In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cell Malignancies

• ClinicalTrials.gov Identifier: NCT01430390
• Recruitment Status: Recruiting
• First Posted: September 8, 2011
• Last Update Posted: February 11, 2021
• Sponsor: Memorial Sloan Kettering Cancer Center
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

Tracking Information

• First Submitted Date: September 6, 2011
• First Posted Date: September 8, 2011
• Last Update Posted Date: February 11, 2021
• Study Start Date: September 2011
• Estimated Primary Completion Date: September 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 20, 2019): 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. [ Time Frame: 3 years ]

Original Primary Outcome Measures (submitted: September 7, 2011)

toxicities [ Time Frame: 3 years ]

Toxicity will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 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 DLT.

Current Secondary Outcome Measures (submitted: November 20, 2019)

• To assess the effects of the adoptively transferred CD19 specific T-cells on the progression of leukemia. [ Time Frame: 3 years ]
• 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. [ Time Frame: 3 years ]
• To assess long-term status of treated patients [ Time Frame: 15 years ]

Original Secondary Outcome Measures (submitted: September 7, 2011)

• effects of the adoptively transferred CD19 specific T-cells on the progression of leukemia. [ Time Frame: 3 years ]
  plan to record clinical leukemia responses as defined in Section 12.2 for descriptive analysis of the effects of the adoptively transferred CD19 specific T-cells on the progression of leukemia.
• To quantitate the number of chimeric antigen receptor (CAR) positive T-cells in the blood [ Time Frame: 3 years ]
  at defined intervals post infusion in order to determine their survival and proliferation in the host.
• long-term status [ Time Frame: 15 years ]
  patients will be followed annually for up to 15 years to assess long-term clinical status

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
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+

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Acute Lymphocytic Leukemia
• Lymphoma

Intervention

• Biological: Biological/Genetically Modified T cells
  Following completion of the chemotherapy, genetically modified T cells will be given intravenously at one of 3 dose levels. After the infusion patients will be monitored clinically and with serial blood and marrow evaluations to assess toxicity, therapeutic effects, and the in-vivo survival of the genetically modified T-cells. A fixed CAR EBV-CTL dose (3x106 EBV-CTLs/kg) which has been demonstrated to be the ideal manufacturing dose allowing for multiple infusions and potential for multiple patient treatments per cell line generated will be used for all patients on this trial. Cohorts will be determined separately but cohort 3 will not begin to accrue until cohort 2 has treated three (3) patients without a DLT. Each patient is eligible for up to three (3) infusions.
• Drug: Cyclophosphamide-based chemotherapy
  Cyclophosphamide-based chemotherapy regimen will be the preferred conditioning chemotherapy prior to CAR T cell infusion for patients with CD19+ malignancy in cohort 1. Recommended chemotherapy regimen consists of single agent Cyclophosphamide at a dose of 3000 mg/m2/dose IV over 1 hour or 1500mg/m2/dose x 2 doses given daily over 1 hour given for 2 days (patients may received reduced dose of cyclophosphamide based on the clinical status of the patient at discretion of the treating physician and with written approval by the MSKCC PI of this study). Alternative cyclophosphamide or non-cyclophosphamide-based regimens based on the clinical status of the patient, disease burden, and likely-hood of response may be used at the discretion of the treating physician with written approval by MSKCC PI of the study. Conditioning chemotherapy will not be given prior to infusions # 2 and #3.

Study Arms

Experimental: Biological/Genetically Modified T cells

Utilizing our initial trial experience, it was amended to include three (3) expansion cohorts. Cohort 1: patients with CD19+ relapse/refractory (R/R) B cell malignancies occurring after allogeneic/autologous HSCT or solid organ transplant (SOT) infusion occurring following conditioning chemotherapy. Cohort 2:patients with CD10+ high risk B cell malignancies eligible for autologous HSCT followed by 19-28z CRA EBV-CTLs (auto-HSCT preparative regimen serves as conditioning chemotherapy. Cohort 3: patients with CD19+ high risk B cell malignancies eligible for allogeneic HSCT followed by consolidative 19-28z CAR EBV-CTLs (allo-HSCT preparative regimen serves as conditioning chemotherapy) Each expansion cohort has a target accrual of 6 patients treated with fixed CAR EBV-CTL dose (3x106 EBV-CTLs/kg) which has been demonstrated to be the ideal manufacturing dose.

Interventions:

• Biological: Biological/Genetically Modified T cells
• Drug: Cyclophosphamide-based chemotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 20, 2019): 24
• Original Estimated Enrollment (submitted: September 7, 2011): 52
• Estimated Study Completion Date: September 2021
• Estimated Primary Completion Date: September 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Kevin Curran, MD; 212-639-5836

Contact: Nancy Kernan, MD; 212-639-7250

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01430390
• Other Study ID Numbers: 11-038
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Memorial Sloan Kettering Cancer Center
• Study Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Not Provided

Investigators

• Principal Investigator: Kevin Curran, MD; Memorial Sloan Kettering Cancer Center

• PRS Account: Memorial Sloan Kettering Cancer Center
• Verification Date: February 2021