ALLPhase 1NCT01593696
Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma
A Phase 1 study testing Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) in people with ALL and B Cell Lymphoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: Although progress has been made in treating children with B-cell cancers such as leukemia or lymphoma, many children do not respond to the standard treatments. One possible treatment involves collecting white blood cells called T cells from the person with cancer and modifying the cells to attack the… Read more about this study
- Who is it for?
- Ages 1 year to 30 years
- Conditions the study is for
- ALL, B Cell Lymphoma, Leukemia
- What is being tested?
- Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 53 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Jun 2012to 2 Oct 2017
- 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 1 year to 30 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patient must have a cluster of differentiation 19 (CD19)-expressing B cell ALL or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy and one salvage regimen. In view of the principal investigator (PI) and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have disease activity that prohibits SCT at this time.
- CD19 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 30% by flow cytometry in a Clinical Laboratory Improvement Amendments (CLIA) approved test in the Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), or from the referring institution or reference laboratory. The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient. In general immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples.
- Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
- Greater than or equal to 1 year of age (and at least 15 kg) and less than or equal to 30 years of age.
- Adequate absolute CD3 count estimated to be required to obtain target cell dose based on discussion with Department of Transfusion Medicine (DTM) apheresis and Cell Processing Section, DTM.
- Subjects with the following central nervous system (CNS) status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:
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- CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs;
- CNS 2, defined as presence of < 5/uL white blood cells (WBCs) in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm
- CNS3 with marrow disease who has failed salvage systemic and intensive IT chemotherapy (and therefore not eligible for radiation)
- Patients with isolated CNS relapse will be eligible if they have previously been treated with cranial radiation (at least centigray (cGy)).
- Ability to give informed consent. For subjects <18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
- Clinical performance status: Patients > 10 years of age: Karnofsky greater than or equal to 50%; Patients less than or equal to 10 years of age: Lansky scale greater than or equal to 50%. Subjects who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
- Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
- Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.
- Cardiac function: Left ventricular ejection fraction greater than or equal to 40% by multi-gated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI), or fractional shortening greater than or equal to 28% by echocardiogram (ECHO) or left ventricular ejection fraction greater than or equal to 50% by ECHO.
- Patients with history of allogeneic stem cell transplantation are eligible if at least 100 days post-transplant, if there is no evidence of active graft versus host disease (GVHD) and no longer taking immunosuppressive agents for at least 30 days prior to enrollment.
Who cannot join
- Subjects meeting any of the following criteria are not eligible for participation in the study:
- Recurrent or refractory ALL limited to isolated testicular disease.
- Hepatic function: Inadequate liver function defined as total bilirubin > 2x upper limit of normal (ULN) (except in the case of subjects with documented Gilbert's disease > 3x ULN) or transaminase (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 20x ULN based on age and laboratory specific normal ranges;
- Renal function: Greater than age-adjusted normal serum creatinine (see below) and a creatinine clearance < 60 mL/min/1.73 m^2.
- Age:
- <= 5 yrs (Maximum Serum Creatinine = 0.8 mg/dL)
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- 5 < age <=10 yrs (Maximum Serum Creatinine =1.0 mg/dL)
- > 10 yrs (Maximum Serum Creatinine = 1.2 mg/dL)
- Hematologic function:
- Absolute neutrophil count (ANC) < 750/microliter, or platelet count < 50,000/microliter, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy);
- A subject will not be excluded because of pancytopenia greater than or equal to Grade 3 if it is due to disease, based on the results of bone marrow studies.
- Hyperleukocytosis (greater than or equal to 50,000 blasts/microliter) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy;
- Pregnant or breast-feeding females;
- Recent prior therapy:
- Systemic chemotherapy less than or equal to 2 weeks (6 weeks for nitrosoureas) or radiation therapy less than or equal to 3 weeks prior to apheresis;
- Exceptions:
- There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such;
- Subjects receiving hydroxyurea may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis;
- Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided they meet all other eligibility criteria;
- Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis;
- For radiation therapy: Radiation therapy must have been completed at least 3 weeks prior to enrollment, with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the subject has measurable/evaluable disease outside the radiation port.
- Other anti-neoplastic investigational agents currently or within 30 days prior to apheresis (i.e. start of protocol therapy);
- Subjects must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met. Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion.
- Human immunodeficiency virus/hepatitis B virus/Hepatitis C virus (HIV/HBV/HCV) Infection:
- Seropositive for HIV antibody. (Patients with HIV are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy in the future should study results indicate effectiveness.)
- Seropositive for hepatitis C or positive for Hepatitis B surface antigen (HbsAG).
- Monoclonal antibody therapy administered within 30 days of the agent prior to apheresis;
- Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the principal investigator (PI) would pose an unacceptable risk to the subject;
- Second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and subject is in remission;
- History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells (i.e. gentamicin);
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: Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies
Background:
- Although progress has been made in treating children with B-cell cancers such as leukemia or lymphoma, many children do not respond to the standard treatments. One possible treatment involves collecting white blood cells called T cells from the person with cancer and modifying the cells to attack the B-cell cancer. The cells can then be given back to the participant. This study will use T cells that have been modified to attack the cluster of differentiation 19 (CD19) protein, which is found on the surface of some B-cell cancers.
Read more
Objectives:
- To see if anti-CD19 modified white blood cells are a safe and effective treatment for children and young adults with advanced B-cell cancer.
Eligibility:
- Children and young adults between 1 and 30 years of age who have B-cell cancer (leukemia or lymphoma) that has not responded to standard treatments.
- The leukemia or the lymphoma must have the CD19 protein.
- There must be adequate organ function.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies or bone marrow biopsies may be performed depending on the type of cancer.
- Participants will undergo a process where white blood cells are collected, called apheresis. These cells will be modified to contain the anti-CD19 gene.
- Participants will have 3 days of chemotherapy to prepare their immune system to accept the modified cells.
- Participants will receive an infusion of their own modified white blood cells. They will remain in the hospital until they have recovered from the treatment.
- Participants will have frequent follow-up visits to monitor the outcome of the treatment.
- If the participant benefits from the treatment, then he/she may have the option for another round of treatment.
Read the detailed description
Background:
Chimeric antigen receptors (CAR) that recognize the cluster of differentiation 19(CD19) antigen have been constructed and are in clinical trials at several institutions. In this trial, the Pediatric Oncology Branch (POB) will utilize a chimeric receptor containing the signaling domains of cluster of differentiation 28 (CD28) and cluster of differentiation 3 (CD3)-zeta, currently under study in the Center for Cancer Research (CCR) in adults, for children and young adults with CD19 expressing malignancies.
In co-cultures with CD19-expressing acute lymphoblastic leukemia cells, anti-CD19-CAR-transduced T cells show robust killing, and in xenograft models, can rapidly clear CD19- expressing ALL cell lines.
Objectives:
- Primary: To determine the safety and feasibility of administering escalating doses of anti-CD19-CAR engineered peripheral blood lymphocytes in two strata (prior allogeneic stem cell transplant [SCT] vs. no prior SCT) of children and young adults with B cell malignancies following a cyclophosphamide/fludarabine preparative regimen. COMPLETED March 2014.
- Primary: To determine the safety of administering cells in two groups of children and young adults with B-cell malignancies expressing CD19:
- Arm 1 - Patients without high-burden disease or patients for whom chemotherapy toxicity is a concern will receive standard preparative regimen.
- Arm 2 - Patients with high-burden disease who receive standard chemotherapy to reduce burden, (defined as patients with ALL who have M3 bone marrow blasts and/or presence of peripheral blood blasts on routine complete blood count (CBC), or patients with lymphoma).
- Primary: To determine the feasibility of administering anti-CD19 CAR transduced T cells within 21 days of the target date in children and young adults with B-cell malignancies expressing CD19 enrolled on arm 2: Patients with high-burden disease who receive standard chemotherapy to reduce burden.
- Secondary: 1) To determine if the administration of anti-CD19-CAR engineered peripheral blood lymphocytes can mediate antitumor effects in children with B cell high-burden disease after standard chemotherapy, or in patients without high-burden disease who receive standard preparative regimen. 2) To evaluate the ability of CRS treatment algorithm to reduce the incidence of Grade 4 Cytokine Release Syndrome (CRS) to less than or equal to 10% of patients. 3) To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood, bone marrow and cerebrospinal fluid (CSF) of patients. 4) To describe the toxicity of administration of anti-CD19-CAR engineered peripheral blood lymphocytes in children and young adults with central nervous system (CNS) disease.
Eligibility:
Patients 1-30 years of age, at least 15 kg, with a CD19-expressing B-cell malignancy that has recurred after or not responded to one or more standard chemotherapy-containing regimens for their malignancy and is deemed incurable by standard therapy. Patients with a history of allogeneic stem cell transplant who meet all eligibility criteria are eligible to participate.
Design:
- PBMC will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from fresh or frozen peripheral blood mononuclear cells (PBMCs). On Day -7, PBMC will be enriched for cluster of differentiation 3 (CD3)+ cells and cultured in the presence of anti-CD3/-cluster of differentiation 28 (CD28) beads followed by retroviral vector supernatant containing the anti-cluster of differentiation 19 (CD19) CAR. Total culture time is approximately 7-14 days.
- Patients will be divided into the 2 groups listed above.
Arm 1: Patients will begin preparative regimen comprising fludarabine 25 mg/m(2) on Days -4, -3 and -2 and cyclophosphamide 900 mg/m(2) on day -2.
Arm 2: Patients with high-disease burden will be treated with intensive standard of care chemotherapy to decrease disease burden during cell manufacturing.
- All patients: The CD19-CAR cells will be infused on Day 0, with up to a 72h delay allowed for fresh cells or a 21 day delay if cells are cryopreserved, if needed for resolution of clinical toxicities or to generate adequate cell numbers.
- The previously determined maximum tolerated dose (MTD) of 1 X 10(6) will be administered intravenously.
- Patients will be monitored for toxicity, response and T cell persistence.
- Conditions
- ALL, B Cell Lymphoma, Leukemia, Large Cell Lymphoma, Non-Hodgkin Lymphoma
- Being tested
- Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)
- Keywords
- CD 19 Expressing B Cells, B Cell Lymphoma, ALL, Anti-CD19 Chimeric Antigen Receptor, Adoptive Immunotherapy
- Medical subject headings
- Lymphoma, B-Cell, Leukemia, Dendritic Cell Sarcoma, Interdigitating, 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 (CD)19-Chimeric antigen receptor (CAR)Biological
Cells extracted, followed by induction chemotherapy before Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) infusion (dose escalation.)
| Study group | Role | What they receive |
|---|---|---|
| Lymphodepleting regimen of Fludarabine and Cyclophosphamide | Experimental | Lymphodepleting regimen of Fludarabine and Cyclophosphamide. Receives: Biological: Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) |
| Intensive standard of care chemotherapy | Experimental | Intensive standard of care chemotherapy, in lieu of the lymphodepleting chemotherapy regimen, to decrease tumor burden in preparation for the administration of the Chimeric antigen receptor (CAR) T cells. Receives: Biological: Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Who Received Preparative Chemotherapy Followed by Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells With < Grade 4 Cytokine Release Syndrome
Participants with B cell malignancies who received preparative chemotherapy followed by CD19 CAR T-cells with < Grade 4 cytokine release syndrome.
Measured: Beginning of preparative regimen through Day 28 after CD19 CAR infusion
Number of Participants in Which the Prescribed Dose of Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells Were Successfully Manufactured
Participants who had T-cells collected by apheresis and subsequently had the amount of CAR T-cells manufactured as prescribed by the dose level they were enrolled in.
Measured: Apheresis through completion of CAR manufacturing process, approximately 2 weeks
Secondary outcomes (5)
Number of Participants Who Were Administered Intensive Chemotherapy Prior to Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR Infusion
Participants who were administered intensive chemotherapy prior to Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR): CD19 CAR infusion and received CAR cells within 21 days of the planned infusion date.
Measured: 21 days of target date
Mean Percentage Cluster of Differentiation 19 (CD19) - Chimeric Antigen-Receptor (CAR) T-Cells in Blood, Bone Marrow (BM) and Cerebrospinal Fluid (CSF)
Measure persistence of adoptively-transferred anti-CD19-CAR transduced T cells (defined by percent of CD19 CAR T-cells) in the blood and where possible the bone marrow and Cerebrospinal Fluid (CSF) of patients by flow cytometry assay.
Measured: 28 days (+/- 4 days) after infusion of CD19 CAR T-cells
Number of Patients With a Complete Response (CR)
Complete Response (CR) was assessed by bone marrow evaluation was I defined as <5% leukemic blasts.
Measured: Day 28 (+/- 4 days) after CD19 CAR infusion
Number of Participants With Grade 4 Cytokine Release Syndrome (CRS)
Participants with Grade 4 Cytokine Release Syndrome (CRS). CRS is defined as a clinical syndrome that may occur after cell therapy due to the release of cytokines (substances secreted by immune cells) into the body's blood stream.
Measured: Day 28 (+/- 4 days) after CD19 CAR infusion.
Number of Participants With Serious and Non-Serious Adverse Events
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). 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.
Measured: Date treatment consent signed to date off study, from 1.5 months up to 3.1 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 May 2012 (estimated)
- Study start29 Jun 2012
- Primary completion11 Nov 2016
- Study completion2 Oct 2017
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 (10)Papers the sponsor has linked to this study.
- Other trials for ALLStudies 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
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Nirali N. Shah, M.D., National Cancer Institute (NCI)
- Investigators
- Nirali N Shah, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01593696
- Sponsor's protocol ID
- 120112
- Other IDs
- 12-C-0112
- Status last verified
- Aug 2020
- First submitted
- 5 May 2012
- Last updated
- 31 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, Smith DD, Forman SJ, Jensen MC, Cooper LJ. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006 Nov 15;66(22):10995-1004. doi: 10.1158/0008-5472.CAN-06-0160.
PubMed 17108138Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010 Nov 18;116(20):4099-102. doi: 10.1182/blood-2010-04-281931. Epub 2010 Jul 28.
PubMed 20668228Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010 Apr;18(4):843-51. doi: 10.1038/mt.2010.24. Epub 2010 Feb 23.
PubMed 20179677Aminov S, Giricz O, Melnekoff DT, Sica RA, Polishchuk V, Papazoglu C, Yates B, Wang HW, Sahu S, Wang Y, Gordon-Mitchell S, Leshchenko VV, Schinke C, Pradhan K, Aluri S, Sohn M, Barta SK, Agarwal B, Goldfinger M, Mantzaris I, Shastri A, Matsui W, Steidl U, Brody JD, Shah NN, Parekh S, Verma A. Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency. J Clin Invest. 2024 Feb 20;134(8):e175199. doi: 10.1172/JCI175199.
PubMed 38376944Silbert SK, Madan S, Holland EM, Steinberg SM, Little L, Foley T, Epstein M, Sarkisian A, Lee DW, Nikitina E, Kakumanu S, Ruppin E, Shalabi H, Yates B, Shah NN. A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials. Blood Adv. 2023 Sep 26;7(18):5566-5578. doi: 10.1182/bloodadvances.2023009789.
PubMed 37486616Shalabi H, Martin S, Yates B, Wolters PL, Kaplan C, Smith H, Sesi CR, Jess J, Toledo-Tamula MA, Struemph K, Delbrook CP, Khan OI, Mackall CL, Lee DW, Shah NN. Neurotoxicity following CD19/CD28zeta CAR T-cells in children and young adults with B-cell malignancies. Neuro Oncol. 2022 Sep 1;24(9):1584-1597. doi: 10.1093/neuonc/noac034.
PubMed 35148417Molina JC, Steinberg SM, Yates B, Lee DW, Little L, Mackall CL, Shalabi H, Shah NN. Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation. Transplant Cell Ther. 2022 Jan;28(1):31.e1-31.e9. doi: 10.1016/j.jtct.2021.10.011. Epub 2021 Oct 20.
PubMed 34687939Shah NN, Lee DW, Yates B, Yuan CM, Shalabi H, Martin S, Wolters PL, Steinberg SM, Baker EH, Delbrook CP, Stetler-Stevenson M, Fry TJ, Stroncek DF, Mackall CL. Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL. J Clin Oncol. 2021 May 20;39(15):1650-1659. doi: 10.1200/JCO.20.02262. Epub 2021 Mar 25.
PubMed 33764809Shalabi H, Sachdev V, Kulshreshtha A, Cohen JW, Yates B, Rosing DR, Sidenko S, Delbrook C, Mackall C, Wiley B, Lee DW, Shah NN. Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies. J Immunother Cancer. 2020 Sep;8(2):e001159. doi: 10.1136/jitc-2020-001159.
PubMed 32883871Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015 Feb 7;385(9967):517-528. doi: 10.1016/S0140-6736(14)61403-3. Epub 2014 Oct 13.
PubMed 25319501
Study at a glance
From the registry record, last updated by the sponsor on 31 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies
- ClinicalTrials.gov ID
- NCT01593696
- Acronym / sponsor ID
- 120112
- Conditions
- ALL, B Cell Lymphoma, Leukemia, Large Cell Lymphoma, Non-Hodgkin Lymphoma
- Keywords
- CD 19 Expressing B Cells, B Cell Lymphoma, ALL, Anti-CD19 Chimeric Antigen Receptor, Adoptive Immunotherapy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 53 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 29 Jun 2012 (actual)
- Primary completion
- 11 Nov 2016 (actual)
- Study completion
- 2 Oct 2017 (actual)
- First posted
- 8 May 2012 (estimated)
- Results
- Posted 31 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Although progress has been made in treating children with B-cell cancers such as leukemia or lymphoma, many children do not respond to the standard treatments. One possible treatment involves collecting white blood cells called T cells from the person with cancer and modifying the cells to attack the B-cell cancer. The cells can then be given back to the participant. This study will use T cells that have been modified to attack the cluster of differentiation 19 (CD19) protein, which is found on the surface of some B-cell cancers.
Objectives:
- To see if anti-CD19 modified white blood cells are a safe and effective treatment for children and young adults with advanced B-cell cancer.
Eligibility:
- Children and young adults between 1 and 30 years of age who have B-cell cancer (leukemia or lymphoma) that has not responded to standard treatments.
- The leukemia or the lymphoma must have the CD19 protein.
- There must be adequate organ function.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies or bone marrow biopsies may be performed depending on the type of cancer.
- Participants will undergo a process where white blood cells are collected, called apheresis. These cells will be modified to contain the anti-CD19 gene.
- Participants will have 3 days of chemotherapy to prepare their immune system to accept the modified cells.
- Participants will receive an infusion of their own modified white blood cells. They will remain in the hospital until they have recovered from the treatment.
- Participants will have frequent follow-up visits to monitor the outcome of the treatment.
- If the participant benefits from the treatment, then he/she may have the option for another round of treatment.
