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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 ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00466531
First Posted: April 27, 2007
Last Update Posted: May 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center
April 25, 2007
April 27, 2007
May 10, 2017
March 21, 2007
December 2018   (Final data collection date for primary outcome measure)
  • Safety (phase I) [ Time Frame: 1 year ]
  • efficacy of the two CD19-targeted T cell methods (phase II) [ Time Frame: 1 year ]
Safety
Complete list of historical versions of study NCT00466531 on ClinicalTrials.gov Archive Site
  • Antileukemic effect [ Time Frame: 1 year ]
  • 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 ]
  • Antileukemic effect
  • Comparison of in vivo survival of patients receiving genetically modified anti-CD19 T cells after T cell infusion with vs without prior lymphodepleting therapy
Not Provided
Not Provided
 
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
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

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.

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 Step 3, an additional cohort of Waldenstrom's Macroglobulinemia (WM) patients will be treated with the investigator's choice conditioning chemotherapy followed by 19-28z+ T cells. However, to maximize safety for WM patients, they will be treated at the lower dose of modified T cells (1x106 19-28z+ T cells/kg). If no toxicity is observed in the initial cohort, the dose may be increased in a standard 3-step dose-escalation scheme as described above.

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.

Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Leukemia
  • Biological: therapeutic autologous lymphocytes
  • Drug: cyclophosphamide
Experimental: Patients with CLL or indolent B-cell lymphoma
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 pts will receive the lowest planned dose of 19-28z+ modified T cells. Step 2, a cohort of pts will receive cyclophosphamide conditioning chemotherapy followed by the lowest planned dose of 19-28z+ modified T cells. If less than 33% of pts in the cohort experience unanticipated dose-limiting toxicity,Step 3, a cohort of pts 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 pts in the initial cohort (Step 3) experience unanticipated dose-limiting toxicity, the cohort in Step 3 may be expanded to include up to 15 pts. In Step 3, an additional cohort of Waldenstrom's Macroglobulinemia (WM) pts will be treated with the investigator's choice conditioning chemotherapy followed by 19-28z+ T cells.
Interventions:
  • Biological: therapeutic autologous lymphocytes
  • Drug: cyclophosphamide
Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011 Nov 3;118(18):4817-28. doi: 10.1182/blood-2011-04-348540. Epub 2011 Aug 17.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
50
December 2018
December 2018   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00466531
06-138
MSKCC-06138
Not Provided
Not Provided
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Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center
National Cancer Institute (NCI)
Principal Investigator: Jae Park, MD Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center
May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP