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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01087294
First received: March 13, 2010
Last updated: June 25, 2014
Last verified: May 2014
  Purpose

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 four 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. To reduce the risk of side effects, participants who received a stem cell transplant from an unrelated donor will receive a lower dose of anti-CD19 T cells than those who received a transplant from a related donor.
  • Recipients will be hospitalized for 3 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 1, 2, 3, 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.

Condition Intervention Phase
Leukemia, B-cell
Lymphoma, Hodgkins
Lymphoma, Non-hodgkins
Lymphoma, B-cell
Procedure: Allogeneic stem cell transplant
Biological: Anti-CD19-chimeric-antigenreceptor- traduced T cell
Drug: Cyclophosphamide
Drug: Pentostatin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To assess the safety of allogeneic anti-CD19-CAR [ Time Frame: 4-5 weeks after the first dose ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 36
Study Start Date: February 2010
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
Dose escalation for recipients of HLA-matched sibling allogeneic stemm cell transplant
Procedure: Allogeneic stem cell transplant
Allogeneic stem cell transplant
Biological: Anti-CD19-chimeric-antigenreceptor- traduced T cell
Patients receive T cells genetically engineered to express an anti-CD19 CAR
Drug: Cyclophosphamide
180 mg/m2 IV infusion over 30 minutes on days -4, -3 and -2
Drug: Pentostatin
4 mg/m2 IV infusion over 30 minutes following the cyclophosphamide on day -4
Experimental: Group B
Dose escalation for recipients of unrelated donor allogeneic stem cell transplants
Procedure: Allogeneic stem cell transplant
Allogeneic stem cell transplant
Biological: Anti-CD19-chimeric-antigenreceptor- traduced T cell
Patients receive T cells genetically engineered to express an anti-CD19 CAR
Drug: Cyclophosphamide
180 mg/m2 IV infusion over 30 minutes on days -4, -3 and -2
Drug: Pentostatin
4 mg/m2 IV infusion over 30 minutes following the cyclophosphamide on day -4

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Inclusion Criteria: Recipient

  1. Recipients (patients with B-cell malignancy) must have received an HLA-identical sibling allogeneic hematopoietic stem cell transplant, a 1-antigen mismatched related transplant, or a greater than or equal to 7/8-matched unrelated donor (URD) alloHSCT for any CD19+ B-cell malignancy. Patients with any CD19+ B-cell malignancy that is persistent or relapsed after all of the following interventions are eligible:

    1. Donor T cell engraftment after alloHSCT (> 50% donor chimerism of the T cell compartment and a circulating T cell population for at least 12 weeks).
    2. A trial of withdrawal of immunosuppressive therapy.
    3. At least one donor lymphocyte infusion (DLI) with a minimum T cell dose of 1 times 10(7) CD3+ cells/kg in the case of HLA-identical sibling transplants and 1-antigen mismatched related transplants or 1 times 10(6) CD3+ cells/kg in the case of greater than or equal to 7/8-matched HLA-matched URD transplants.

    Only patients with ALL are eligible after full-donor T cell engraftment and a trial of withdraw of immunosuppression. Prior DLI is not an eligibility requirement for patients with ALL.

    At least 4 weeks must have elapsed since the latest trial of withdraw of immunosuppression or DLI until the patient can be deemed to have persistent disease.

  2. 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.
  3. Patients must be 18-75 years of age.
  4. Performance status: ECOG less than or equal to 2 (Karnofsky performance status greater than or equal to 60%)
  5. Life expectancy greater than or equal to 3 months.
  6. 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 mild global score chronic GVHD (as defined by the 2005 NIH consensus project) or no chronic GVHD. Subjects with disease that is controlled to stage I acute GVHD or to mild global score chronic GVHD with local therapy only, e.g., topical cutaneous steroids or oral budesonide, will be eligible for enrollment.
  7. Provision for a Durable Power of Attorney.
  8. Ability to give informed consent.
  9. Prior Therapy: Therapy with monoclonal antibodies and/or chemotherapy must be stopped at least 7 days prior to anti-CD19 CAR-transduced T cell infusion, and recovery of treatment-associated toxicity to < grade 2 is required prior to infusion of cells. For patients that have received prior DLI, 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 DLI until anti-CD19 CAR-transduced T cells are infused. Systemic immunosuppression 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.
  10. 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.
  11. Previous allogeneic donor must be willing and available to donate again.
  12. 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.
  13. Normal left ventricular function as evaluated by echocardiograph within 6 weeks of anti- CD19-CAR-transduced T cell infusion

Inclusion Criteria: Donor

  1. 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.
  2. Adequate venous access for peripheral leukapheresis, or consent to use a temporary central venous catheter for leukapheresis.
  3. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative.
  4. Ability to give informed consent.
  5. Donor selection will be in accordance with NIH/CC Department of Transfusion Medicine (DTM) criteria and, in the case of an unrelated donor from a Transplant Center, the National Marrow Donor Program (NMDP) standards. When a potentially eligible recipient of an unrelated donor product from an NMDP Center is identified, the recipient will complete an NMDP search transfer request to allow NIH NMDP staff to contact the NMDP Coordinating Center, who will, in turn, contact the donor s prior Donor Center. The NMDP Policy for Subsequent Donation Requests will be followed and the appropriate forms (Subsequent Donation Request form) and Therapeutic T Cell Collection Prescription will be submitted as required.

EXCLUSION CRITERIA:

Exclusion Criteria: Recipients

  1. Active infection that is not responding to antimicrobial therapy.
  2. Evidence of infection with HIV, Hepatitis B or Hepatitis C. Patients must be HIV negative, Hepatitis B surface antigen, and Hepatitis C antibody negative. The high degree of immune suppression that may be used in this study may lead to the activation or progression of these viral illnesses.
  3. 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).
  4. 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.
  5. 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 times the upper limit of normal).
  6. Absolute neutrophil count of less than 500 cells/microL unless low neutrophil count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
  7. Active cerebrospinal fluid involvement with malignancy or brain metastasis.
  8. Platelet count less than 10,000/microL unless low platelet count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
  9. Anemia (Hb < 9 gm/dl) that cannot be corrected with transfusion. It is not atypical to have recipients with Hb levels < 9 gm/dl following transplantation, due to multiple factors (e.g. medications, low serum erythropoietin levels, etc.). As such, recipients with Hb < 9 gm/dl will be eligible if Hb can be increased and sustained (> 7days) with transfusion and the case is individually approved by the NIH Blood Bank. All patients with Hb < 9 gm/dl will undergo full evaluation for anemia.
  10. Receiving corticosteroids above physiological dosing within 28 days prior to anti-CD19-CAR-transduced T cell administration.

Exclusion Criteria: Donors

  1. History of psychiatric disorder which may compromise compliance with this protocol or which does not allow for appropriate informed consent.
  2. History of hypertension that is not controlled by medication, stroke, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.
  3. Donors must not be pregnant.
  4. Anemia (Hb < 11 gm/dl) or thrombocytopenia (platelets < 100,000 per microL). However, potential donors with Hb levels < 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy. The NIH Clinical Center, Department of Transfusion Medicine/NMDP physicians will determine the appropriateness of individuals as donors.
  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: NCT01087294

Contacts
Contact: James N Kochenderfer, M.D. (301) 594-5340 kochendj@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: James N Kochenderfer, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01087294     History of Changes
Other Study ID Numbers: 100054, 10-C-0054
Study First Received: March 13, 2010
Last Updated: June 25, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
CD19
Chimeric-Antigen-Receptor
Gene Therapy
Adoptive T Cell Therapy
Allogeneic Stem Cell Transplantation
B Cell Cancer
Allogenic Stem Cell Transplant

Additional relevant MeSH terms:
Lymphoma, B-Cell
Leukemia, B-Cell
Hodgkin Disease
Leukemia
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Lymphoid
Cyclophosphamide
Pentostatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Adenosine Deaminase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014