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

Phase 1

Recruiting

• Conditions: Recurrent Mantle Cell Lymphoma; Refractory Mantle Cell Lymphoma; CD19 Positive; Refractory Chronic Lymphocytic Leukemia; Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Follicular Lymphoma; Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma
• Interventions: Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Biological: Tocilizumab

• Registration Number: NCT04007029
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2019-06-20
• Study First Submitted QC: 2019-07-01
• Study First Posted: 2019-07-05
• Study Start: 2019-10-04
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-01
• Last Update Posted: 2024-11-04
• Primary Completion: 2025-08-01
• Study Completion: 2026-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 24

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (fludarabine, cyclophosphamide, CD19/CD20 T-cells)	Chimeric Antigen Receptor T-Cell Therapy	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.
Treatment (fludarabine, cyclophosphamide, CD19/CD20 T-cells)	Cyclophosphamide	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.
Treatment (fludarabine, cyclophosphamide, CD19/CD20 T-cells)	Fludarabine Phosphate	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.
Treatment (fludarabine, cyclophosphamide, CD19/CD20 T-cells)	Tocilizumab	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.

Primary Outcome Measures

Name	Time	Method
Incidence of adverse events	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.
Dose-limiting toxicities	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

Name	Time	Method
Clinical response	Up to 15 years	Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used.
Duration of remission	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.
Objective response rate (ORR)	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.
Chimeric antigen receptor (CAR) T-cell (T) 19/20 bispecific transgenic T-cell persistence	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.
Duration of B-cell aplasia following CART19/20 infusion.	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.
Progression-free survival	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.
Overall survival (OS)	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).
Frequency of T cell phenotypic markers on CART19/20 cells using flow cytometry	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.

Trial Locations

Locations (1)

UCLA / Jonsson Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States