Treatment of Relapsed or Chemotherapy Refractory Chronic Lymphocytic Leukemia or Indolent B Cell Lymphoma Using Autologous T Cells Genetically Targeted to the B Cell Specific Antigen CD19

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00466531
First received: April 25, 2007
Last updated: April 21, 2014
Last verified: April 2014
  Purpose

RATIONALE: Using T cells from the patient that have been treated in the laboratory may help the body build an effective immune response to kill cancer cells. 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 laboratory-treated T cells together with cyclophosphamide may kill more cancer cells.

PURPOSE: This is a two-stage protocol, consisting of a single-institution phase I safety study and multi-institution phase IIa extension study.


Condition Intervention Phase
Leukemia
Biological: therapeutic autologous lymphocytes
Drug: cyclophosphamide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/IIa Trial For The Treatment of Relapsed or Chemotherapy Refractory Chronic Lymphocytic Leukemia or Indolent B Cell Lymphoma Using Autologous T Cells Genetically Targeted to the B Cell Specific Antigen CD19

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Safety (phase I) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • efficacy of the two CD19-targeted T cell methods (phase II) [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Antileukemic effect [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Comparison of in vivo survival of patients receiving genetically modified anti-CD19 T cells after T-cell infusion with vs without lymphodepleting therapy [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: March 2007
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Patients with CLL or indolent B-cell lymphoma
This is a two-stage protocol, consisting of a single-institution phase I safety study & multi-institution phase IIa extension study. The first stage is a standard 3-step phase I dose escalation trial to assess the safety of 19-28z CAR expressing autologous T cells with or without prior conditioning chemotherapy.Step 1, a cohort of patients will receive the lowest planned dose of 19-28z+ modified T cells. Step 2, a cohort of patients will receive cyclophosphamide conditioning chemotherapy followed by the lowest planned dose of 19-28z+ modified T cells. If less than 33% of patients in the cohort (Step 2) experience unanticipated dose-limiting toxicity,Step 3, a cohort of patients will be treated with the investigator's choice conditioning chemotherapy followed by the higher dose of 19-28z+ modified T cells. If less than 33% of patients in the initial cohort (Step 3) experience unanticipated dose-limiting toxicity, the cohort in Step 3 may be expanded to include up to 15 patients.
Biological: therapeutic autologous lymphocytes Drug: cyclophosphamide

Detailed Description:

OBJECTIVES:

Phase 1: The primary objective is to assess the safety of autologous T cells genetically modified to express chimeric antigen receptor (CAR) targeting CD19 antigen (19-28z) with or without conditioning chemotherapy.

• Phase IIa: The primary objective is to compare the relative engraftment and persistence of the two CAR modified CD19-targeted T cells expressing different co-stimulatory signaling domain CD28 (19-28z) and 4-1BB (CART-19:CD3z-4-1BB) in the CAR construct.

To compare the in vivo survival of genetically modified 19-28z CAR+ T cells after T cell infusion alone or in combination with conditioning chemotherapy.

  • To compare the gene transfer/expression efficiency of the two viral vectors (retrovirus vs. lentivirus).
  • To assess the anti-leukemic activity of adoptively transferred CD19-targeted modified T cells linked to the CD28 (19-28z) and 4-1BB signaling domains (CART-19:CD3z-4-1BB).

OUTLINE:

The first stage is a standard 3-step phase I dose escalation trial to assess the safety of 19-28z CAR expressing autologous T cells with or without prior conditioning chemotherapy. In Step 1, a cohort of patients will receive the lowest planned dose of 19-28z+ modified T cells. In Step 2, a cohort of patients will receive cyclophosphamide conditioning chemotherapy followed by the lowest planned dose of 19-28z+ modified T cells. If less than 33% of patients in the cohort (Step 2) experience unanticipated dose-limiting toxicity. In Step 3, a cohort of patients will be treated with the investigator's choice conditioning chemotherapy followed by the higher dose of 19-28z+ modified T cells. If less than 33% of patients in the initial cohort (Step 3) experience unanticipated dose-limiting toxicity, the cohort in Step 3 may be be expanded to include up to 15 patients.

In the Phase IIa extension part of the trial, 12 patients from MSKCC will be enrolled, and will be treated with co-infusion of 19-28z and CART-19:CD3z-4-1BB+ modified T cells mixed at 1:1 ratio at the MTD of T cells determined from the phase I trial.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion:

• Patients must have the following CD19+ B cell leukemia or lymphoma either with relapsed or chemotherapy-refractory disease or with evidence of residual disease following therapy.

In all cases, patient's disease must be confirmed at MSKCC.

  • CLL: Patients must have a diagnosis of CLL as evidenced by flow cytometry, bone marrow histology, and/or cytogenetics.
  • Other low grade B-cell neoplasms are eligible for study, such as small lymphocytic lymphoma (SLL), follicular lymphoma, Waldenstrom's macroglobulinemia, hairy cell leukemia, marginal zone lymphomas, and mantle cell lymphomas.
  • Creatinine ≤2.0 mg/100 ml, bilirubin ≤2.0 mg/100 ml, AST and ALT ≤3.0x normal, PT and PTT ≤ 2x normal outside the setting of stable chronic anticoagulation therapy, granulocytes ≥1,000/mm3, platelets ≥50,000/mm3, hemoglobin ≥8.0g/dl with transfusion support
  • Adequate cardiac function (LVEF ≥40%) as assessed by ECHO or MUGA scan performed within 1 month of treatment.
  • Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air by pulse oximetry.
  • Life expectancy of > 3 months.

Exclusion:

  • Karnofsky performance status <70.
  • CLL patients with active transformed disease (Richter's transformation) are ineligible for enrollment on this study.
  • Patients with 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 EF ≤20%
  • Patients with HIV, hepatitis B or hepatitis C infection are ineligible.
  • Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00466531

Contacts
Contact: Jae Park, MD 212-639-4048
Contact: Craig Sauter, MD 212-639-3460

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Jae Park, MD    212-639-4048      
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Jae Park, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00466531     History of Changes
Other Study ID Numbers: 06-138, MSKCC-06138
Study First Received: April 25, 2007
Last Updated: April 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
refractory chronic lymphocytic leukemia
06-138

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on July 22, 2014