CD19-Positive Neoplastic Cells PresentPhase 1/2NCT01865617
Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia
A Phase 1/2 study testing Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes in people with CD19-Positive Neoplastic Cells Present and Recurrent Adult Acute Lymphoblastic Leukemia, run by Fred Hutchinson Cancer Center at 1 site in United States.
Trial summary
This phase I/II trial studies the side effects and best dose of laboratory treated T cells to see how well they work in treating patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia that have come back or have not responded to treatment. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- CD19-Positive Neoplastic Cells Present, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Chronic Lymphocytic Leukemia
- What is being tested?
- Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 204 participants
- Where
- 1 siteUnited States
- Study dates
- 22 May 2013to 26 Mar 2021
- Phase
- Phase 1/2
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- INCLUSIONS FOR SCREENING AND LEUKAPHERESIS
- Patients with CD19 expressing acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL)
- Ability to understand and provide informed consent
- Not human immunodeficiency virus (HIV) infected
- INCLUSIONS FOR CAR-T CELL THERAPY
- Patients with:
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- CLL who are beyond first remission and who have failed combination chemoimmunotherapy with regimens containing a purine analogue and anti-CD20 antibody or who were not eligible for such therapy; patients with CLL for whom ibrutinib is now standard first line therapy, must have progressed on ibrutinib; patients with fludarabine refractory disease are eligible; patients may be treated following allogeneic hematopoietic cell transplant (HCT); for the concurrent ibrutinib cohort, patients must agree to continue on or be restarted on ibrutinib and must not have had prior intolerance to ibrutinib that would prevent this; patients managed with prior dose reductions for toxicity will continue at the reduced dose for the remainder of this study
- Indolent NHL or mantle cell NHL who are beyond first remission and previously treated with chemoimmunotherapy or who were not eligible for such therapy; patients who have relapsed following autologous or allogeneic HCT are eligible
- Aggressive NHL such as diffuse large B-cell lymphoma (DLBCL), who have relapsed or have residual disease following treatment with curative intent; patients should have relapsed following, or not be eligible for high-dose therapy and autologous HCT; patients with chemotherapy refractory disease or marrow involvement or comorbidities precluding successful autologous HCT are eligible; patients may be treated following allogeneic HCT
- Patients with CD19 expressing, relapsed or refractory ALL
- Patients with one of the above diagnoses whose disease state does not qualify but who have prognostic indicators that suggest a high risk of progression of disease may be screened and undergo leukapheresis; enrollment for T cell therapy would require meeting the full disease state eligibility
- Confirmation of diagnosis
- Evidence of CD19 expression by immunohistochemistry or flow cytometry on any prior or current tumor specimen or high likelihood of CD19 expression based on disease histology
- Karnofsky performance status >= 60%
- All patients of childbearing potential must be willing to use a contraceptive method before, during, and for at least two months after the T cell infusion
- Ability to understand and provide informed consent
Who cannot join
- EXCLUSIONS FOR CAR-T CELL THERAPY
- Patients requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of prednisone per day (or equivalent); pulsed corticosteroid use for disease control is acceptable
- Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the Principal Investigator (PI)
- Serum creatinine > 2.5 mg/dL
- Serum glutamic oxaloacetic transaminase (SGOT) > 5 x upper limit of normal
- Bilirubin > 3.0 mg/dL
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- Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing; those with a forced expiratory volume in one second (FEV1) of < 50 % of predicted will be excluded
- Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% will be excluded
- Significant cardiovascular abnormalities as defined by any one of the following: New York Heart Association (NYHA) class III or IV congestive heart failure, clinically significant hypotension, uncontrolled symptomatic coronary artery disease, or a documented ejection fraction of < 35%
- Uncontrolled active infection
Trial locations and contacts
1 site in 1 country.
United States1 site
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, 98109
About this study
Official title: Phase I/II Study of Immunotherapy for Advanced CD19+ Chronic Lymphocytic Leukemia, Acute Lymphoblastic Leukemia/Lymphoma and Non-Hodgkin Lymphoma With Defined Subsets of Autologous T Cells Engineered to Express a CD19-Specific Chimeric Antigen Receptor
This phase I/II trial studies the side effects and best dose of laboratory treated T cells to see how well they work in treating patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia that have come back or have not responded to treatment. T cells that are treated in the laboratory before being given back to the patient may make the body build an immune response to kill cancer cells.
