Clinical trial NCT01430390: In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cell Malignancies
Official title: A Phase I Trial Using In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cell Malignancies
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Acute Lymphocytic Leukemia
Lymphoma
Keywords: In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic
T-Lymphocytes (EBV-CTLs)
CD19 specific T-cells
11-038
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
First posted: 2011-09-08
Enrollment: 19
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a phase I trial designed to identify tolerable and clinically active doses of allogeneic Epstein - Barr virus specific cytotoxic T lymphocytes (EBV-CTLs) genetically modified to target the B-cell antigen CD19 when administered to patients with CD19+
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to test the safety of giving the patient special cells from a donor called "Modified T-cells". The goal is to assess the toxicities of T-cells for patients with relapsed B cell leukemia or lymphoma after a blood SCT organ SCT or for patients who are at high risk for relapse of their B cell leukemia or lymphoma.


Eligibility criteria: Inclusion Criteria:

* History of CD19+ relapse/refractory (R/R) B cell malignancies occurring after allogeneic/autologous HSCT or solid organ transplant (SOT. (cohort 1)
* Relapse on this protocol is detection of CD19+ malignancies in bone marrow morphology ≥ 5% any extramedullary lesion (radiographic), or detection of any disease level by cytogenetics, molecular, and/or flow cytometry.
* History of relapsed or refractory CD19+ malignancies (e.g. Non Hodgkin Lymphoma) or considered high risk for relapse and and require autologous or allogeneic hematopoietic stem cell transplant (HSCT). Evidence of disease not required. (cohort 2 and 3)
* No age restriction for patients
* KPS or Lansky score \> or = to 50
* Renal function (measured prior to conditioning chemotherapy)
* Creatinine ≤ 2.0mg/dL for patients over 18 years of ≤ 2.5 x institutional ULN for age.
* Hepatic function (measured prior to conditioning chemotherapy):
* AST ≤ 5 x the institutional ULN 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 know hepatotoxic medication (e.g. azoles).
* Total bilirubin ≤ 2.5 x the institutional ULN
* Adequate cardiac function (e.g. LVEF ≥ 40%) as assessed by ECHO or MUGA or other similar cardia imaging performed within 1 month of treatment.
* Pulmonary function (measured prior to treatment):
* Oxygen saturation ≥ 90% on room air

Donor Eligibility:

* 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 5ml/kg per draw from pediatric donors.
* 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 as this is considered above minimal risk to the donor.
* There is no upper age limit for a 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.
* Evidence of prior sensitization to EBV by EBV serology testing (seropositive)
* Donor's high resolution HLA typing must be available for review
* CBC within one week of donation. Results of tests must be within a range that would not preclude donating blood or undergoing leukapheresis.
* Serologic testing for transmissible diseases will be performed as per institutional guidelines adopted from extant NMDP and FACT guidelines. Donors should be considered eligible to donate leukapheresis or blood based on these guidelines (i.e. blood donation guidelines)

Exclusion Criteria:

* Patients with active 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 ALL.
* 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 ≤ 6months 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 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 irreversible 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.
* 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 tere 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.

Primary outcomes:
measure: Evaluate the safety/persistence of (including GVHD) of allogeneic EBV specific CTL modified to express artificial T cell receptors targeting CD19 molecule given for persistence or relapse of B-Cell ALL post allogeneic HSCT.
timeFrame: 3 years
Secondary outcomes:
measure: To assess the effects of the adoptively transferred CD19 specific T-cells on the progression of leukemia.
timeFrame: 3 years
measure: To quantitate the number of chimeric antigen receptor (CAR) positive T-cells and donor EBV-CTL in the blood at defined intervals post infusion in order to determine their survival and proliferation in the host.
timeFrame: 3 years
measure: To assess long-term status of treated patients
timeFrame: 15 years
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Kevin Curran, MD
role: PRINCIPAL_INVESTIGATOR
References: