Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02659943
Recruitment Status : Active, not recruiting
First Posted : January 21, 2016
Results First Posted : May 4, 2021
Last Update Posted : May 4, 2021
Sponsor:
Information provided by (Responsible Party):
James Kochenderfer, M.D., National Cancer Institute (NCI)

Brief Summary:

Background:

The immune system fights infection and can affect cancer cells. T cells are white blood cells that are a major part of the immune system. T cells can destroy tumors. Researchers want to try to manipulate the immune system to better recognize and kill tumor cells.

Objective:

To test the safety of giving T cells expressing a novel fully-human anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) to people with advanced B-cell cancer.

Eligibility:

People ages 18-73 with a B-cell cancer that has not been controlled by other therapies.

Design:

Participants will be screened with:

Physical exam

Blood and urine tests

Heart tests

Bone marrow sample taken

Scans in machines that take pictures

Participants will have apheresis. Blood is removed through a needle in an arm. T cells are removed. The rest of the blood is returned through a needle in the other arm.

The cells will be changed in a laboratory.

Participants will get 2 chemotherapy drugs over 3 days.

Two days later, participants will check into the hospital. They will get an intravenous (IV) catheter in an arm or chest vein. They will get the T cells through the IV in 1 infusion.

After this, participants will stay in the hospital for at least 9 days and stay nearby for 2 weeks. Then they will have blood tests and see a doctor.

Participants will have visits 6 visits for 1 year after the infusion. Some may have more follow-up visits.

Participants may samples taken of spinal fluid, bone marrow, and tumors.

...


Condition or disease Intervention/treatment Phase
Lymphoma, B-Cell Lymphoma, Non-hodgkins Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells Drug: Cyclophosphamide Drug: Fludarabine Phase 1

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: T Cells Expressing a Fully-Human Anti-CD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
Actual Study Start Date : January 21, 2016
Actual Primary Completion Date : June 12, 2018
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Fludarabine

Arm Intervention/treatment
Experimental: LEVEL 1 - Participants Who Received 0.66x10^6 CAR T Cells Only
LEVEL 1 - participants who received - 0.66x10^6 Chimeric Antigen Receptor (CAR) T cells only
Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells
Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0

Experimental: LEVEL 1 Foll/by LEVEL 2-Participants Who Received - 0.66x10^6 CAR T Cells Foll/by 2x10^6 CAR T Cells
LEVEL 1 followed by LEVEL 2 - participants who received - 0.66x10^6 Chimeric Antigen Receptor (CAR) T cells followed by 2x10^6 CAR T cells
Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells
Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0

Drug: Cyclophosphamide
300 mg/m^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3
Other Name: Cytoxan

Drug: Fludarabine
30 mg/m^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
Other Name: Fludara

Experimental: LEVEL 1 Foll/by LEVEL 3 - Participants Who Received 0.66x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells
LEVEL 1 followed by LEVEL 3 - participant who received - 0.66x10^6 Chimeric Antigen Receptor (CAR) T cells followed by 6x10^6 CAR T cells
Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells
Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0

Drug: Cyclophosphamide
300 mg/m^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3
Other Name: Cytoxan

Drug: Fludarabine
30 mg/m^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
Other Name: Fludara

Experimental: LEVEL 2 - Participants Who Received 2x10^6 CAR T Cells Only
LEVEL 2 - participants who received - 2x10^6 Chimeric Antigen Receptor (CAR) T cells only
Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells
Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0

Experimental: LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells
LEVEL 2 followed by LEVEL 3 - participants who received - 2x10^6 Chimeric Antigen Receptor (CAR) T cells followed by 6x10^6 CAR T cells
Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells
Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0

Drug: Cyclophosphamide
300 mg/m^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3
Other Name: Cytoxan

Drug: Fludarabine
30 mg/m^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
Other Name: Fludara

Experimental: LEVEL 3 - Participants Who Received 6x10^6 CAR T Cells Only
LEVEL 3 - participants who received - 6x10^6 Chimeric Antigen Receptor (CAR) T cells only
Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells
Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0




Primary Outcome Measures :
  1. Percentage of Enrolled Participants Who Actually Get Treated [ Time Frame: 4-5 weeks after the first dose ]
    Percentage of participants enrolled who received treatment with Chimeric Antigen Receptor (CAR) T cells, Fludarabine and cyclophosphamide.


