Fludarabine Phosphate, Cyclophosphamide, and Laboratory-Treated T Cells in Treating Younger Patients with Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia or Lymphoma
This phase I trial studies the side effects and best dose of laboratory-treated T cells when given together with fludarabine phosphate and cyclophosphamide in treating younger patients with B-cell acute lymphoblastic leukemia or lymphoma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Placing a gene that has been created in the laboratory into white blood cells may make the body build an immune response to kill cancer cells. Giving fludarabine phosphate and cyclophosphamide before laboratory-treated T cells may kill more cancer cells.
Inclusion Criteria
- Patient must have a CD19-expressing B cell acute lymphoblastic leukemia (ALL) or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy and one salvage regimen; in view of the principal investigator (PI) and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have disease activity that prohibits SCT at this time
- CD19 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 30% by flow cytometry in a Clinical Laboratory Improvement Amendments (CLIA) approved test in the Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH) or from the referring institution or reference laboratory; the choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient; in general immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples
- Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis
- At least 15 kg
- Adequate absolute CD3 count estimated to be required to obtain target cell dose based on discussion with Department of Transfusion Medicine (DTM) apheresis and Cell Processing Section, DTM
- Subjects with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy: * CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of white blood cells (WBCs); * CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm * CNS3 with marrow disease who has failed salvage systemic and intensive intrathecally (IT) chemotherapy (and therefore not eligible for radiation) * Patients with isolated CNS relapse will be eligible if they have previously been treated with cranial radiation (at least 1800 cGy)
- Ability to give informed consent; for subjects < 18 years old their legal guardian must give informed consent; pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those >= 12 years of age, when appropriate
- Clinical performance status: patients > 10 years of age: Karnofsky >= 50%; patients =< 10 years of age: Lansky scale >= 50%; subjects who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score
- Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen
- Females of child-bearing potential must have a negative pregnancy test
- Cardiac function: left ventricular ejection fraction >= 40% by multi gated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI), or fractional shortening >= 28% by echocardiogram (ECHO)or left ventricular ejection fraction >= 50% by ECHO
- Patients with history of allogeneic stem cell transplantation are eligible if at least 100 days post-transplant, if there is no evidence of active graft-versus-host disease (GVHD) and no longer taking immunosuppressive agents for at least 30 days prior to enrollment
Exclusion Criteria
- Recurrent or refractory ALL limited to isolated testicular disease
- Total bilirubin > 2 x upper limit of normal (ULN) (except in the case of subjects with documented Gilbert’s disease > 3 x ULN)
- Transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) > 20 x ULN based on age- and laboratory specific normal ranges
- Greater than age-adjusted normal serum creatinine (see below) and a creatinine clearance < 60 mL/min/1.73 m^2 * =< 0.8 mg/dL (age =< 5 years) * =< 1.0 mg/dL (5 years < age =< 10 years) * =< 1.2 mg/dL (age > 10 years)
- Absolute neutrophil count (ANC) < 750/uL, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy)
- Platelet count < 50,000/uL, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy)
- A subject will not be excluded because of pancytopenia >= grade 3 if it is due to disease, based on the results of bone marrow studies
- Hyperleukocytosis (>= 50,000 blasts/uL) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy
- Pregnant or breast-feeding females
- Recent prior therapy: * Systemic chemotherapy =< 2 weeks (6 weeks for nitrosoureas) or radiation therapy =< 3 weeks prior to apheresis; exceptions: ** There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such; ** Subjects receiving hydroxyurea may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis; ** Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided they meet all other eligibility criteria; ** Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis; ** For radiation therapy: radiation therapy must have been completed at least 3 weeks prior to enrollment, with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the subject has measurable/evaluable disease outside the radiation port
- Other anti-neoplastic investigational agents currently or within 30 days prior to apheresis (i.e. start of protocol therapy)
- Subjects must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met; cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion
- Human immunodeficiency virus (HIV)/hepatitis B virus (HBV)/hepatitis C virus (HCV) infection: * Seropositive for HIV antibody * Seropositive for hepatitis C or positive for hepatitis B surface antigen (HbsAG)
- Monoclonal antibody therapy administered within 30 days of the agent prior to apheresis
- Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject
- Second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and subject is in remission
- History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells (i.e. gentamicin)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01593696.
