T Lymphocytes, Chronic Lymphocytic Leukemia, B-cell Lymphoma or Multiple Myeloma, CHARKALL
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Purpose
Patients have a type of cancer called non-Hodgkin Lymphoma, Multiple Myeloma or Chronic Lymphocytic Leukemia. The lymphoma, MM or CLL has come back or has not gone away after treatment. Because there is no standard treatment for the cancer at this time or because the currently used treatments do not work completely in all cases, the patient is being asked to volunteer in 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 we 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, we found that T cells work better if we 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, we expect to be able to make cells that will last for a longer time in the body (because of the presence of the CD28). We 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 Food and Drug Administration.
| Condition | Intervention | Phase |
|---|---|---|
|
Lymphoma Myeloma Leukemia |
Biological: Genetically modified T cells |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized 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 Chronic Lymphocytic Leukemia, B-Cell Lymphoma or Multiple Myeloma |
- Evaluate safety of auto T cells genetically modified to express chimeric antigen receptors targeting the kappa-light chain of human immunoglobulin in pts with CLL, B cell non-Hodgkin Lymphoma or Multiple Myeloma whose tumors express Kappa-light chain. [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
- To measure the survival and function of CAR-K+ T cells in vivo. [ Time Frame: 15 years ] [ Designated as safety issue: No ]
- To measure the anti-tumor effects of CAR-K+ T lymphocytes. [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 18 |
| Study Start Date: | July 2009 |
| Estimated Study Completion Date: | July 2030 |
| Estimated Primary Completion Date: | July 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Infusion of Kappa CD28 T cells
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 Genetically modified T cells |
Biological: Genetically modified T cells
Pts with B-CLL will receive 12.5 mg/kg of Cyclophosphamide as a single i.v. infusion. In contrast pts with lymphoma will receive cyclophosphamide only if the count of CD3+ lymphocytes in the peripheral blood is >500 ul. T cells infused 4 days after cyclophosphamide, during the developing nadir to maximize exposure to the regenerative cytokine milieu. 3 dose levels will be evaluated. Cohorts of size 2 will be enrolled at each dose level. Each patient will receive one injection of each dose. |
Hide Detailed DescriptionDetailed Description:
To get the kappa antibody (with CD28) to attach to the surface of the T cell, we 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 us find the T cells in the patient's blood after we inject them. 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 you enroll 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 we infuse the kappa-CD28 T cells. Although we do not 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. If you were given cyclophosphamide as stated above, the T-cells will be given 4-7 days after the cyclophosphamide. If the patient has recently received other chemotherapy, the T-cells will be given at least 4 days after the last chemotherapy. We would prefer that patients not receive other chemotherapy until 6 weeks after the cell infusion but they can do so if their doctor thinks it is medically necessary. If the patient recently had a stem cell transplant, the T-cells will be given 14-60 days after the transplant. Before the patient receives the injection, they will be given a dose of Benadryl and Tylenol. The injection will take about 20 minutes. We 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 up to three 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.
Medical tests before treatment—
- Before being treated, the patient will receive a series of standard medical tests:
- Physical exam
- Blood tests to measure blood cells, kidney and liver function
- Measurements of the tumor by scans and/or bone marrow studies (to include a chest x ray at pre-infusion if not already done)
Medical tests during and after treatment—
Patients will receive standard medical tests when they are getting the infusions and after:
- Physical exams
- Blood tests to measure blood cells, kidney and liver function
- Measurements of the tumor by scans and/or bone marrow studies 6 weeks after the infusion
To learn more about the way the kappa-CD28 chimeric receptor T cells working and how long they last in the body, extra blood will be drawn. The total amount on any day is about 10 teaspoons. This volume is considered safe, but may be decreased if the patient is anemic.
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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:
- Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
- Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
- Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
- Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months.
Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs:
- Unintentional weight loss of 10% or more within the previous 6 months;
- Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual activities);
- Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection; or
- Night sweats for more than 1 month without evidence of infection.
- Patients who have resistant disease after primary treatment
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
Contacts and Locations| Contact: Carlos Ramos, MD | 832-824-4817 | caramos@txch.org |
| Contact: Vicky Torrano | 832-824-7821 | vxtorran@txch.org |
| United States, Texas | |
| The 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 | |
| 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: | August 20, 2012 |
| 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 |
ClinicalTrials.gov processed this record on May 19, 2013