Kappa-CD28 T Lymphocytes, Chronic Lymphocytic Leukemia, B-cell Lymphoma or Multiple Myeloma, CHARKALL

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Baylor College of Medicine
Sponsor:
Collaborators:
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Carlos Ramos, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT00881920
First received: April 14, 2009
Last updated: April 25, 2014
Last verified: April 2014
  Purpose

Patients have a type of cancer called NHL, Multiple Myeloma (MM) or CLL. The lymphoma, MM or CLL has come back or has not gone away after treatment. There is no standard treatment for the cancer at this time or the currently used treatments do not work completely in all cases like these. This is a gene transfer research study using special immune cells.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, that investigators hope will work together. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients.

T lymphocytes can kill tumor cells but there normally are not enough of them or they are not able to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person.

The antibody used in this study recognizes a protein on the lymphoma, MM or CLL cells called kappa immunoglobulin. Antibodies can stick to lymphoma, MM or CLL cells when it recognizes the kappa molecules present on the tumor cells. For this study, the kappa antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These chimeric receptor-T cells seem to kill some of the tumor, but they don't last very long and so their chances of fighting the cancer are limited.

In the laboratory, investigators found that T cells work better if they also add a protein that stimulates T cells to grow called CD28. By joining the anti-kappa antibody to the T cells and adding the CD28, the investigators expect to be able to make cells that will last for a longer time in the body (because of the presence of the CD28). They are hoping this will make the cells work better. This research is taking place to assess the safety of different doses of these cells. These chimeric T cells (kappa-CD28) are an investigational product not approved by the FDA.


Condition Intervention Phase
Lymphoma
Myeloma
Leukemia
Biological: Kappa CD28 T cells
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Adoptive Transfer of Autologous T Lymphocytes Engrafted With a Chimeric Antigen Receptor Targeting the Kappa Light Chain of Immunoglobulin Expressed in Patients With CLL, B-Cell Lymphoma or Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Number of Patients with Dose-Limiting Toxicities (DLT) [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    DLT will be defined as any grade 3-5 toxicity that is NOT (1) pre-existing, or (2) due to infection (to which patients with CLL and NHL are so predisposed), or (3) due to underlying malignancy, and that is considered to be possibly, probably, or definitely related to the study drug. Toxicity will be evaluated using NCI criteria version 4.X.


Secondary Outcome Measures:
  • Survival and Function of CAR-K+ T cells [ Time Frame: 15 years ] [ Designated as safety issue: No ]
    The frequency of T cells expressing CAR-Kappa will be summarized at pre and post-infusion time points using mean ± SD, medians and ranges to evaluate their expansion and persistence. Plots of growth curves will be generated to graphically illustrate patterns of T-cell expansion. Plots will be generated to depict patterns of survival and expansion of T cells for each of the two vectors. Longitudinal modeling techniques will also be used.

  • To measure the anti-tumor effects of CAR-K+ T lymphocytes. [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    We will summarize tumor response by calculating overall response rates. Tumor sites will be measured before and after T cell therapy using RECIST.


Estimated Enrollment: 54
Study Start Date: July 2009
Estimated Study Completion Date: July 2034
Estimated Primary Completion Date: July 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Kappa CD28 T cells
T cells will be infused 4 days after cyclophosphamide. Three dose levels will be evaluated. Cohorts of size 2 will be enrolled at each dose level. Each patient will receive one injection 2-30 mL of each dose over 1 to 10 minutes.
Biological: Kappa CD28 T cells

Patients with B-CLL will receive 12.5 mg/kg of Cyclophosphamide as a single i.v. infusion. In contrast patients with lymphoma will receive cyclophosphamide only if the count of CD3+ lymphocytes in the peripheral blood is >500 ul.

Group 1: Day 0 2x10^7 cells/m^2 CAR-Kappa

Group 2: Day 0 1x10^8 cells/m^2 CAR-Kappa

Group 3: Day 0 2x10^8 cells/m^2 CAR-Kappa


Detailed Description:

To prepare the lymphoma, MM or CLL specific T cells investigators will take 240 ml (up to 16 tablespoonfuls)of blood from the patient. This would be drawn as 2 (two) separate blood collections of 120 ml (up to 8 tablespoonfuls) of blood.

To get the kappa antibody (with CD28) to attach to the surface of the T cell, investigators inserted the antibody gene into the T cell. This is done with a virus called a retrovirus that has been made for this study and will carry the antibody gene into the T cell. This virus also helps investigators find the T cells in the patient's blood after they're injected. Because the patient has received cells with a new gene in them patients will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.

When a subject enrolls on this study, patients will be assigned to one of three groups of different doses receiving kappa-CD28 T cells.

