Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Modified Immune Cells (CD19/CD20 CAR-T Cells) in Treating Patients With Recurrent or Refractory B-Cell Lymphoma or Chronic Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04007029
Recruitment Status : Recruiting
First Posted : July 3, 2019
Last Update Posted : October 9, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Parker Institute for Cancer Immunotherapy
Information provided by (Responsible Party):
Jonsson Comprehensive Cancer Center

Brief Summary:
This phase I trial studies the side effects and best dose of CD19/CD20 chimeric antigen receptor (CAR) T-cells when given together with chemotherapy, and to see how effective they are in treating patients with non-Hodgkin's B-cell lymphoma or chronic lymphocytic leukemia that has come back (recurrent) or has not responded to treatment (refractory). In CAR-T cell therapy, a patient's white blood cells (T cells) are changed in the laboratory to produce an engineered receptor that allows the T cell to recognize and respond to CD19 and CD20 proteins. CD19 and CD20 are commonly found on non-Hodgkin?s B-cell lymphoma and chronic lymphocytic leukemia cells. Chemotherapy drugs such as fludarabine phosphate and cyclophosphamide can control cancer cells by killing them, by preventing their growth, or by stopping them from spreading. Combining CD19/CD20 CAR-T cells and chemotherapy may help treat patients with recurrent or refractory B-cell lymphoma or chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
CD19 Positive CD20 Positive Recurrent Chronic Lymphocytic Leukemia Recurrent Diffuse Large B-Cell Lymphoma Recurrent Follicular Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Diffuse Large B-Cell Lymphoma Refractory Follicular Lymphoma Refractory Mantle Cell Lymphoma Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma Refractory Small Lymphocytic Lymphoma Biological: Chimeric Antigen Receptor T-Cell Therapy Drug: Cyclophosphamide Drug: Fludarabine Phosphate Biological: Tocilizumab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety of the autologous anti-CD19/anti-CD20 CAR-expressing naive/memory T cells (CART19/20), including determination of the maximum tolerated dose and assessment for replication competent lentivirus (RCL).

SECONDARY OBJECTIVES:

I. Clinical response. Ia. Overall response rate. Ib. Duration of remission. Ic. Progression-free survival. Id. Overall survival. II. CD19/CD20 bispecific CAR transgenic T-cell persistence. IIa. T-cell monitoring and analyses. IIb. Evidence of B-cell aplasia.

EXPLORATORY OBJECTIVES:

I. To determine the serum levels of cytokines associated with cytokine release syndrome (CRS) in subjects exhibiting > grade-2 CRS following CART19/20 cell treatment.

OUTLINE: This is a dose-escalation study of CD19/CD20 CAR-T cells.

CONDITIONING CHEMOTHERAPY: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes and cyclophosphamide IV over 60 minutes 5, 4, and 3 days before cell infusion.

T-CELL INFUSION: Patients receive CD19/CD20 CAR-T cells IV on day 0. Patients with cytokine release syndrome may also receive tocilizumab IV on day 2 at the discretion of the clinical investigator.

After completion of study treatment, patients are followed up daily for 14 days, on days 30, 45, 60, 70, 90, and 120, every 3 months for 2 years, every 6 months for 3 years, and then annually for a minimum of 15 years.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR)-T Cells for the Treatment of Relapsed or Refractory B-Cell Lymphomas and Chronic Lymphocytic Leukemia (CD20 - Cluster of Differentiation Antigen 20)
Actual Study Start Date : October 4, 2019
Estimated Primary Completion Date : August 1, 2022
Estimated Study Completion Date : August 1, 2023


Arm Intervention/treatment
Experimental: Treatment (fludarabine, cyclophosphamide, CD19/CD20 T-cells)

CONDITIONING CHEMOTHERAPY: Patients receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 60 minutes 5, 4, and 3 days before cell infusion.

T-CELL INFUSION: Patients receive CD19/CD20 CAR-T cells IV on day 0. Patients with cytokine release syndrome may also receive tocilizumab IV on day 2 at the discretion of the clinical investigator.

