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