Several studies suggest that the infused T cells need room to be able to grow and accomplish their functions and that this may not happen if there are too many other T cells in circulation. Because of that, if the level of circulating T cells is relatively high or the patient has B-CLL, the patient may receive one treatment of cyclophosphamide four to seven days prior to the infusion of the T cells. This drug will decrease the numbers of the patients own T cells before infusion of the kappa-CD28 T cells. Although investigators don't expect any effect on the tumor with the dose that the patient will receive, this drug is part of many regimens that are used to treat lymphoma, MM or CLL.

Patients will be given an injection of cells into the vein through an IV line at the assigned dose. The injection will take about 20 minutes. Investigators will follow the patient in the clinic after the injection for up to 3 hours. The treatment will be given by the Center for Cell and Gene Therapy at Texas Childrens Hospital or The Methodist Hospital.

If after a 4-6 week evaluation period after the infusion, the patient seems to be experiencing a benefit (confirmed by radiological studies, physical exam and/or symptoms), the patient may be able to receive additional doses of the T cells if they wish. These additional infusions would be at least 4-6 weeks apart and at the same dose level they received the first time or a lower dose.

  Eligibility

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

INCLUSION CRITERIA:

  • Eligibility Criteria for BLOOD PROCUREMENT:
  • B-CLL or recurrent or refractory B-cell lymphoma (or other B-cell neoplasm) and Multiple Myeloma (MM) or multiple myeloma monoclonal for Kappa-light chain
  • Life expectancy of at least 12 weeks or greater.
  • No history of other cancer (except non-melanoma skin cancer or in situ breast cancer or cervix cancer) unless the tumor was successfully treated with curative intent at least 2 years before trial entry
  • If requires pheresis to collect blood, Cre and AST less than 1.5 upper limit of normal
  • If requires pheresis to collect blood, PT and PTTK less than 1.5 upper limit normal

ELIGIBILITY CRITERIA FOR T CELL TREATMENT:

Diagnosis of B-CLL monoclonal for Kappa light chain with one of the following criteria:

  1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
  2. Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
  3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
  4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months.
  5. Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs:

    1. Unintentional weight loss of 10% or more within the previous 6 months;
    2. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual activities);
    3. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection; or
    4. Night sweats for more than 1 month without evidence of infection.
    5. Patients who have resistant disease after primary treatment
    6. Patients who have a short time to progression after the first treatment (less than 2 years)

      OR

      -Indolent or aggressive B-cell lymphoma (or other B-cell neoplasm) monoclonal for Kappa-light chain with measurable disease after receiving at least one chemotherapy regimen that includes Rituximab or an equivalent monoclonal antibody

      OR

      • Multiple myeloma monoclonal for Kappa-light chain with measurable disease after receiving at least one chemotherapy regimen
      • Life expectancy of at least 12 weeks or greater.
      • Recovered from the toxic effects of all prior chemotherapy before entering this study.
      • ANC > 500, HgB > 8.0.
      • Bilirubin less than 3 times the upper limit of normal.
      • AST less than 5 times the upper limit of normal.
      • Serum creatinine less than 3 times upper limit of normal.
      • Pulse oximetry of > 90% on room air
      • Karnofsky score of > 60%.

      Negative serology for HIV.

      • Available autologous transduced peripheral blood T-cells with 15% or more expression of CAR-Kappa determined by flow-cytometry.
      • Patients must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects. Patients will be given a copy of the consent form.
      • Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 3 months after the study is concluded. The male partner should use a condom.
      • If patient has CLL, must have negative Coombs test.

      EXCLUSION CRITERIA:

      BLOOD PROCUREMENT:

      • Active infection requiring antibiotics
      • Active autoimmune disease

      Exclusion for T CELL TREATMENT:

      • Symptomatic cardiac disease.
      • History of hypersensitivity reactions to murine protein-containing products. Currently receiving any investigational agents within the previous six weeks or received any tumor vaccines within the previous 6 weeks.
      • Tumor in a location where enlargement could cause airway obstruction.
      • Pregnant or lactating.
  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: NCT00881920

Contacts
Contact: Carlos Ramos, MD 832-824-4817 caramos@txch.org
Contact: Vicky Torrano 832-824-7821 vxtorran@txch.org

Locations
United States, Texas
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: George Carrum, MD    713-441-1450    gcarrum@bcm.edu   
Contact: Vicky Torrano    832-824-7821    vxtorran@txch.org   
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Carlos A Ramos, MD       caramos@bcm.edu   
Contact: Vicky Torrano    832-824-7821    vxtorran@txch.org   
Sponsors and Collaborators
Baylor College of Medicine
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
Principal Investigator: Carlos Ramos, MD Baylor College of Medicine/Texas Children's Hospital
  More Information

No publications provided

Responsible Party: Carlos Ramos, Assistant Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00881920     History of Changes
Other Study ID Numbers: H-23574-CHARKALL, CHARKALL
Study First Received: April 14, 2009
Last Updated: April 25, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:
Lymphocytic
Leukemia
B Cell
Non-Hodgkin
Multiple Myeloma
Lymphoma

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Lymphoma, B-Cell
Leukemia, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoma, Non-Hodgkin
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on July 24, 2014