Secondary Outcome Measures :
  1. Number of Participants Who Had a Best Response of Complete Remission (CR), Partial Remission (PR), Stable Disease (SD), and Progressive Disease (PD) [ Time Frame: 30 days post Chimeric Antigen Receptor (CAR) T-cells up to 5 years ]
    Response was assessed by the Revised Response Criteria for Malignant Lymphoma, and Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. Complete Remission is complete disappearance of all detectable clinical evidence of disease. Partial Remission is ≥50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Progressive Disease is ≥50% increase from nadir in the sum of the products of at least two lymph nodes, or if a single node is involved at least a 50% increase in the product of the diameters of this one node. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.

  2. Number of Participants With a Duration of Best Response in Months [ Time Frame: Response duration is the time from first documentation of response, which is one month after cell infusion in all participants, until progression, initiation of off-study treatment or the last documentation on ongoing response, approx. one month -5 years. ]
    Best Response defined as the first documentation of response was assessed by the Revised Response Criteria for Malignant Lymphoma, and Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.

  3. Number of Participants That Had Any Grade 2, 3, 4 and 5 Adverse Events [ Time Frame: Date treatment consent signed to date off study, approximately 49 months and 19 days. ]
    Adverse Events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening or disabling, and Grade 5 is fatal.

  4. Median Peak Chimeric Antigen Receptor (CAR) T Cells Level for Participants Treated [ Time Frame: All post-infusion time-points up to at least 2 months after infusion, and CAR+ T cell analysis will continue until the CAR+ T cell level drops to undetectable levels unless a stable low level of CAR+ T cells is present at more than 3 years after infusion. ]
    A quantitative polymerase chain reaction (PCR) assay or a flow cytometry assay will be used to quantitate Chimeric Antigen Receptor (CAR) + T cells. The absolute number of CAR+ peripheral blood mononuclear cells (PBMC) will be estimated by multiplying the percentage of CAR+ PBMC determined by PCR by the absolute number of lymphocytes plus monocytes per microliter of blood.

  5. Number of Participants Who Had a Second or Third Infusion of Chimeric Antigen Receptor (CAR)+ T Cells [ Time Frame: Participants could receive subsequent cell infusions any time 1 month after CAR T-cell infusion until 5 years after cell infusion. ]
    Number of participants who had a second or third Infusion Chimeric Antigen Receptor (CAR)+ T cells. Participants were eligible for a subsequent CAR T-cell infusion if the response at one month after CAR T-cell infusion was partial remission (PR) or stable disease (SD). Participants could also receive a subsequent CAR T-cell infusion if the response was complete remission (CR) but the malignancy later relapsed. CR, PR, and SD was assessed by the Revised Response Criteria for Malignant Lymphoma, and Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. Complete Remission is complete disappearance of all detectable clinical evidence of disease. Partial Remission is ≥50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.

  6. Number of Participants Who Had Anti-Lymphoma Activity [ Time Frame: 14 days up to 5 years post cell infusion. ]
    Depending on the type of disease, we use PET/CT imaging, tumor biopsies as well as bone marrow biopsies using immunohistochemistry and flow cytometry.

  7. Number of Participants With Evidence of Immunogenicity of the Chimeric Antigen Receptor (CAR) T-cell Product [ Time Frame: 9 days to 6 weeks after CAR T-cell infusion ]
    Enzyme-linked spot (ELISPOT) assays were performed to look for anti-CAR T-cell responses.


Other Outcome Measures:
  1. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [ Time Frame: Date treatment consent signed to date off study, approximately 49 months and 19 days. ]
    Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  2. MTD [ Time Frame: Within 60 days of Chimeric Antigen Receptor (CAR) T cells infusion ]
    The maximum tolerated dose is the dose at which a maximum of 1 of 6 patients has a dose limiting toxicity (DLT- Grade 3 toxicities possibly or probably related to toxicities possibly or probably related to either the anti-CD19 CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days . Grade 4 toxicities possibly or probably related to the study interventions.).