Biological: Chimeric Antigen Receptor T-Cell Therapy
Given Autologous anti-CD19/anti-CD20 CAR-expressing naive/memory T cells IV
Other Names:
  • CAR T Infusion
  • CAR T Therapy
  • CAR T-cell therapy
  • Chimeric Antigen Receptor T-cell Infusion

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP (cyclophosphamide) monohydrate
  • CTX (cytoxan)
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP fludarabine: 2-Fluoroadenine 9-beta-D-Arabinofuranoside 5'-Monophosphate
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Biological: Tocilizumab
Given IV
Other Names:
  • Actemra
  • Immunoglobulin G1, Anti-(Human Interleukin 6 Receptor) (Human-Mouse Monoclonal MRA Heavy Chain), Disulfide with Human-Mouse Monoclonal MRA Kappa-Chain, Dimer
  • MRA (myeloma receptor antibody)
  • R-1569
  • RoActemra




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 28 days from infusion ]
    Will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with the exception of cytokine release syndrome (CRS), which will be graded on the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS scale. Simple descriptive statistics will be used to summarize toxicities observed after each transgenic T-cell infusion in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by CTCAE toxicity table) and minimum or maximum values for laboratory measures, time of onset, duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects. Adverse events will be tabulated by treatment group and will include the number of patients for whom the event occurred, the rate of occurrence, and the severity and relationship to study drug.

  2. Dose-limiting toxicities [ Time Frame: Up to 28 days from infusion ]
    Will be assessed per CTCAE version 5.0 with the exception of CRS as mentioned above.


Secondary Outcome Measures :
  1. Clinical response [ Time Frame: Up to 15 years ]
    Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used.

  2. Duration of remission [ Time Frame: Time from complete remission (CR)/partial remission (PR) measurement criteria are first met until the first date that recurrent or progressive disease is objectively documented, or until death, assessed up to 15 years ]
    Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used. Will also be summarized descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum). Figures showing the Kaplan-Meier estimates will also be presented.

  3. Objective response rate (ORR) [ Time Frame: Up to 15 years ]
    Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used. ORR and the individual rate for CR and PR will be summarized with the frequency count and the percentage of subjects in each category, along with a 2-sided 95% exact confidence interval.

  4. Progression-free survival [ Time Frame: From time of study entry to documentation of objective disease progression or death due to any cause assessed up to 15 years ]
    Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used. Will also be summarized descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum). Figures showing the Kaplan-Meier estimates will also be presented.

  5. Overall survival (OS) [ Time Frame: From date of enrollment until death, assessed up to 15 years ]
    Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used. Will be summarized with figures using the Kaplan-Meier method. The Kaplan-Meier estimates for the 1-year OS (rates and the 2-sided 95% confidence interval of the rates using the Greenwood?s formula will be reported. Will also be summarized descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum).

  6. Chimeric antigen receptor (CAR) T-cell (T) 19/20 bispecific transgenic T-cell persistence [ Time Frame: Up to 5 years post-infusion ]
    Descriptive statistics of T-cell counts over time, including simple summary measures and plots appropriate for longitudinal data will be used.

  7. Frequency of T cell phenotypic markers on CART19/20 cells using flow cytometry [ Time Frame: Up to 5 years post-infusion ]
    The frequency of CART19/20 cell properties will be assessed using flow cytometry to indicate the % and/or total number of CART19/20 cells expressing critical markers, for example CD3 (cluster of differentiation 3), CD4 (cluster of differentiation 4), and CD8 (cluster of differentiation 8), to determine correlations between CART19/20 properties, treatment efficacy, and CART19/20 cell persistence.

  8. Duration of B-cell aplasia following CART19/20 infusion. [ Time Frame: Up to 2 years post-infusion ]
    The duration of time patients experience B-cell aplasia (<3% of lymphocytes in the peripheral blood expressing either CD19 or CD20, measured with immunohistochemistry (IHC) and/or flow cytometry) following infusion of CART19/20 cells will be determined.


Other Outcome Measures:
  1. Analysis of proteins/cytokines (c-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)) concentration in peripheral blood following CART19/20 infusion. [ Time Frame: Up to 30 days post-infusion ]
    The cytokine levels in patients who receive CAR therapies will be monitored to help clarify the complex relationship between CRS severity, toxicity, T-cell survival, and disease eradication. Cytokine levels will be quantified in patients exhibiting any > grade-2 CRS. Cytokine levels in patients who do not exhibit CRS, or exhibit =< grade-2 CRS, will be quantified at the discretion of the investigator. The concentration in blood of each protein will be measured (CRP: mg/dL; IL-6, TNF-α, IFN-γ: pg/mL).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL) that is refractory to standard-of-care options

