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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


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Leukemia

Thank you

Trial Information

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


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. 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. In all cohorts, 3-6 patients will
be treated at each dose level, and dose escalation will proceed (from step 3 to step 3) if
less than 33% of patients in a cohort experience unanticipated dose-limiting toxicity.

In the Phase IIa extension part of the trial, 6 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.

Inclusion 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, 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.

- Patients previously treated with allogeneic bone marrow or stem cell transplantation
are ineligible.

- Patients who are immediate candidates for allogeneic bone marrow or stem cell
transplantation. Patient who refuse this option remain eligible.

- CLL patients with transformed disease (Richter's transformation) are ineligible for
enrollment on this study.

- 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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety (phase I)

Outcome Time Frame:

1 year

Safety Issue:

Yes

Principal Investigator

Renier Brentjens, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

06-138

NCT ID:

NCT00466531

Start Date:

March 2007

Completion Date:

December 2013

Related Keywords:

  • Leukemia
  • refractory chronic lymphocytic leukemia
  • 06-138
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, B-Cell

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021