Detailed description
Background:
Chimeric antigen receptors (CAR) that recognize the cluster of differentiation 19(CD19) antigen have been constructed and are in clinical trials at several institutions. In this trial, the Pediatric Oncology Branch (POB) will utilize a chimeric receptor containing the signaling domains of cluster of differentiation 28 (CD28) and cluster of differentiation 3 (CD3)-zeta, currently under study in the Center for Cancer Research (CCR) in adults, for children and young adults with CD19 expressing malignancies.
In co-cultures with CD19-expressing acute lymphoblastic leukemia cells, anti-CD19-CAR-transduced T cells show robust killing, and in xenograft models, can rapidly clear CD19- expressing ALL cell lines.
Objectives:
- Primary: To determine the safety and feasibility of administering escalating doses of anti-CD19-CAR engineered peripheral blood lymphocytes in two strata (prior allogeneic stem cell transplant [SCT] vs. no prior SCT) of children and young adults with B cell malignancies following a cyclophosphamide/fludarabine preparative regimen. COMPLETED March 2014.
- Primary: To determine the safety of administering cells in two groups of children and young adults with B-cell malignancies expressing CD19:
- Arm 1 - Patients without high-burden disease or patients for whom chemotherapy toxicity is a concern will receive standard preparative regimen.
- Arm 2 - Patients with high-burden disease who receive standard chemotherapy to reduce burden, (defined as patients with ALL who have M3 bone marrow blasts and/or presence of peripheral blood blasts on routine complete blood count (CBC), or patients with lymphoma).
- Primary: To determine the feasibility of administering anti-CD19 CAR transduced T cells within 21 days of the target date in children and young adults with B-cell malignancies expressing CD19 enrolled on arm 2: Patients with high-burden disease who receive standard chemotherapy to reduce burden.
- Secondary: 1) To determine if the administration of anti-CD19-CAR engineered peripheral blood lymphocytes can mediate antitumor effects in children with B cell high-burden disease after standard chemotherapy, or in patients without high-burden disease who receive standard preparative regimen. 2) To evaluate the ability of CRS treatment algorithm to reduce the incidence of Grade 4 Cytokine Release Syndrome (CRS) to less than or equal to 10% of patients. 3) To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood, bone marrow and cerebrospinal fluid (CSF) of patients. 4) To describe the toxicity of administration of anti-CD19-CAR engineered peripheral blood lymphocytes in children and young adults with central nervous system (CNS) disease.
Eligibility:
Patients 1-30 years of age, at least 15 kg, with a CD19-expressing B-cell malignancy that has recurred after or not responded to one or more standard chemotherapy-containing regimens for their malignancy and is deemed incurable by standard therapy. Patients with a history of allogeneic stem cell transplant who meet all eligibility criteria are eligible to participate.
Design:
- PBMC will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from fresh or frozen peripheral blood mononuclear cells (PBMCs). On Day -7, PBMC will be enriched for cluster of differentiation 3 (CD3)+ cells and cultured in the presence of anti-CD3/-cluster of differentiation 28 (CD28) beads followed by retroviral vector supernatant containing the anti-cluster of differentiation 19 (CD19) CAR. Total culture time is approximately 7-14 days.
- Patients will be divided into the 2 groups listed above.
Arm 1: Patients will begin preparative regimen comprising fludarabine 25 mg/m(2) on Days -4, -3 and -2 and cyclophosphamide 900 mg/m(2) on day -2.
Arm 2: Patients with high-disease burden will be treated with intensive standard of care chemotherapy to decrease disease burden during cell manufacturing.
- All patients: The CD19-CAR cells will be infused on Day 0, with up to a 72h delay allowed for fresh cells or a 21 day delay if cells are cryopreserved, if needed for resolution of clinical toxicities or to generate adequate cell numbers.
- The previously determined maximum tolerated dose (MTD) of 1 X 10(6) will be administered intravenously.
- Patients will be monitored for toxicity, response and T cell persistence.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lymphodepleting regimen of Fludarabine and Cyclophosphamide | Experimental | Biological: Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)Lymphodepleting regimen of Fludarabine and Cyclophosphamide. |
| Intensive standard of care chemotherapy | Experimental | Biological: Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)Intensive standard of care chemotherapy, in lieu of the lymphodepleting chemotherapy regimen, to decrease tumor burden in preparation for the administration of the Chimeric antigen receptor (CAR) T cells. |
Who may qualify
- Ages
- 1 year to 30 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (16 listed)
- Patient must have a cluster of differentiation 19 (CD19)-expressing B cell ALL or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy and one salvage regimen. In view of the principal investigator (PI) and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have disease activity that prohibits SCT at this time.
- CD19 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 30% by flow cytometry in a Clinical Laboratory Improvement Amendments (CLIA) approved test in the Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), or from the referring institution or reference laboratory. The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient. In general immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples.
- Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
- Greater than or equal to 1 year of age (and at least 15 kg) and less than or equal to 30 years of age.
- Adequate absolute CD3 count estimated to be required to obtain target cell dose based on discussion with Department of Transfusion Medicine (DTM) apheresis and Cell Processing Section, DTM.
Key exclusion criteria (30 listed)
- Subjects meeting any of the following criteria are not eligible for participation in the study:
- Recurrent or refractory ALL limited to isolated testicular disease.
- Hepatic function: Inadequate liver function defined as total bilirubin > 2x upper limit of normal (ULN) (except in the case of subjects with documented Gilbert's disease > 3x ULN) or transaminase (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 20x ULN based on age and laboratory specific normal ranges;
- Renal function: Greater than age-adjusted normal serum creatinine (see below) and a creatinine clearance < 60 mL/min/1.73 m^2.
- Hematologic function:
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 (CD)19-Chimeric antigen receptor (CAR)Cells extracted, followed by induction chemotherapy before Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) infusion (dose escalation.) | Biological | Intensive standard of care chemotherapy, Lymphodepleting regimen of Fludarabine and Cyclophosphamide |
Primary outcome
Number of Participants Who Received Preparative Chemotherapy Followed by Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells With < Grade 4 Cytokine Release Syndrome
Time frame: Beginning of preparative regimen through Day 28 after CD19 CAR infusion
Participants with B cell malignancies who received preparative chemotherapy followed by CD19 CAR T-cells with < Grade 4 cytokine release syndrome.
Number of Participants in Which the Prescribed Dose of Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells Were Successfully Manufactured
Time frame: Apheresis through completion of CAR manufacturing process, approximately 2 weeks
Participants who had T-cells collected by apheresis and subsequently had the amount of CAR T-cells manufactured as prescribed by the dose level they were enrolled in.
5 secondary outcomes
Number of Participants Who Were Administered Intensive Chemotherapy Prior to Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR Infusion
Time frame: 21 days of target date
Mean Percentage Cluster of Differentiation 19 (CD19) - Chimeric Antigen-Receptor (CAR) T-Cells in Blood, Bone Marrow (BM) and Cerebrospinal Fluid (CSF)
Time frame: 28 days (+/- 4 days) after infusion of CD19 CAR T-cells
Number of Patients With a Complete Response (CR)
Time frame: Day 28 (+/- 4 days) after CD19 CAR infusion
Number of Participants With Grade 4 Cytokine Release Syndrome (CRS)
Time frame: Day 28 (+/- 4 days) after CD19 CAR infusion.
Number of Participants With Serious and Non-Serious Adverse Events
Time frame: Date treatment consent signed to date off study, from 1.5 months up to 3.1 years.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 17108138Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, Smith DD, Forman SJ, Jensen MC, Cooper LJ. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006 Nov 15;66(22):10995-1004. doi: 10.1158/0008-5472.CAN-06-0160.