    • DLBCL and PMBCL: primary refractory; relapsed after two prior lines of therapy
    • MCL, FL, CLL, and SLL: primary refractory; relapsed after three or more prior rounds of therapy
  • > 30% positivity in malignant cells of either CD19 and/or CD20
  • Minimum tumor burden of 1.5 cm^3 for lymphoma
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Adequate bone marrow and major organ function to undergo a T cell transplant determined within 30?60 days prior to enrollment using standard phase I criteria for organ function. Blood may be evaluated while a patient is receiving growth factor support. Patients will be re-evaluated for organ function within 14 days of beginning conditioning chemotherapy
  • Absolute neutrophil count (ANC) >= 1 x 10^9 cells/L (within 30-60 days prior to enrollment)
  • Platelets >= 75 x 10^9/L (within 30-60 days prior to enrollment)
  • Hemoglobin >= 8 g/dL (with or without transfusion) (within 30-60 days prior to enrollment)
  • Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x upper limit of normal (ULN) (within 30-60 days prior to enrollment)
  • Total bilirubin =< 2 x ULN (except patients with documented Gilbert?s syndrome) (within 30-60 days prior to enrollment)
  • Creatinine < 2 mg/dL (or a glomerular filtration rate > 45) (within 30-60 days prior to enrollment)
  • Must be willing and able to accept at least one leukapheresis procedure
  • Must be willing and able to provide written informed consent

Exclusion Criteria:

  • Inability to purify >= 1 x 10^7 T cells from leukapheresis product
  • Previously known hypersensitivity to any of the agents used in this study; known sensitivity to cyclophosphamide or fludarabine
  • Received systemic treatment for cancer, including immunotherapy, within 14 days prior to initiation of conditioning chemotherapy administration within this protocol. Patients who have received anti-CD19 CAR T-cells will be excluded from this trial. Consistent with current trials, patients may otherwise be given bridging therapy at the discretion of the lead study investigator
  • Patients who have received an allograft transplant will NOT be allowed to participate in the trial. Patients who have received an autologous transplant will not be excluded and may participate in the trial
  • Potential requirement for systemic corticosteroids or concurrent immunosuppressive drugs based on prior history or received systemic steroids within the last 2 weeks prior to enrollment (inhaled or topical steroids at standard doses are allowed)
  • Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired immune deficiency state, which would increase the risk of opportunistic infections and other complications during chemotherapy-induced lymphodepletion. If there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist
  • Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would increase the likelihood of hepatic toxicities from the chemotherapy conditioning regimen and supportive treatments. If there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist
  • Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol
  • Known clinically active brain metastases. Prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases. A brain magnetic resonance imaging (MRI) scan taken within 60 days of screening may be used, otherwise a brain MRI must be performed to confirm absence of brain metastases
  • A Tiffeneau-Pinelli index < 70% of the predicted value. Subjects will be excluded if pulmonary function tests indicate they have insufficient pulmonary capability
  • A left ventricular ejection fraction as determined by an echocardiogram lower than 40% would preclude participation
  • Pregnancy or breast-feeding. Female patients must be surgically sterile or be postmenopausal for two years, or must agree to use effective contraception during the period of treatment and for 6 months afterwards. All female patients with reproductive potential must have a negative pregnancy test (serum/urine) at screening and again within 14 days from starting the conditioning chemotherapy. The definition of effective contraception will be based on the judgment of the study investigators. Patients who are breastfeeding are not allowed on this study
  • History of other malignancy in the past 3 years with the following exceptions:

    • Malignancy treated with curative intent and no known active disease
    • Adequately treated non-melanoma skin cancer without evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Adequately treated breast ductile carcinoma without evidence of disease
    • Prostate cancer with a Gleason score less than 6 with undetectable prostate specific antigen over 12 months
    • Adequately treated urothelial non-invasive carcinoma or carcinoma in situ
    • Similar neo-plastic conditions with an expectation of greater than 95% disease free survival

Information from the National Library of Medicine

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

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04007029


Contacts
Layout table for location contacts
Contact: Bruck Habtemariam 310 794-0242 BHabtemariam@mednet.ucla.edu

Locations
Layout table for location information
United States, California
UCLA / Jonsson Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90095
Contact: Bruck Habtemariam    310-794-0242    BHabtemariam@mednet.ucla.edu   
Principal Investigator: Sarah Larson, M.D.         
Sponsors and Collaborators
Jonsson Comprehensive Cancer Center
National Cancer Institute (NCI)
Parker Institute for Cancer Immunotherapy
Investigators
Layout table for investigator information
Principal Investigator: Sarah Larson, MD UCLA / Jonsson Comprehensive Cancer Center

Layout table for additonal information
Responsible Party: Jonsson Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04007029     History of Changes
Other Study ID Numbers: 18-001989
NCI-2019-03190 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
18-001989 ( Other Identifier: UCLA / Jonsson Comprehensive Cancer Center )
P30CA016042 ( U.S. NIH Grant/Contract )
First Posted: July 3, 2019    Key Record Dates
Last Update Posted: October 9, 2019
Last Verified: October 2019

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Leukemia
Lymphoma, Follicular
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Leukemia, B-Cell
Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic