Epstein-Barr Virus Specific Cytotoxic T-Cells in Treating Patients with Relapsed Acute Lymphoblastic Leukemia Who Have Undergone Donor Stem Cell Transplant
This phase I trial studies the side effects and best dose of Epstein-Barr virus specific cytotoxic T-cells given together with cyclophosphamide in treating patients with relapsed acute lymphocytic leukemia who have undergone donor stem cell transplant. Vaccines made from a donor's gene-modified T-cells may help the body build an effective immune response to kill cancer cells that express cluster of differentiation (CD)19. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving Epstein-Barr virus specific cytotoxic T-cells together with chemotherapy may kill more cancer cells.
- History of CD19+ malignancy with evidence of relapse or persistent minimal residual disease (MRD) following autologous or allogeneic hematopoietic stem cell transplantation (cohort 1) * Relapse on this protocol is detection of CD19+ malignancies in bone marrow (>= 5%) or extramedullary lesion by morphology, cytogenetics, molecular, radiographic, and/or flow cytometry * Persistent minimal residual disease after transplantation must be demonstrated by morphology, karyotype, fluorescent in situ hybridization (FISH), flow cytometry, or reverse transcriptase (RT)-polymerase chain reaction (PCR)
- History of relapsed or refractory CD19+ malignancies (e.g. non Hodgkin lymphoma) who have failed prior treatment and require autologous hematopoietic stem cell transplant; evidence of disease not required (cohort 2)
- Karnofsky performance status (KPS) or Lansky score > 50
- Creatinine =< 2.0 mg/dL for patients over 18 years or =< 2.5 x institutional upper limit of normal (ULN) for age, measured prior to conditioning chemotherapy
- Aspartate aminotransferase (AST) =< 5 x the institutional ULN, measured prior to conditioning chemotherapy; elevation secondary to leukemic involvement is not an exclusion criterion; leukemic involvement will be determined by the presence of progressive relapse defined by escalating bone marrow or peripheral blood leukemia blasts within the previous month and the absence of initiation of known hepatotoxic medication (e.g. azoles)
- Total bilirubin =< 2.5 x the institutional ULN, measured prior to conditioning chemotherapy
- Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) or other similar cardia imaging performed within 1 month of treatment
- Oxygen saturation >= 90% on room air, measured prior to treatment
- DONOR: The patient's HSCT donor, or if HSCT donor is not available a third party donor, must consent to a leukapheresis or whole blood donation(s) obtained at one or more phlebotomies which, in aggregate, will total approximately 250 ml for adults and no more than 5 ml/kg per draw from pediatric donors
- DONOR: Related donors < 18 years of age requiring placement of a leukapheresis catheter will donate peripheral blood collected by phlebotomy (including a unit of blood if weight permits) and shall not undergo catheter placement for leukapheresis
- DONOR: There is no upper age limit for donors; however, the minimum age for a related donor is 7 years as this is the youngest age a person can be considered capable of giving assent to participate in a research study
- DONOR: Evidence of prior sensitization to EBV by EBV serology testing (seropositive)
- DONOR: Donor's high resolution human leukocyte antigen (HLA) typing must be available for review
- DONOR: Complete blood count (CBC) within one week of donation; results of tests must be within a range that would not preclude donating blood or undergoing leukapheresis
- DONOR: Serologic testing for transmissible disease will be performed as per institutional guidelines adopted from extant National Marrow Donor Program (NMDP) and Foundation for Advancement in Cancer Therapy (FACT) guidelines; donors should be considered eligible to donate leukapheresis or blood based on these guidelines (i.e. blood donation guidelines)
- Patients with active human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection
- Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation
- Females who are pregnant
- Patients will be excluded if they have isolated extra-medullary relapse of acute lymphoblastic leukemia (ALL)
- Previous infusion of CD19 CAR T cells at another institution
- Patients with active (grade 2-4) acute graft versus host disease (GVHD), chronic GVHD, or an overt autoimmune disease (e.g. hemolytic anemia) requiring glucocorticosteroid treatment (> 0.5 mg/kg/day prednisone or its equivalent) as treatment
- Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF) or symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurologic dysfunction) within 28 days of treatment; prophylactic intrathecal medication is not a reason for exclusion
- Adult patients (>= 18 years old) with the following cardiac conditions will be excluded: * New York Heart Association (NYHA) stage III or IV congestive heart failure * Myocardial infarction =< 6 months prior to enrollment * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration * History of severe non-ischemic cardiomyopathy with ejection fraction (EF) =< 20%
- 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 treating investigator would pose an unacceptable risk to the subject
- Prior neurologic toxicity to previous immunotherapy
- Preceding and/or ongoing organ dysfunction or other co-morbidity including but not limited to uncontrolled infection that would impair the patient’s ability to endure known side effects of cytokine release syndrome or neurological toxicity
- Recent prior therapy: systematic chemotherapy less than 2 weeks prior to infusion; 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 or oral maintenance chemotherapy may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis or treatment * Subjects receiving steroid therapy at physiological replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to subject starting apheresis or treatment * 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
- Rapidly progressive disease that in the estimation of the treating physician would compromise ability to complete study therapy
Locations & Contacts
Contact: Kevin J. Curran
Trial Objectives and Outline
I. Assess the toxicities of in vitro expanded derived allogeneic Epstein-Barr virus specific cytotoxic T-lymphocytes (EBV-CTLs) genetically modified to target CD19+ cells administered in vivo to patients with: persistent minimal residual disease/relapse of CD19+ malignancy after autologous or allogeneic hematopoietic stem cell transplant (HSCT) (cohort 1); and relapsed or refractory CD19+ malignancies (e.g. non-Hodgkin lymphoma [NHL]) in the setting of autologous HSCT (cohort 2).
II. Assessment of toxicity will include assessment of the incidence and severity of graft versus host disease (GVHD) in treated patients since the development of GVHD may be a dose limiting toxicity (DLT).
I. To assess the effects of the adoptively transferred CD19 specific T-cells on the progression of CD19+ malignancy.
II. To quantitate the number of chimeric antigen receptor (CAR) positive T-cells in the blood at defined intervals post infusion in order to determine their survival and proliferation in the host.
III. To assess long-term status of treated patients.
IV. Feasibility of generating multiple doses of 19-28z CAR EBV-CTLs from donor EBV-CTL cell lines.
OUTLINE: This is a phase I, dose-escalation study.
Patients with CD19+ malignancy receive cyclophosphamide intravenously (IV) over 1 hour on day -2. Patients unable to tolerate/benefit from cyclophosphamide may receive an alternative conditioning chemotherapy at the discretion of the treating physician. Patients with relapsed (rel)/refractory (ref) CD19+ NHL undergoing auto-HSCT conditioning/cytoreductive chemotherapy will be selected by the treating physician based on prior therapy, prior adverse reactions, and the highest likelihood to achieve an optimal response. Patients then receive allogeneic EBV-CTLs IV over 1-2 hours on days 0-1 or up to 90 days following infusion of autologous HSCs (day 2-3). In the absence of dose limiting toxicities attributed to the infused T cells, patients may receive up to 2 more infusions of allogeneic EBV-CTLs every 7-30 days.
After completion of study treatment, patients are followed up monthly at months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and then annually for 14 years.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
Kevin J. Curran
Secondary IDs NCI-2011-03000
Clinicaltrials.gov ID NCT01430390