- Background: PubMed 20668228Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010 Nov 18;116(20):4099-102. doi: 10.1182/blood-2010-04-281931. Epub 2010 Jul 28.
- Background: PubMed 20179677Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010 Apr;18(4):843-51. doi: 10.1038/mt.2010.24. Epub 2010 Feb 23.
- Derived from this study: PubMed 38376944Aminov S, Giricz O, Melnekoff DT, Sica RA, Polishchuk V, Papazoglu C, Yates B, Wang HW, Sahu S, Wang Y, Gordon-Mitchell S, Leshchenko VV, Schinke C, Pradhan K, Aluri S, Sohn M, Barta SK, Agarwal B, Goldfinger M, Mantzaris I, Shastri A, Matsui W, Steidl U, Brody JD, Shah NN, Parekh S, Verma A. Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency. J Clin Invest. 2024 Feb 20;134(8):e175199. doi: 10.1172/JCI175199.
- Derived from this study: PubMed 37486616Silbert SK, Madan S, Holland EM, Steinberg SM, Little L, Foley T, Epstein M, Sarkisian A, Lee DW, Nikitina E, Kakumanu S, Ruppin E, Shalabi H, Yates B, Shah NN. A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials. Blood Adv. 2023 Sep 26;7(18):5566-5578. doi: 10.1182/bloodadvances.2023009789.
- Derived from this study: PubMed 35148417Shalabi H, Martin S, Yates B, Wolters PL, Kaplan C, Smith H, Sesi CR, Jess J, Toledo-Tamula MA, Struemph K, Delbrook CP, Khan OI, Mackall CL, Lee DW, Shah NN. Neurotoxicity following CD19/CD28zeta CAR T-cells in children and young adults with B-cell malignancies. Neuro Oncol. 2022 Sep 1;24(9):1584-1597. doi: 10.1093/neuonc/noac034.
- Derived from this study: PubMed 34687939Molina JC, Steinberg SM, Yates B, Lee DW, Little L, Mackall CL, Shalabi H, Shah NN. Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation. Transplant Cell Ther. 2022 Jan;28(1):31.e1-31.e9. doi: 10.1016/j.jtct.2021.10.011. Epub 2021 Oct 20.
- Derived from this study: PubMed 33764809Shah NN, Lee DW, Yates B, Yuan CM, Shalabi H, Martin S, Wolters PL, Steinberg SM, Baker EH, Delbrook CP, Stetler-Stevenson M, Fry TJ, Stroncek DF, Mackall CL. Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL. J Clin Oncol. 2021 May 20;39(15):1650-1659. doi: 10.1200/JCO.20.02262. Epub 2021 Mar 25.
- Derived from this study: PubMed 32883871Shalabi H, Sachdev V, Kulshreshtha A, Cohen JW, Yates B, Rosing DR, Sidenko S, Delbrook C, Mackall C, Wiley B, Lee DW, Shah NN. Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies. J Immunother Cancer. 2020 Sep;8(2):e001159. doi: 10.1136/jitc-2020-001159.
- Derived from this study: PubMed 25319501Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015 Feb 7;385(9967):517-528. doi: 10.1016/S0140-6736(14)61403-3. Epub 2014 Oct 13.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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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.
Nirali N Shah, 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 (CD)19-Chimeric antigen receptor (CAR) in people with ALL and B Cell Lymphoma, 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 16 inclusion and 30 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 31 Aug 2020. 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 31 Aug 2020). 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?
Number of Participants Who Received Preparative Chemotherapy Followed by Cluster of Differentiation (CD)19-Chimeric Antigen Receptor (CAR): CD19 CAR T-cells With < Grade 4 Cytokine Release Syndrome (time frame: Beginning of preparative regimen through Day 28 after CD19 CAR infusion). The study lists 2 primary outcomes in all. 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 NCT01593696, which also lists 10 linked publications.
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 31 Aug 2020.