PRIMARY OBJECTIVES:
I. To determine the safety and feasibility of administering escalating doses of anti-cluster of differentiation (CD)19-chimeric antigen receptor (CAR) engineered peripheral blood lymphocytes (anti-CD19-CAR retroviral vector-transduced autologous T cells) in two strata (prior allogeneic stem cell transplant [SCT] versus (vs.) no prior SCT) of children and young adults with B cell malignancies following a cyclophosphamide/fludarabine (fludarabine phosphate) lymphodepletion regimen. (Completed)
II. To determine the safety of administering cells in two groups of children and young adults with B-cell malignancies expressing CD19: patients without high-burden disease or patients for whom chemotherapy toxicity is a concern will receive standard preparative regimen (Arm 1); patients with high-burden disease who receive standard chemotherapy to reduce burden (Arm 2).
III. To determine the feasibility of administering anti-CD19 CAR transduced T cells within 21 days of the target date in children and young adults with B-cell malignancies expressing CD19 enrolled on arm 2: patients with high-burden disease who receive standard chemotherapy to reduce burden.
SECONDARY OBJECTIVES:
I. Explore whether the administration of anti-CD19-CAR engineered peripheral blood lymphocytes can mediate antitumor effects in children with B cell malignancies who 1) do NOT have high-burden disease and receive standard preparative regimen, or 2) have high-burden disease and receive standard cytotoxic chemotherapy to reduce disease burden.
II. To evaluate the ability of cytokine release syndrome (CRS) treatment algorithm to reduce the incidence of grade 4 cytokine release syndrome (CRS) to =< 10% of patients receiving anti-CD19 CAR engineered peripheral blood lymphocytes at the maximum tolerate dose (MTD).
III. Measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood and where possible the bone marrow and cerebrospinal fluid (CSF) of patients.
IV. To describe the toxicity of administration of anti-CD19-CAR engineered peripheral blood lymphocytes in children and young adults with central nervous system (CNS) disease.
V. To assess cognitive functioning (memory, attention, processing speed, and executive functioning [primary outcome = CogState One Card Learning score]) pre- and post-infusion to examine the cognitive effects of the anti-CD19 CAR infusion.
VI. Define the cardiovascular toxicity associated with CD-19 CAR therapy infusion and associated cytokine release syndrome (CRS).
VII. Explore the relationship between cardiac function, inflammatory and cardiac biomarkers and cardiac imaging to evaluate cardiac function pre- and post-CAR to determine whether specific markers could provide an early signal for subjects at risk of developing cardiac dysfunction post-infusion.
TERTIARY OBJECTIVES:
I. Describe the safety, feasibility and clinical impact of administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes in patients who received clinical benefit from the initial infusion.
II. Explore the relationships between cognitive test scores and serum cytokine levels (e.g. interferon [IFN]-gamma, IL-2, IL-6, and tumor necrosis factor [TNF]alpha).
III. Explore whether sequence-based genomic analysis can detect minimal residual disease (MRD) in patients who are MRD negative by flow cytometry.
OUTLINE: This is a dose-escalation study of anti-CD19-CAR retroviral vector-transduced autologous T cells.
LYMPHODEPLETING REGIMEN: Patients are assigned to 1 of 2 arms.
ARM I: Patients without high-burden disease or patients for whom chemotherapy toxicity is a concern receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2.
ARM II: Patients with high-burden disease receive intensive standard of care chemotherapy comprising: fludarabine phosphate IV over 30 minutes and cytarabine IV over 4 hours on days -12 to -8; or etoposide IV over 1 hour and ifosfamide IV over 1 hour on days -12 to -8. Treatment regimen determined by the research team based on the patient’s prior therapies, e.g. total lifetime anthracycline doses, responses to prior regimens, and toxicities from prior regimens.
ANTI-CD19 CAR T CELL INFUSION: Patients receive anti-CD19-CAR retroviral vector-transduced autologous T cell IV over 10-20 minutes on day 0. Eligible patients may receive a second infusion at least 28 days later after undergoing a second preparative lymphodepleting regimen.
After completion of study treatment, patients are followed up for 28 days; at 2, 3, 6, 9, and 12 months; every 6 months for 1 year; and then annually for 13 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationNCI - Center for Cancer Research
Principal InvestigatorNirali N. Shah
- Primary ID12-C-0112
- Secondary IDsNCI-2013-01518, 120112, P09594
- ClinicalTrials.gov IDNCT01593696