
• Presence of active severe infection, defined as:

• Positive blood culture within 48 hours of enrollment, OR
• Fever above 38.2 degrees Celsius (C), AND clinical signs of infection within 48 hours of enrollment.
• Primary immunodeficiency syndrome.
• Subject has received prior virotherapy.
• Subject and/or legally authorized representative unwilling to provide consent/assent for participation in the 15-year follow-up period, required if FH-FOLR1 CAR T cell therapy is administered.
• Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol.
• Considered by the investigator to be unable to tolerate a lymphodepleting regimen.