T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
- Conditions
- Lymphoma, Non-hodgkinsLymphoma, B-Cell
- Interventions
- Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells
- Registration Number
- NCT02659943
- Lead Sponsor
- 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.
...
- Detailed Description
Background:
* Improved treatments for a variety of treatment-resistant B-cell malignancies including Bcell lymphomas and chronic lymphocytic leukemia (CLL), are needed.
* A particular need is development of new treatments for chemotherapy-refractory B-cell malignancies.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen cluster of differentiation 19 (CD19) have caused complete remissions in a small number of patients with leukemia or lymphoma. These results demonstrate that anti-CD19 CAR-expressing T cells have antimalignancy activity in humans.
* The vast majority of B-cell malignancies express CD19.
* CD19 is not expressed by normal cells except for B cells.
* We have constructed a novel fully-human anti-CD19 CAR that can specifically recognize CD19-expressing target cells in vitro and eradicate CD19-expressing tumors in mice.
* This fully-human CAR targeting CD19 has not been tested in humans before.
* Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of normal B cells is probable, and unknown toxicities are also possible.
Objectives:
Primary
-Determine the safety and feasibility of administering T cells expressing a novel fully-human anti-CD19 CAR to patients with advanced B-cell malignancies.
Secondary
* Evaluate the in vivo persistence and peak blood levels of anti-CD19 CAR T cells after initial and repeated CAR T-cell infusions. CAR T-cell blood levels will be compared retrospectively to results with an anti-CD19 CAR containing an antigen-recognition moiety derived from a murine antibody.
* Assess for evidence of anti-malignancy activity by anti-CD19 CAR T cells
* Assess the impact of repeated CAR T-cell infusions on residual malignancy after an initial CAR T-cell infusion.
* Assess the immunogenicity of the CAR used in this protocol.
Eligibility:
* Patients must have any B-cell lymphoma, or CLL/small lymphocytic lymphoma (SLL). Lower grade lymphomas transformed to DLBCL are potentially eligible as is primary mediastinal B-cell lymphoma and all other subtypes of Diffuse large B-cell lymphoma (DLBCL).
* Patients must have malignancy that is measurable on a computed tomography (CT) scan or by flow cytometry of bone marrow or blood.
* Patients must have a creatinine of 1.4 mg/dL or less and a normal cardiac ejection fraction.
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 is required.
* No active infections are allowed including any history of hepatitis B or hepatitis C.
* Absolute neutrophil count greater than or equal to1000/microliter, platelet count greater than or equal to 45,000/microliter, hemoglobin greater than or equal to 8g/dL
* 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.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and initiation of protocol enrollment.
* The patients malignancy will need to be assessed for CD19 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffinembedded bone marrow or lymphoma sections are available from prior biopsies, these can be used to determine CD19 expression by immunohistochemistry; otherwise, patients will need to come to the NIH for a biopsy to determine CD19 expression. The sample for CD19 expression can come from a biopsy obtained at any time before enrollment.
* Patients who have never had an allogeneic hematopoietic stem cell transplant are potentially eligible.
Design:
* This is a phase I dose-escalation trial
* Patients will undergo leukapheresis
* T-cells obtained by leukapheresis will be genetically modified to express an anti-CD19 CAR
* Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused anti-CD19-CAR-expressing T cells.
* The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m(2) daily for 3 days and fludarabine 30 mg/m(2) daily for 3 days. Fludarabine will be given on the same days as the cyclophosphamide.
* Two days after the chemotherapy ends, patients will receive an infusion of anti-CD19-CAR-expressing T cells.
* The initial dose level of this dose-escalation trial will be 0.66x10(6) CAR+ T cells/kg of recipient bodyweight.
* The cell dose administered will be escalated until a maximum tolerated dose is determined.
* Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.
* Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 6, 9, and 12 months after the CAR T-cell infusion. Long-term gene-therapy follow-up consisting of yearly visits to a doctor near the patient s home for 4 more years and then yearly telephone contact for 10 additional years will be required.
* Repeat treatments consisting of the conditioning chemotherapy followed by a CAR T-cell infusion are planned for eligible patients with any best responses except continuing complete remission or progressive malignancy.
* Re-enrollment will be allowed for a small number of subjects.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 27
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description LEVEL 1 - Participants Who Received 0.66x10^6 CAR T Cells Only Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells LEVEL 1 - participants who received - 0.66x10\^6 Chimeric Antigen Receptor (CAR) T cells only LEVEL 2 - Participants Who Received 2x10^6 CAR T Cells Only Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells LEVEL 2 - participants who received - 2x10\^6 Chimeric Antigen Receptor (CAR) T cells only LEVEL 1 Foll/by LEVEL 2-Participants Who Received - 0.66x10^6 CAR T Cells Foll/by 2x10^6 CAR T Cells Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (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 LEVEL 1 Foll/by LEVEL 3 - Participants Who Received 0.66x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (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 LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (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 LEVEL 3 - Participants Who Received 6x10^6 CAR T Cells Only Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells LEVEL 3 - participants who received - 6x10\^6 Chimeric Antigen Receptor (CAR) T cells only LEVEL 1 Foll/by LEVEL 2-Participants Who Received - 0.66x10^6 CAR T Cells Foll/by 2x10^6 CAR T Cells Cyclophosphamide 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 LEVEL 1 Foll/by LEVEL 2-Participants Who Received - 0.66x10^6 CAR T Cells Foll/by 2x10^6 CAR T Cells Fludarabine 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 LEVEL 1 Foll/by LEVEL 3 - Participants Who Received 0.66x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells Fludarabine 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 LEVEL 1 Foll/by LEVEL 3 - Participants Who Received 0.66x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells Cyclophosphamide 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 LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells Cyclophosphamide LEVEL 2 followed by LEVEL 3 - participants who received - 2x10\^6 Chimeric Antigen Receptor (CAR) T cells followed by 6x10\^6 CAR T cells LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells Fludarabine LEVEL 2 followed by LEVEL 3 - participants who received - 2x10\^6 Chimeric Antigen Receptor (CAR) T cells followed by 6x10\^6 CAR T cells
- Primary Outcome Measures
Name Time Method Percentage of Enrolled Participants Who Actually Get Treated 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
Name Time Method Number of Participants With a Duration of Best Response in Months 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.
Number of Participants That Had Any Grade 2, 3, 4 and 5 Adverse Events 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.
Median Peak Chimeric Antigen Receptor (CAR) T Cells Level for Participants Treated 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.
Number of Participants Who Had a Best Response of Complete Remission (CR), Partial Remission (PR), Stable Disease (SD), and Progressive Disease (PD) 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.
Number of Participants Who Had a Second or Third Infusion of Chimeric Antigen Receptor (CAR)+ T Cells 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.
Number of Participants Who Had Anti-Lymphoma Activity 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.
Number of Participants With Evidence of Immunogenicity of the Chimeric Antigen Receptor (CAR) T-cell Product 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.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States