Read the detailed description
PRIMARY OBJECTIVES:
- To evaluate the feasibility and safety of adoptive T cell therapy using ex vivo expanded autologous CD8 positive (+) and CD4+ CD19 chimeric antigen receptor (CAR)-T cells for patients with advanced CD19+ B cell malignancies.
SECONDARY OBJECTIVES:
- To determine the duration of in vivo persistence of adoptively transferred T cells, and the phenotype of persisting T cells.
II. To determine if adoptively transferred T cells traffic to the bone marrow and function in vivo.
III. To determine if the adoptive transfer of CD19 CAR-T cells results in depletion of CD19+ B cells in vivo as a surrogate for functional activity.
IV. To determine if the adoptive transfer of CD19 CAR-T cells has antitumor activity in patients with measurable tumor burden prior to T cell transfer.
- To determine if the adoptive transfer of CD19 CAR-T cells is associated with tumor lysis syndrome.
OUTLINE: This is a phase I, dose-escalation study of autologous CD19 CAR T-cells followed by a phase II study.
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells intravenously (IV) over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
DOSE DENSE EXPANSION COHORT: An additional cohort will receive a second anti-CD19-CAR lentiviral vector-transduced autologous T cell infusion without additional lymphodepleting chemotherapy 10-21 days after the first infusion if adequate CD19 CAR-T cells can be produced and appropriate criteria are met.
After completion of study treatment, patients are followed up for at least 15 years.
- Conditions
- CD19-Positive Neoplastic Cells Present, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Chronic Lymphocytic Leukemia, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Non-Hodgkin Lymphoma
- Being tested
- Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesBiological
Given IV
| Study group | Role | What they receive |
|---|---|---|
| ALL (high tumor burden) dose level 1 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 1 up to 2x105 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| ALL (high tumor burden) dose level 2 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 2 up to 2x106 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| ALL (high tumor burden) dose level 3 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 3 up to 2x107 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| ALL (low tumor burden) dose level 1 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: low Dose level: 1 up to 2x105 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| ALL (low tumor burden) dose level 2 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: ALL Tumor Burden: high Dose level: 2 up to 2x106 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| CLL dose level 1 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL Dose level: 1 up to 2x105 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| CLL dose level 2 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL Dose level: 2 up to 2x106 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| CLL dose level 3 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL Dose level: 3 up to 2x107 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| CLL (ibrutinib) dose level 2 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: CLL (ibrutinib) Dose level: 2 up to 2x106 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| NHL dose level 1 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 1 up to 2x105 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| NHL dose level 2 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 2 up to 2x106 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| NHL dose level 3 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 3 up to 2x107 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
| NHL (dose dense) dose level 2 | Experimental | Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
Disease subgroup: NHL Dose level: 2 up to 2x106 EGFR+ cells/kg Receives: Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes |
What is being measured
The primary outcome is the main question the study is designed to answer.
Death Within 8 Weeks of the Study Cell Infusion Thought to be Definitely or Probably Related to Chimeric Antigen Receptor (CAR) T Cell Therapy
Death within 8 weeks of the study cell infusion thought to be definitely or probably related to CAR T cell therapy will be assessed.
Measured: Within 8 weeks of the study cell infusion
Dose Limiting Toxicities
Outcome will be reported as a count of participants that experienced a dose limiting toxicity on the study within 30 days post infusion.
Measured: 30 days
Objective Response Rate of Complete Response and Partial Response
Outcome will be reported as the count of patients per arm that experienced a complete response/partial response.
Complete response (CR): CR per Lugano criteria for nodal disease and minimal residual disease (MRD)-negative CR by flow cytometry for marrow disease.
Partial response (PR): > 50% reduction of the sum of the products of the perpendicular diameters of marker lesions, no progression of any existing lesions, and no new lesions.
Measured: Up to 1 year
Overall Survival
Outcome will be reported as a count of patients who survived up to 1 year post infusion.
Measured: Up to 1 year
Progression Free Survival
Outcome will be reported as the count of patients per arm that survived and whose disease did not progress in the 1 year timeframe post infusion.
Measured: Up to 1 year
Secondary outcomes (2)
Duration of Persistence of Adoptively Transferred CD19 Chimeric Antigen Receptor (CAR)-T Cells
Duration of persistence of adoptively transferred CD19 chimeric antigen receptor (CAR)-T cells. Outcome will be reported for each of the 3 cohorts on the study. Outcome data is both count of patients alive after 1 year and count of patients with CAR-T cells detected at 1 year.