  3. Number of Participants With a Dose-Limiting Toxicity (DLT) [ Time Frame: Within 60 days of Chimeric Antigen Receptor (CAR) T cells infusion ]
    Number of participants with DLT's defined as follows: Grade 3 toxicities possibly or probably related to toxicities possibly or probably related to either the anti-CD19 CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days. Grade 4 toxicities possibly or probably related to the study interventions.

  4. Maximum Feasible Dose [ Time Frame: Within 60 days of Chimeric Antigen Receptor (CAR) T cells infusion ]
    Maximum feasible dose is the dose determined when the maximum tolerated dose (MTD) cannot be reached.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 73 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Malignancy criteria:

    • Patients with the following malignancies are potentially eligible: any B-cell lymphoma, and chronic lymphocytic leukemia (CLL). Patients with indolent malignancies that have transformed to diffuse large B-cell lymphoma are eligible.
    • Clear cluster of differentiation 19 (CD19) expression must be uniformly detected on 75% or more of malignant cells from either bone marrow or a leukemia or lymphoma mass by flow cytometry or immunohistochemistry. These assays must be performed at the National Institutes of Health. It is preferable but not required that the specimen used for CD19 determination comes from a sample that was obtained after the patient's most recent treatment. If paraffin embedded unstained samples of bone marrow involved with malignancy or a lymphoma mass are available, these can be shipped to the National Institutes of Health (NIH) for CD19 staining; otherwise, new biopsies will need to be performed for determination of CD19 expression.
    • Diffuse large B-cell lymphoma (DLBCL) patients must have received at least two prior chemotherapy-containing regimens at least one of which must have contained doxorubicin and a monoclonal antibody. Follicular lymphoma patients must have received at least 2 prior regimens including at least 1 regimen with chemotherapy. All other lymphoma and leukemia patients must have had at least 1 prior chemotherapy-containing regimen. All patients with CLL or small lymphocytic lymphoma must have had prior treatment with ibrutinib or another signal transduction inhibitor.
    • Patients must have measurable malignancy as defined by at least one of the criteria below.

      • Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest diameter) by computed tomography (CT) scan is required for all diagnoses except CLL. All masses must be less than 10 cm in the largest diameter.
      • For a lymphoma mass to count as measurable malignancy, it must have abnormally increased metabolic activity when assessed by positron emission tomography (PET) scan.
      • For CLL and lymphoma with only bone marrow involvement no mass is necessary, but if a mass is not present, bone marrow malignancy must be detectable by flow cytometry in lymphoma and CLL.
  • Other inclusion criteria:

    • Greater than or equal to 18 years of age and less than or equal to age 73.
    • Able to understand and sign the Informed Consent Document.
    • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0-1
    • Room air oxygen saturation of 92% or greater
    • Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
    • Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus. Women of child-bearing potential are defined as all women except women who are post-menopausal or who have had a hysterectomy. Postmenopausal will be defined as women over the age of 55 who have not had a menstrual period in at least 1 year.
    • Seronegative for human immunodeficiency virus (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.)
    • Patients with a known history of hepatitis B or hepatitis C are not eligible due to the risk of re-activation of hepatitis after prolonged B-cell depletion due to anti-CD19 CAR T cells.
    • Seronegative for hepatitis B antigen, positive hepatitis B tests can be further evaluated by confirmatory tests, and if confirmatory tests are negative, the patient can be enrolled. Patients with a known history of hepatitis B are not eligible.
    • Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of ribonucleic acid (RNA) by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) RNA negative. Patients with a known history of hepatitis C are not eligible.
    • Absolute neutrophil count greater than or equal to 1000/mm(3) without the support of filgrastim or other growth factors.
    • Platelet count greater than or equal to 45,000/mm(3) without transfusion support
    • Hemoglobin greater than 8.0 g/dl.
    • Less than 5% malignant cells in the peripheral blood leukocytes
    • Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
    • Serum creatinine less than or equal to 1.4 mg/dL.
    • Total bilirubin less than or equal to 2.0 mg/dl.
    • At least 14 days must have elapsed since any prior systemic therapy prior to apheresis and prior to the initiation of chemotherapy (including systemic corticosteroids at any dose). Because this protocol requires collection of autologous blood cells by leukapheresis in order to prepare CAR T cells, systemic anti-malignancy therapy including systemic corticosteroid therapy of any dose are not allowed within 14 days prior to the required leukapheresis. NOTE: Because of the long half-life and potential to affect CAR T cells, 60 days must elapse from the time of administration of anti-Programmed cell death protein 1 (PD-1) or anti-Programmed death-ligand 1 (PD-L1) antibodies or other agents that in the opinion of the PI can stimulate immune activity and infusion of CAR T cells.
    • Normal cardiac ejection fraction (greater than or equal to 55% by echocardiography) and no evidence of hemodynamically significant pericardial effusion as determined by an echocardiogram within 4 weeks of the start of the treatment protocol.
    • Patients must not take corticosteroids including prednisone, dexamethasone or any other corticosteroid for 14 days before apheresis and CAR T-cell infusion. Patients must also not take corticosteroids at doses higher than 5 mg/day of prednisone or equivalent at any time after the CAR T cell infusion.
    • Patients who have been treated on other protocols of genetically-modified T cells at the NIH only are potentially eligible under these conditions:

      • At least 6 months have elapsed since the last genetically-modified T-cell therapy that the patient received and there is no evidence of replication-competent retroviruses (evidence must be provided from prior NIH gene-therapy protocol Principal Investigator) and persisting genetically-modified T cells are not detectable in the patient's blood (evidence must be provided by prior NIH gene-therapy protocol Principal Investigator).

EXCLUSION CRITERIA:

  • Patients that require urgent therapy due to tumor mass effects or spinal cord compression.
  • Patients that have active hemolytic anemia.
  • Patients with second malignancies in addition to their B-cell malignancy are not eligible if the second malignancy has required treatment (including maintenance therapy) within the past 4 years or is not in complete remission. There are two exceptions to this criterion: successfully treated non-metastatic basal cell or squamous cell skin carcinoma.
  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
  • Active uncontrolled systemic infections (defined as infections causing fevers and infections requiring intravenous antibiotics when intravenous antibiotics have been administered for less than 72 hours), active coagulation disorders or other major uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary or immune system, history of myocardial infarction, history of ventricular tachycardia or ventricular fibrillation, active cardiac arrhythmias (active atrial fibrillation is not allowed, resolved atrial fibrillation not requiring current treatment is allowed (anticoagulants count as current treatment) ), active obstructive or restrictive pulmonary disease, active autoimmune diseases such as rheumatoid arthritis.
  • Patients will not be seen for screening appointments or enrolled on the protocol if they have been hospitalized within the 7 days prior to the screening appointment or the date of protocol enrollment.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • Systemic corticosteroid steroid therapy of any dose is not allowed within 14 days prior to the required leukapheresis, or the initiation of the conditioning chemotherapy regimen. Corticosteroid creams, ointments, and eye drops are allowed.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • Patients with current central nervous system (CNS) involvement by malignancy (either by imaging or cerebrospinal fluid involvement or biopsy-proven).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02659943


Locations
Layout table for location information
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: James N Kochenderfer, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by James Kochenderfer, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] September 17, 2020

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: James Kochenderfer, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02659943    
Other Study ID Numbers: 160054
16-C-0054
First Posted: January 21, 2016    Key Record Dates
Results First Posted: May 4, 2021
Last Update Posted: May 4, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by James Kochenderfer, M.D., National Cancer Institute (NCI):
Gene Therapy
Adoptive T Cell Therapy
Allogeneic Stem Cell Transplantation
T-cell infusion
Residual Malignancy
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Neoplasms
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists