B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma, B-Cell Prolymphocytic Leukemia, High Grade B-Cell Lymphoma, Not Otherwise Specified, Post-Transplant Lymphoproliferative Disorder, Recurrent Adult Burkitt Lymphoma, Recurrent Chronic Lymphocytic Leukemia, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Follicular Lymphoma, Recurrent Hairy Cell Leukemia, Recurrent Lymphoplasmacytic Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma
Conditions
Brief summary
This phase I trial studies the side effects and best dose of cellular immunotherapy following chemotherapy in treating patients with non-Hodgkin lymphomas, chronic lymphocytic leukemia, or B-cell prolymphocytic leukemia that has come back. Placing a modified gene into white blood cells may help the body build an immune response to kill cancer cells.
Detailed description
PRIMARY OBJECTIVES: I. To assess the safety of adoptive therapy using ex vivo expanded autologous memory T cells (central memory T cells \[Tcm\] or naive and memory T-cells \[Tn/mem\]) that are enriched and genetically modified to express a cluster of differentiation (CD)19-specific, hinged optimized, CD28-costimulatory chimeric antigen receptor (CAR) as well as a truncated human epidermal growth factor receptor (EGFR) (CD19R\[EQ\]28zeta/truncated EGFR \[EGFRt\]+ Tcm or CD19R\[EQ\]28zeta/EGFRt+ Tn/mem) shortly following lymphodepletion for adults with recurrent/progressive/residual CD19 + B-cell lymphoproliferative neoplasms (non-Hodgkin lymphoma \[NHL\], chronic lymphocytic leukemia \[CLL\]/prolymphocytic leukemia \[PLL\]) and who are not eligible for or decline City of Hope (COH) Institutional Review Board (IRB) Protocol Number (No.) 13277. II. To determine the recommended Phase II dose (RP2D) in the two Tn/mem strata (NHL; CLL/PLL). SECONDARY OBJECTIVE: I. To study antitumor activity of CD19R(EQ)CD28zeta/EGFRt+Tcm or CD19R\[EQ\]28zeta/EGFRt+ Tn/mem (e.g., detection of CAR+ T cells, B cells, and tumor burden). OUTLINE: This is a dose-escalation study of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing enriched T cells (T-cell infusion). Participants are assigned to 1 of 2 groups based on disease status. GROUP I (NON-HODGKIN LYMPHOMA \[NHL\]): LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide. CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes \>= 28 days post T cell infusion. GROUP II (CHRONIC LYMPHOCYTIC LEUKEMIA \[CLL\] AND/OR PROLYMPHOCYTIC LEUKEMIA \[PLL\]): LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine phosphate, etoposide. CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15 minutes on day 0. Patients with relapsed, residual or progressive disease may receive an optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes \>= 28 days post T cell infusion. After completion of study treatment, patients are followed up at every 2 days for 14 days, weekly for 1 month, monthly for 1 year, and then yearly for at least 15 years.
Interventions
DRUGBendamustine Hydrochloride
Given IV
DRUGCyclophosphamide
Given IV
DRUGEtoposide
Given IV
DRUGFludarabine Phosphate
Given IV
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* SCREENING INCLUSION CRITERIA: * COH pathology review confirms that research participant's diagnostic material is consistent with recurrent/progressive/residual B cell lymphoproliferative neoplasms as listed below AND the research participant is not eligible for or declines COH IRB Protocol No. 13277; additionally, CD19 positivity must be documented in a pathology report if the research participant previously received CD19-targeted therapy; however, it is not a requirement that the CD19 testing be performed by a COH pathologist * Disease stratum 1 (NHL): Unclassifiable high grade lymphoma, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) and all its subtypes, Burkitt lymphoma (BL), marginal zone B-cell lymphoma, hairy cell leukemia, lymphoplasmacytic lymphoma, B cell lymphoma unclassifiable with features intermediate between DLBCL and BL, B cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma, and those research participants who either declined or were not eligible for COH IRB Protocol No. 13277, or who collected autologous T cells for COH IRB Protocol No. 13277 but then became ineligible for autologous hematopoietic stem cell transplant (HSCT) or participants who have relapsed following prior T cell therapy on either COH IRB Protocol No. 09174 or 12224 may be enrolled on this study * Disease stratum 2 (CLL/PLL/SLL): chronic lymphocytic leukemia (CLL), and B-cell prolymphocytic leukemia (PLL), and small lymphocytic lymphoma (SLL) * Karnofsky performance status (KPS) of \>= 70% * Life expectancy \>= 16 weeks at time of screening * The effects of CD19R(EQ)28zeta/EGFRt+ TCM or CD19R(EQ)28zeta/EGFRt+ TN/MEM on the developing fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately * All subjects must have the ability to understand and the willingness to sign a written informed consent * Note: For research participants who do not speak English, a short form consent may be used with a COH certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed; however, the research participant is allowed to proceed with lymphodepletion and T cell infusion only after the translated full consent form is signed * PROTOCOL-SPECIFIC CRITERIA: * COH pathology review confirms that research participant's diagnostic material is consistent with a lymphoproliferative B-cell neoplasm * Documentation of recurrence/progression/residual disease following prior therapy * Negative serum pregnancy test for women of childbearing potential * A pretreatment creatinine clearance (CrCl) of \>= 60 mL/minute (min), calculated by Cockcroft Gault * Patients must have a serum bilirubin =\< 2.0 mg/dl * Patients must have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 times the institutional upper limits of normal * Ejection fraction measured by echocardiogram or multi gated acquisition scan (MUGA) \> 45% (evaluation within 6 weeks of screening does not need to be repeated) * ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION * Research participant must have appropriate venous access * Research participant must be at least 2 weeks from having received the last dose of immunosuppressant medications (e.g. calcineurin inhibitors, methotrexate, immunosuppressive antibodies, etc) * The last dose of prior chemotherapy, immunotherapy or radiation must be at least 2 weeks before the leukapheresis procedure * The last dose of cytotoxic chemotherapeutic agents that are not considered lymphotoxic must be at least one week before the leukapheresis procedure; oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 3 half-lives have elapsed prior to leukapheresis * The last dose of lymphotoxic chemotherapeutic agents (e.g. cyclophosphamide, ifosofamide, bendamustine, etc) must be at least 2 weeks before the leukapheresis procedure * The last dose of investigational agents must be at least 2 weeks before leukapheresis procedure unless no response or disease progression is documented on the experimental therapy and at least 3 half-lives must have elapsed prior to leukapheresis * Note: exceptions may be made at the discretion of the principal investigator (PI)/study team * ELIGIBILITY TO UNDERGO LYMPHODEPLETION: * Research participant has a released cryopreserved T cell product for T cell infusions on approximately day 0 * Research participant must be at least 2 weeks out from having received the last dose of investigational agent * The last dose of cytotoxic chemotherapeutic agents that are not considered lymphotoxic must be at least one week before lymphodepletion; oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 3 half-lives have elapsed prior to lymphodepletion * The last dose of lymphotoxic chemotherapeutic agents (e.g. cyclophosphamide, ifosofamide, bendamustine, etc) must be at least 2 weeks before lymphodepletion * Toxicity related to prior therapy must either have returned to =\< grade 3, baseline, or deemed irreversible * KPS \>= 70% * Participants of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 8 weeks after T cell infusion * Absolute neutrophil count (ANC) \> 0.75 * Platelets \> 50 K without growth factor or transfusion support for a week at least * Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air * Not requiring pressor support, not having symptomatic cardiac arrhythmias * Preservation of renal function, serum creatinine did NOT increase by more than 2 fold above the normal range * Total bilirubin =\< 2.0 mg/dL * Research participant without clinically significant encephalopathy/new focal deficits * No clinical evidence of uncontrolled active infectious process * (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS): Research participant has completed prescribed lymphodepletion * (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS): Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air * (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS): Not requiring pressor support, not having symptomatic cardiac arrhythmias * (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS): Preservation of renal function, serum creatinine did NOT increase by more than 2 fold above the normal range * (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS): Total bilirubin =\< 2.0 mg/dL * (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS): Research participant without clinically significant encephalopathy/new focal deficits * (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS): No clinical evidence of uncontrolled active infectious process
Exclusion criteria
* SCREENING
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity profile of T-cell infusion as defined by all toxicities associated with T cells at the probably or definite levels | Up to 15 years | Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0) and modified cytokine release syndrome grading as applicable. Tables will summarize all toxicities and side effects by dose, time post treatment (first 28 days, days 29-60, 61-100, \>100 days), organ and severity. |
| Dose-limiting toxicity rate at the recommended phase II dose assessed using CTCAE v4.0 | Up to 28 days | Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Detection of transferred T cells in the circulation for at least 28 days by quantitative-polymerase chain reaction | 28 days | Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. |
| Disease response by physical exam, lab data, radiographic imaging and, in the case of stratum 2 (chronic lymphocytic leukemia/prolymphocytic leukemia) and leukemic phase non-Hodgkin lymphoma patients by flow cytometry and bone marrow biopsy | Up to 15 years | Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. |
| CD19 B cell aplasia/immunoglobulin G levels | Up to 15 years | Normal CD19+ B cell levels and immunoglobulin G levels will be reported over the study period using both descriptive statistics and graphical methods. |
Countries
United States
Outcome results
None listed