Measured: Up to day 365
Migration of Adoptively Transferred CD19 Chimeric Antigen Receptor (CAR)-T Cells
Migration of adoptively transferred CD19 chimeric antigen receptor (CAR)-T cells. Outcome will be reported for each of the 3 cohorts on the study. Outcome data is both count of patients with bone marrow disease involvement and count of patients with CAR-T cells detected in bone marrow at restaging.
Measured: Up to 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 May 2013 (estimated)
- Study start22 May 2013
- Primary completion26 Mar 2021
- Study completion26 Mar 2021
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 (12)Papers the sponsor has linked to this study.
- Other trials for CD19-Positive Neoplastic Cells PresentStudies of the same condition, open and under way.
- More trials run by Fred Hutchinson Cancer CenterThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 204 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fred Hutchinson Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Principal investigator, Alexandre Hirayama, Fred Hutchinson Cancer Center
- Investigators
- Jordan Gauthier, Principal investigator, Fred Hutch/University of Washington Cancer Consortium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01865617
- Sponsor's protocol ID
- 2639.00
- Other IDs
- NCI-2013-00073, 2639, RG9213011, P50CA107399, R01CA136551
- Status last verified
- May 2022
- First submitted
- 28 May 2013
- Last updated
- 25 May 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ortiz-Maldonado V, Liang EC, Huang JJ, Jeon Y, Hirayama AV, Kimble EL, Portuguese AJ, Khouderchah C, Braathen K, Torkelson A, Kirchmeier D, Shadman M, Maloney DG, Riddell SR, Turtle CJ, Gauthier J. A novel dose-dense strategy for CD19-directed CAR T-cell therapy is associated with durable responses without increased toxicity in patients with B-cell non-Hodgkin lymphoma. Haematologica. 2026 Jul 2. doi: 10.3324/haematol.2025.300321. Online ahead of print.
PubMed 42389828Fiorenza S, Zheng Y, Purushe J, Bock TJ, Sarthy J, Janssens DH, Sheih AS, Kimble EL, Kirchmeier D, Phi TD, Gauthier J, Hirayama AV, Riddell SR, Wu Q, Gottardo R, Maloney DG, Yang JYH, Henikoff S, Turtle CJ. Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion. Nat Commun. 2024 Sep 27;15(1):8309. doi: 10.1038/s41467-024-52503-2.
PubMed 39333103Liang EC, Albittar A, Huang JJ, Hirayama AV, Kimble EL, Portuguese AJ, Chapuis A, Shadman M, Till BG, Cassaday RD, Milano F, Kiem HP, Riddell SR, Turtle CJ, Maloney DG, Gauthier J. Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL. Blood Adv. 2023 Nov 28;7(22):6990-7005. doi: 10.1182/bloodadvances.2023011399.
PubMed 37774014Juluri KR, Wu QV, Voutsinas J, Hou J, Hirayama AV, Mullane E, Miles N, Maloney DG, Turtle CJ, Bar M, Gauthier J. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy. Blood Adv. 2022 Apr 12;6(7):2055-2068. doi: 10.1182/bloodadvances.2020004142.
PubMed 34666344Ernst 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 34515338Gauthier J, Bezerra ED, Hirayama AV, Fiorenza S, Sheih A, Chou CK, Kimble EL, Pender BS, Hawkins RM, Vakil A, Phi TD, Steinmetz RN, Jamieson AW, Bar M, Cassaday RD, Chapuis AG, Cowan AJ, Green DJ, Kiem HP, Milano F, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood. 2021 Jan 21;137(3):323-335. doi: 10.1182/blood.2020006770.
PubMed 32967009Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Riddell SR, Maloney DG, Turtle CJ. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood. 2019 Aug 15;134(7):636-640. doi: 10.1182/blood.2019000905.
PubMed 31648294Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, Li D, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Acharya UH, Cassaday RD, Chapuis AG, Dhawale TM, Hendrie PC, Kiem HP, Lynch RC, Ramos J, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood. 2019 Apr 25;133(17):1876-1887. doi: 10.1182/blood-2018-11-887067. Epub 2019 Feb 19.
PubMed 30782611Tuazon SA, Li A, Gooley T, Eunson TW, Maloney DG, Turtle CJ, Linenberger ML, Connelly-Smith LS. Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies. Transfusion. 2019 May;59(5):1773-1780. doi: 10.1111/trf.15178. Epub 2019 Feb 6.
PubMed 30729531Hay KA, Gauthier J, Hirayama AV, Voutsinas JM, Wu Q, Li D, Gooley TA, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Schoch G, Chapuis AG, Till BG, Kiem HP, Ramos JD, Shadman M, Cassaday RD, Acharya UH, Riddell SR, Maloney DG, Turtle CJ. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019 Apr 11;133(15):1652-1663. doi: 10.1182/blood-2018-11-883710. Epub 2019 Feb 6.
PubMed 30728140Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, Riddell SR, Maloney DG, Boeckh M, Turtle CJ. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018 Jan 4;131(1):121-130. doi: 10.1182/blood-2017-07-793760. Epub 2017 Oct 16.
PubMed 29038338Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016 Jun 1;126(6):2123-38. doi: 10.1172/JCI85309. Epub 2016 Apr 25.
PubMed 27111235
Study at a glance
From the registry record, last updated by the sponsor on 25 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study of Immunotherapy for Advanced CD19+ Chronic Lymphocytic Leukemia, Acute Lymphoblastic Leukemia/Lymphoma and Non-Hodgkin Lymphoma With Defined Subsets of Autologous T Cells Engineered to Express a CD19-Specific Chimeric Antigen Receptor
- ClinicalTrials.gov ID
- NCT01865617
- Acronym / sponsor ID
- 2639.00
- Conditions
- CD19-Positive Neoplastic Cells Present, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Chronic Lymphocytic Leukemia, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Non-Hodgkin Lymphoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 204 participants (actual)
- Lead sponsor
- Fred Hutchinson Cancer CenterUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 22 May 2013 (actual)
- Primary completion
- 26 Mar 2021 (actual)
- Study completion
- 26 Mar 2021 (actual)
- First posted
- 31 May 2013 (estimated)
- Results
- Posted 25 May 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase I/II trial studies the side effects and best dose of laboratory treated T cells to see how well they work in treating patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia that have come back or have not responded to treatment. T cells that are treated in the laboratory before being given back to the patient may make the body build an immune response to kill cancer cells.
Detailed description
PRIMARY OBJECTIVES:
- To evaluate the feasibility and safety of adoptive T cell therapy using ex vivo expanded autologous CD8 positive (+) and CD4+ CD19 chimeric antigen receptor (CAR)-T cells for patients with advanced CD19+ B cell malignancies.
SECONDARY OBJECTIVES:
- To determine the duration of in vivo persistence of adoptively transferred T cells, and the phenotype of persisting T cells.
II. To determine if adoptively transferred T cells traffic to the bone marrow and function in vivo.
III. To determine if the adoptive transfer of CD19 CAR-T cells results in depletion of CD19+ B cells in vivo as a surrogate for functional activity.
IV. To determine if the adoptive transfer of CD19 CAR-T cells has antitumor activity in patients with measurable tumor burden prior to T cell transfer.
- To determine if the adoptive transfer of CD19 CAR-T cells is associated with tumor lysis syndrome.
OUTLINE: This is a phase I, dose-escalation study of autologous CD19 CAR T-cells followed by a phase II study.
Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells intravenously (IV) over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity.
DOSE DENSE EXPANSION COHORT: An additional cohort will receive a second anti-CD19-CAR lentiviral vector-transduced autologous T cell infusion without additional lymphodepleting chemotherapy 10-21 days after the first infusion if adequate CD19 CAR-T cells can be produced and appropriate criteria are met.
After completion of study treatment, patients are followed up for at least 15 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 13
| Arm | Type | Receives |
|---|---|---|
| ALL (high tumor burden) dose level 1 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: ALL Tumor Burden: high Dose level: 1 up to 2x105 EGFR+ cells/kg |
| ALL (high tumor burden) dose level 2 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: ALL Tumor Burden: high Dose level: 2 up to 2x106 EGFR+ cells/kg |
| ALL (high tumor burden) dose level 3 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: ALL Tumor Burden: high Dose level: 3 up to 2x107 EGFR+ cells/kg |
| ALL (low tumor burden) dose level 1 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: ALL Tumor Burden: low Dose level: 1 up to 2x105 EGFR+ cells/kg |
| ALL (low tumor burden) dose level 2 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: ALL Tumor Burden: high Dose level: 2 up to 2x106 EGFR+ cells/kg |
| CLL dose level 1 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: CLL Dose level: 1 up to 2x105 EGFR+ cells/kg |
| CLL dose level 2 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: CLL Dose level: 2 up to 2x106 EGFR+ cells/kg |
| CLL dose level 3 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: CLL Dose level: 3 up to 2x107 EGFR+ cells/kg |
| CLL (ibrutinib) dose level 2 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: CLL (ibrutinib) Dose level: 2 up to 2x106 EGFR+ cells/kg |
| NHL dose level 1 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: NHL Dose level: 1 up to 2x105 EGFR+ cells/kg |
| NHL dose level 2 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: NHL Dose level: 2 up to 2x106 EGFR+ cells/kg |
| NHL dose level 3 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: NHL Dose level: 3 up to 2x107 EGFR+ cells/kg |
| NHL (dose dense) dose level 2 | Experimental | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesPatients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells IV over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or without additional lymphodepleting chemotherapy if there is persistent disease in the absence of unacceptable toxicity. Disease subgroup: NHL Dose level: 2 up to 2x106 EGFR+ cells/kg |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- INCLUSIONS FOR SCREENING AND LEUKAPHERESIS
- Patients with CD19 expressing acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL)
- Ability to understand and provide informed consent
- Not human immunodeficiency virus (HIV) infected
- INCLUSIONS FOR CAR-T CELL THERAPY
Key exclusion criteria (10 listed)
- EXCLUSIONS FOR CAR-T CELL THERAPY
- Patients requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of prednisone per day (or equivalent); pulsed corticosteroid use for disease control is acceptable
- Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the Principal Investigator (PI)
- Serum creatinine > 2.5 mg/dL
- Serum glutamic oxaloacetic transaminase (SGOT) > 5 x upper limit of normal
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 |
|---|---|---|
| Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T LymphocytesGiven IV | Biological | ALL (high tumor burden) dose level 1, ALL (high tumor burden) dose level 2, ALL (high tumor burden) dose level 3, ALL (low tumor burden) dose level 1, ALL (low tumor burden) dose level 2, CLL (ibrutinib) dose level 2, CLL dose level 1, CLL dose level 2, CLL dose level 3, NHL (dose dense) dose level 2, NHL dose level 1, NHL dose level 2, NHL dose level 3 |
Primary outcome
Death Within 8 Weeks of the Study Cell Infusion Thought to be Definitely or Probably Related to Chimeric Antigen Receptor (CAR) T Cell Therapy
Time frame: Within 8 weeks of the study cell infusion
Death within 8 weeks of the study cell infusion thought to be definitely or probably related to CAR T cell therapy will be assessed.
Dose Limiting Toxicities
Time frame: 30 days
Outcome will be reported as a count of participants that experienced a dose limiting toxicity on the study within 30 days post infusion.
Objective Response Rate of Complete Response and Partial Response
Time frame: Up to 1 year
Outcome will be reported as the count of patients per arm that experienced a complete response/partial response. Complete response (CR): CR per Lugano criteria for nodal disease and minimal residual disease (MRD)-negative CR by flow cytometry for marrow disease. Partial response (PR): > 50% reduction of the sum of the products of the perpendicular diameters of marker lesions, no progression of any existing lesions, and no new lesions.
Overall Survival
Time frame: Up to 1 year
Outcome will be reported as a count of patients who survived up to 1 year post infusion.
Progression Free Survival
Time frame: Up to 1 year
Outcome will be reported as the count of patients per arm that survived and whose disease did not progress in the 1 year timeframe post infusion.
2 secondary outcomes
Duration of Persistence of Adoptively Transferred CD19 Chimeric Antigen Receptor (CAR)-T Cells
Time frame: Up to day 365
Migration of Adoptively Transferred CD19 Chimeric Antigen Receptor (CAR)-T Cells
Time frame: Up to 1 year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 May 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42389828Ortiz-Maldonado V, Liang EC, Huang JJ, Jeon Y, Hirayama AV, Kimble EL, Portuguese AJ, Khouderchah C, Braathen K, Torkelson A, Kirchmeier D, Shadman M, Maloney DG, Riddell SR, Turtle CJ, Gauthier J. A novel dose-dense strategy for CD19-directed CAR T-cell therapy is associated with durable responses without increased toxicity in patients with B-cell non-Hodgkin lymphoma. Haematologica. 2026 Jul 2. doi: 10.3324/haematol.2025.300321. Online ahead of print.
- Derived from this study: PubMed 39333103Fiorenza S, Zheng Y, Purushe J, Bock TJ, Sarthy J, Janssens DH, Sheih AS, Kimble EL, Kirchmeier D, Phi TD, Gauthier J, Hirayama AV, Riddell SR, Wu Q, Gottardo R, Maloney DG, Yang JYH, Henikoff S, Turtle CJ. Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion. Nat Commun. 2024 Sep 27;15(1):8309. doi: 10.1038/s41467-024-52503-2.
- Derived from this study: PubMed 37774014Liang EC, Albittar A, Huang JJ, Hirayama AV, Kimble EL, Portuguese AJ, Chapuis A, Shadman M, Till BG, Cassaday RD, Milano F, Kiem HP, Riddell SR, Turtle CJ, Maloney DG, Gauthier J. Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL. Blood Adv. 2023 Nov 28;7(22):6990-7005. doi: 10.1182/bloodadvances.2023011399.
- Derived from this study: PubMed 34666344Juluri KR, Wu QV, Voutsinas J, Hou J, Hirayama AV, Mullane E, Miles N, Maloney DG, Turtle CJ, Bar M, Gauthier J. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy. Blood Adv. 2022 Apr 12;6(7):2055-2068. doi: 10.1182/bloodadvances.2020004142.
- 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.
- Derived from this study: PubMed 32967009Gauthier J, Bezerra ED, Hirayama AV, Fiorenza S, Sheih A, Chou CK, Kimble EL, Pender BS, Hawkins RM, Vakil A, Phi TD, Steinmetz RN, Jamieson AW, Bar M, Cassaday RD, Chapuis AG, Cowan AJ, Green DJ, Kiem HP, Milano F, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood. 2021 Jan 21;137(3):323-335. doi: 10.1182/blood.2020006770.
- Derived from this study: PubMed 31648294Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Riddell SR, Maloney DG, Turtle CJ. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood. 2019 Aug 15;134(7):636-640. doi: 10.1182/blood.2019000905.
- Derived from this study: PubMed 30782611Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, Li D, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Acharya UH, Cassaday RD, Chapuis AG, Dhawale TM, Hendrie PC, Kiem HP, Lynch RC, Ramos J, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood. 2019 Apr 25;133(17):1876-1887. doi: 10.1182/blood-2018-11-887067. Epub 2019 Feb 19.
- Derived from this study: PubMed 30729531Tuazon SA, Li A, Gooley T, Eunson TW, Maloney DG, Turtle CJ, Linenberger ML, Connelly-Smith LS. Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies. Transfusion. 2019 May;59(5):1773-1780. doi: 10.1111/trf.15178. Epub 2019 Feb 6.
- Derived from this study: PubMed 30728140Hay KA, Gauthier J, Hirayama AV, Voutsinas JM, Wu Q, Li D, Gooley TA, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Schoch G, Chapuis AG, Till BG, Kiem HP, Ramos JD, Shadman M, Cassaday RD, Acharya UH, Riddell SR, Maloney DG, Turtle CJ. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019 Apr 11;133(15):1652-1663. doi: 10.1182/blood-2018-11-883710. Epub 2019 Feb 6.
- Derived from this study: PubMed 29038338Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, Riddell SR, Maloney DG, Boeckh M, Turtle CJ. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018 Jan 4;131(1):121-130. doi: 10.1182/blood-2017-07-793760. Epub 2017 Oct 16.
- Derived from this study: PubMed 27111235Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016 Jun 1;126(6):2123-38. doi: 10.1172/JCI85309. Epub 2016 Apr 25.
- Individual participant dataSharing planned: No
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.
Jordan Gauthier principal investigator
Fred Hutch/University of Washington Cancer Consortium
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T Lymphocytes in people with CD19-Positive Neoplastic Cells Present and Recurrent Adult Acute Lymphoblastic Leukemia, run by Fred Hutchinson Cancer Center 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 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 25 May 2022. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 25 May 2022). 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?
Death Within 8 Weeks of the Study Cell Infusion Thought to be Definitely or Probably Related to Chimeric Antigen Receptor (CAR) T Cell Therapy (time frame: Within 8 weeks of the study cell infusion). The study lists 5 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 NCT01865617, which also lists 12 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 25 May 2022.