Lymphoma, B-CellPhase 1NCT02659943
T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
A Phase 1 study testing Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells, Cyclophosphamide and Fludarabine in people with Lymphoma, B-Cell and Lymphoma, Non-hodgkins, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 73 years
- Conditions the study is for
- Lymphoma, B-Cell, Lymphoma, Non-hodgkins
- What is being tested?
- Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells, Cyclophosphamide and Fludarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 1 siteUnited States
- Study dates
- 21 Jan 2016to 31 Dec 2022
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 73 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 31Show fewer
- 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).
Who cannot join
- 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.
Show all 10Show fewer
- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: T Cells Expressing a Fully-Human Anti-CD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
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.
Read more
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.
...
Read the 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.
- Conditions
- Lymphoma, B-Cell, Lymphoma, Non-hodgkins
- Being tested
- Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells, Cyclophosphamide, Fludarabine
- Keywords
- Gene Therapy, Adoptive T Cell Therapy, Allogeneic Stem Cell Transplantation, T-cell infusion, Residual Malignancy
- Medical subject headings
- Lymphoma, B-Cell, Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cellsBiological
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
CyclophosphamideDrug
Also called Cytoxan
300 mg/m^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3
FludarabineDrug
Also called Fludara
30 mg/m^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
| Study group | Role | What they receive |
|---|---|---|
| LEVEL 1 - Participants Who Received 0.66x10^6 CAR T Cells Only | Experimental | LEVEL 1 - participants who received - 0.66x10^6 Chimeric Antigen Receptor (CAR) T cells only Receives: Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (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 | Experimental | 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 Receives: Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells; Drug: Cyclophosphamide; Drug: Fludarabine |
| LEVEL 1 Foll/by LEVEL 3 - Participants Who Received 0.66x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells | Experimental | 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 Receives: Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells; Drug: Cyclophosphamide; Drug: Fludarabine |
| LEVEL 2 - Participants Who Received 2x10^6 CAR T Cells Only | Experimental | LEVEL 2 - participants who received - 2x10^6 Chimeric Antigen Receptor (CAR) T cells only Receives: Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells |
| LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells | Experimental | LEVEL 2 followed by LEVEL 3 - participants who received - 2x10^6 Chimeric Antigen Receptor (CAR) T cells followed by 6x10^6 CAR T cells Receives: Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells; Drug: Cyclophosphamide; Drug: Fludarabine |
| LEVEL 3 - Participants Who Received 6x10^6 CAR T Cells Only | Experimental | LEVEL 3 - participants who received - 6x10^6 Chimeric Antigen Receptor (CAR) T cells only Receives: Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Enrolled Participants Who Actually Get Treated
Percentage of participants enrolled who received treatment with Chimeric Antigen Receptor (CAR) T cells, Fludarabine and cyclophosphamide.
Measured: 4-5 weeks after the first dose
Secondary outcomes (7)
Number of Participants Who Had a Best Response of Complete Remission (CR), Partial Remission (PR), Stable Disease (SD), and Progressive Disease (PD)
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.
Measured: 30 days post Chimeric Antigen Receptor (CAR) T-cells up to 5 years
Number of Participants With a Duration of Best Response in Months
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.
Measured: 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.
Number of Participants That Had Any Grade 2, 3, 4 and 5 Adverse Events
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.
Measured: Date treatment consent signed to date off study, approximately 49 months and 19 days.
Median Peak Chimeric Antigen Receptor (CAR) T Cells Level for Participants Treated
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.
Measured: 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.
Number of Participants Who Had a Second or Third Infusion of Chimeric Antigen Receptor (CAR)+ T Cells
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.
Measured: 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 Anti-Lymphoma Activity
Depending on the type of disease, we use PET/CT imaging, tumor biopsies as well as bone marrow biopsies using immunohistochemistry and flow cytometry.
Measured: 14 days up to 5 years post cell infusion.
Number of Participants With Evidence of Immunogenicity of the Chimeric Antigen Receptor (CAR) T-cell Product
Enzyme-linked spot (ELISPOT) assays were performed to look for anti-CAR T-cell responses.
