Administration of Anti-CD19-chimeric-antigen-receptor-transduced T Cells From the Original Transplant Donor to Patients With Recurrent or Persistent B-cell Malignancies After Allogeneic Stem Cell Transplantation

NCT01087294 | Completed Phase 1 FDA Drug

• 2 other identifiers: 10005410-C-0054
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 2

Brief Summary

Background:

• Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure that transplants bone marrow cells (stem cells) from a matching donor into a recipient in order to allow the donor stem cells to produce cells that will attack the recipient s cancer cells. AlloHSCT is performed when chemotherapy, immunotherapy, or radiation therapy do not adequately control cancer growth. However, cancers that are not controlled by alloHSCT frequently become resistant to other standard treatment options.
• The outcomes of alloHSCT might be improved if certain kinds of white blood cells (T cells) could be manipulated so that they generate a more potent effect against the cancer cells. This effect can be augmented by genetically engineering donor T cells to specifically recognize cancerous cells in order to attack them. For this purpose, researchers are studying a specific kind of genetically engineered T cell known as the anti-CD19-CAR-transduced T cell. More research is needed to determine if this T cell will be an effective treatment for certain kinds of B cell cancer (such as non-Hodgkin s lymphoma and chronic lymphocytic leukemia) that has not been controlled with alloHSCT. Objectives: \- To assess the safety and effectiveness of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell cancer that has not responded to alloHSCT. Eligibility:
• Individuals between 18 and 75 years of age who have received allogeneic hematopoietic stem cell transplantation for a B cell cancer, but whose cancer has either not responded to or recurred after the transplant.
• Recipients must have the same stem cell donor from their previous procedure. Design:
• Before the start of the study, all participants will be screened with a medical history and blood tests. Recipients will have tumor imaging scans, additional blood tests, and other tests as directed by the study doctors.
• Donor participants will undergo apheresis to provide white blood cells for researchers to use in the treatment.
• Recipients will have dose escalation to determine the most effective yet safe dose of anti-CD19 T cells. There will be six dose levels of anti-CD19 T cells. The first patients enrolled will have the smallest dose, and the dose will be increased when a level has been determined to be safe. .
• Recipients will be hospitalized for at least 9 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 2, 4, 8, and 12 weeks after the infusion.
• Additional scans and frequent blood tests will be required for the first 3 months after the infusion, followed by less frequent visits over time.
• Recipients will be followed for a maximum of 15 years after receiving the infusion.

Conditions

Leukemia, B-cell; Lymphoma, Hodgkins; Lymphoma, B-Cell; Lymphoma, Non-hodgkins

Keywords

CD19; Chimeric-Antigen-Receptor; Gene Therapy; Adoptive T Cell Therapy; Allogeneic Stem Cell Transplantation

Outcome Measures

Primary Outcomes (1)

• To assess the safety of allogeneic anti-CD19 CAR

  List of adverse event frequency

  4-5 weeks after first dose

Secondary Outcomes (2)

• To measure the persistence of anti-CD19-CAR- transduced T cells in the blood of patients after infusion

  Until the patient goes off-study for malignancy response assessment.

• To determine if administering anti-CD19-CAR-transduced T cells from the original transplant donor can cause regression of B-cell malignancies that are relapsed or persistent after alloHSCT

  at progression

Study Arms (3)

1A/T cell Arm (closed)

EXPERIMENTAL

Dose escalation of CAR+ T cells based on the patients actual body-weight

Procedure: Allogeneic stem cell transplant; Biological: Anti-CD19-chimeric-antigen-receptor-transduced T cells

1B/T memory stem cell arm

EXPERIMENTAL

Dose Escalation with 5 dose levels of CAR+ T memory cells based on the patients actual body-weight

Procedure: Allogeneic stem cell transplant; Biological: Anti-CD19-chimeric-antigen-receptor-transduced T cells

2/Donor arm

OTHER

Leukapheresis

Procedure: Leukapheresis

Interventions

Allogeneic stem cell transplant PROCEDURE

Allogeneic stem cell transplant

1A/T cell Arm (closed); 1B/T memory stem cell arm

Anti-CD19-chimeric-antigen-receptor-transduced T cells BIOLOGICAL

Patients receive T cells genetically engineered to express an anti-CD19 CAR. The cells are cultured in media containing IL-21, IL-7, and TWS119. TWS119 is a glycogen synthase 3 inhibitor

1A/T cell Arm (closed); 1B/T memory stem cell arm

Leukapheresis PROCEDURE

Donors will undergo leukapheresis

2/Donor arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipients (patients with B-cell malignancy) must have received an HLA-identical or 9/10 matched sibling allogeneic hematopoietic stem cell transplant, or a greater than or equal to 9/10-matched unrelated donor (URD) alloHSCT for any CD19+ B-cell malignancy. Haploidentical donors will not be used in this protocol. Patients with any CD19+ B-cell malignancy that is persistent or relapsed after all of the following interventions are eligible:
• Donor engraftment after alloHSCT (\>50% donor chimerism of the blood T cells or whole blood leukocytes or whole bone marrow).
• A trial of withdrawal of immunosuppressive therapy.
• NOTE: At least 28 days must have elapsed since the latest trial of withdraw of immunosuppression or DCI until the patient can be deemed to have persistent disease.
• CD19 expression must be detected on the majority of the malignant cells by immunohistochemistry or by flow cytometry in the Laboratory of Pathology, CCR, NCI, NIH. Definition of which cells are malignant must be determined for each patient by the Laboratory of Pathology using techniques to demonstrate monoclonality such as kappa/lambda restriction (other techniques can be used to determine monoclonality at the discretion of the Laboratory of Pathology). The choice of whether to use flow cytometry or immuohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies and bone marrow biopsies. Flow cytometry will be used for peripheral blood, fine needle aspirate, and bone marrow aspirate samples.
• Patients must be 18-75 years of age.
• Performance status: ECOG less than or equal to 2
• Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic GVHD while off of systemic immunosuppressive therapy for at least 28 days. Minimal clinical evidence of acute GVHD is defined as grade 0 to I acute GVHD. Minimal evidence of chronic GVHD is defined as chronic GVHD with no organ site with a score exceeding 1, except for the skin, for which a score of 1 or 2 will be allowable (as defined by the 2005 NIH consensus project) or no chronic GVHD. Subjects with disease that is controlled to stage I acute GVHD or chronic GVHD meeting the above criteria with local therapy only, e.g., topical cutaneous steroids, will be eligible for enrollment.
• Ability to give informed consent.
• Prior Therapy: Therapy with monoclonal antibodies and/or chemotherapy must be stopped at least 14 days prior to anti-CD19 CAR-transduced T cell infusion, and recovery of treatment-associated toxicity to less than or equal to grade 2 is required prior to infusion of cells. For patients that have received prior DCI, the last dose must be at least 28 days prior to anti-CD19 CAR-transduced T cell administration. Note that patients can be enrolled on this study at any time after or during therapy, but at least 14 days must elapse from the time of prior monoclonal antibody administration or chemotherapy until anti-CD19 CAR-transduced T cells are infused, and at least 28 days must elapse from the time of withdraw of immunosuppression, or DCI, or other immunomodulatory therapies such as lenalidomide until anti-CD19 CAR-transduced T cells are infused. Systemic immunosuppression given for graft versus host disease must be stopped at least 28 days prior to protocol entry. There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such.
• Recipients of unrelated donor transplants from a National Marrow Donor Program (NMDP) Center must sign a release of information form to authorize NMDP transfer of information to the NIH.
• Previous allogeneic donor must be willing and available to donate again.
• Patients of childbearing or child-fathering potential must be willing use an effective method of contraception while being treated on this study and for 4 months after the last cell infusion.
• Normal left ventricular function as evaluated by echocardiograph within 4 weeks of protocol therapy
• Donors greater than or equal to 18 years of age must be the same individual whose cells were used as the source for the patient s original stem cell transplant.

You may not qualify if:

• Active infection that is not responding to antimicrobial therapy.
• Sero positive for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)
• Sero positive for hepatitis B antigen, positive hepatitis B tests can be further evaluated by confirmatory tests (HBV DNA), and if confirmatory tests are negative, the patient can be enrolled.
• Sero positive for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of RNA by RT-PCR and be HCV RNA negative.
• Active psychiatric disorder which may compromise compliance with the treatment protocol, or which does not allow for appropriate informed consent (as determined by Principal Investigator and/or his designee).
• Pregnant or lactating. The effects of the immunosuppressive medications that could be required to treat GHVD are likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to an infant.
• Serum total bilirubin \> 2.5 mg/dl, serum ALT and AST values greater than or equal to 2.5 times the upper limit of normal based on age-specific normal values. If the abnormal liver function is attributable to liver involvement by malignancy, patients may be eligible with serum total bilirubin up to 5.0 mg/dl, and serum ALT and AST values up to 5.0 times the upper limit of normal, provided the patient has no evidence of impending hepatic failure (encephalopathy or prothrombin time \>2 time the upper limit of normal).
• Serum creatinine greater than 1.6 mg/dL
• Absolute neutrophil count of less than 1000 cells/ml unless low neutrophil count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
• Active cerebrospinal fluid involvement with malignancy or brain metastasis.
• Platelet count less than 30,000/ml unless low platelet count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
• Hemoglobin less than 8.0 g/dL.
• Receiving systemic corticosteroids including prednisone, dexamethasone or any other corticosteroid at doses of higher than 5 mg/day of prednisone within 28 days prior to anti-CD19-CAR-transduced T cell administration. Corticosteroid creams, ointments, and eye drops are allowed.
• Blood blast percentage higher than 5%.
• History of psychiatric disorder which may compromise compliance with this protocol or which does not allow for appropriate informed consent.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

National Marrow Donor Program

Minneapolis, Minnesota, 55401, United States

Location

Related Publications (1)

• Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, Hakim FT, Halverson DC, Fowler DH, Hardy NM, Mato AR, Hickstein DD, Gea-Banacloche JC, Pavletic SZ, Sportes C, Maric I, Feldman SA, Hansen BG, Wilder JS, Blacklock-Schuver B, Jena B, Bishop MR, Gress RE, Rosenberg SA. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013 Dec 12;122(25):4129-39. doi: 10.1182/blood-2013-08-519413. Epub 2013 Sep 20.

  PMID: 24055823 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia, B-Cell; Hodgkin Disease; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell

Interventions

Leukapheresis

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma

Intervention Hierarchy (Ancestors)

Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques

Study Officials

• James N Kochenderfer, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 13, 2010
• First Posted: March 16, 2010
• Study Start: August 4, 2010
• Primary Completion: March 8, 2024
• Study Completion: April 2, 2024
• Last Updated: May 4, 2026

Record last verified: 2026-04-30

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Clinical data will be available during the study and indefinitely.@@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.

Locations

US (2)