Measured: 9 days to 6 weeks after CAR T-cell infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jan 2016 (estimated)
- Study start21 Jan 2016
- Primary completion12 Jun 2018
- Study completion31 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Lymphoma, B-CellStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, James Kochenderfer, M.D., National Cancer Institute (NCI)
- Investigators
- James N Kochenderfer, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02659943
- Sponsor's protocol ID
- 160054
- Other IDs
- 16-C-0054
- Status last verified
- Mar 2023
- First submitted
- 20 Jan 2016
- Last updated
- 19 Apr 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
PubMed 34515338
Study at a glance
From the registry record, last updated by the sponsor on 19 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- T Cells Expressing a Fully-Human Anti-CD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
- ClinicalTrials.gov ID
- NCT02659943
- Acronym / sponsor ID
- 160054
- Conditions
- Lymphoma, B-Cell, Lymphoma, Non-hodgkins
- Keywords
- Gene Therapy, Adoptive T Cell Therapy, Allogeneic Stem Cell Transplantation, T-cell infusion, Residual Malignancy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 21 Jan 2016 (actual)
- Primary completion
- 12 Jun 2018 (actual)
- Study completion
- 31 Dec 2022 (actual)
- First posted
- 21 Jan 2016 (estimated)
- Results
- Posted 4 May 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| LEVEL 1 - Participants Who Received 0.66x10^6 CAR T Cells Only | Experimental | Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cellsLEVEL 1 - participants who received - 0.66x10^6 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 | Experimental | Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells, Drug: Cyclophosphamide, Drug: FludarabineLEVEL 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 | Experimental | Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells, Drug: Cyclophosphamide, Drug: FludarabineLEVEL 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 - Participants Who Received 2x10^6 CAR T Cells Only | Experimental | Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cellsLEVEL 2 - participants who received - 2x10^6 Chimeric Antigen Receptor (CAR) T cells only |
| LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells | Experimental | Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells, Drug: Cyclophosphamide, Drug: FludarabineLEVEL 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 | Experimental | Biological: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cellsLEVEL 3 - participants who received - 6x10^6 Chimeric Antigen Receptor (CAR) T cells only |
Who may qualify
- Ages
- 18 to 73 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (31 listed)
- Malignancy criteria:
- Other inclusion criteria:
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cellsDose-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 | Biological | LEVEL 1 - Participants Who Received 0.66x10^6 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, LEVEL 1 Foll/by LEVEL 3 - Participants Who Received 0.66x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells, LEVEL 2 - Participants Who Received 2x10^6 CAR T Cells Only, LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells, LEVEL 3 - Participants Who Received 6x10^6 CAR T Cells Only |
| CyclophosphamideAlso: Cytoxan300 mg/m^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 | Drug | LEVEL 1 Foll/by LEVEL 2-Participants Who Received - 0.66x10^6 CAR T Cells Foll/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, LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells |
| FludarabineAlso: Fludara30 mg/m^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3 | Drug | LEVEL 1 Foll/by LEVEL 2-Participants Who Received - 0.66x10^6 CAR T Cells Foll/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, LEVEL 2 Followed by LEVEL 3-Participants Who Received 2x10^6 CAR T Cells Foll/by 6x10^6 CAR T Cells |
Primary outcome
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.
7 secondary outcomes
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
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.
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.
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.
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 Anti-Lymphoma Activity
Time frame: 14 days up to 5 years post cell infusion.
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Apr 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34515338Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
Related trials for Lymphoma, B-Cell
RecruitingPhase 1/2
Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) in Relapsed/Refractory B-cell Lymphoma
Lymphoma, Non-Hodgkin Lymphoma
Active, not recruitingPhase 1/2
Study to Evaluate the Safety and Preliminary Efficacy of Ibrutinib and Pembrolizumab in Patients With Chronic Lymphocytic Leukemia (CLL) or Mantle Cell Lymphoma (MCL)
Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma
RecruitingPhase 1
Anti-CRLF2-R/TSLPR Chimeric Antigen Receptor T Cells (TSLPR-CART) in Participants With Recurrent or Refractory CRLF2-R/TSLPR-Overexpressing B-Cell Acute Lymphoblastic Leukemia (B-ALL)
B-All, Acute Lymphoblastic Leukemia
RecruitingObservational study
Collection of Human Samples to Study Hairy Cell and Other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment
Hairy Cell Leukemia (HCL), Chronic Lymphocytic Leukemia (CLL)
Active, not recruitingPhase 1
Copanlisib and Nivolumab in Treating Patients With Richter's Transformation or Transformed Indolent Non-Hodgkin Lymphoma
Chronic Lymphocytic Leukemia, Diffuse Large B-Cell Lymphoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James N Kochenderfer, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells, Cyclophosphamide and Fludarabine in people with Lymphoma, B-Cell and Lymphoma, Non-hodgkins, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 31 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 May 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Enrolled Participants Who Actually Get Treated (time frame: 4-5 weeks after the first dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02659943, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Apr 2023.