Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia, or B-Cell Prolymphocytic Leukemia

NCT02153580 | Active Not Recruiting Phase 1 DMC

• 9 other identifiers: 13351NCI-2014-0116811402512284212057411165813351/117351115691P30CA033572
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• Toxicity profile of T-cell infusion as defined by all toxicities associated with T cells at the probably or definite levels

  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.

  Up to 15 years

• Dose-limiting toxicity rate at the recommended phase II dose assessed using CTCAE v4.0

  Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.

  Up to 28 days

Secondary Outcomes (3)

• Detection of transferred T cells in the circulation for at least 28 days by quantitative-polymerase chain reaction

  28 days

• 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

• CD19 B cell aplasia/immunoglobulin G levels

  Up to 15 years

Study Arms (2)

Group I (lymphodepletion, cellular immunotherapy)

EXPERIMENTAL

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. Disease status: Patients with Non-Hodgkin lymphoma (NHL).

Biological: Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes; Drug: Bendamustine Hydrochloride; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Fludarabine Phosphate

Group II (lymphodepletion, cellular immunotherapy)

EXPERIMENTAL

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. Disease status: Patients with Chronic lymphocytic leukemia (CLL) and/or Prolymphocytic Leukemia (PLL).

Biological: Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes; Drug: Bendamustine Hydrochloride; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Fludarabine Phosphate

Interventions

Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes BIOLOGICAL

Given IV

Also known as: CD19R(EQ)28zetaEGFRt+ Tn/mem Cells, CD19R(EQ)28zetaEGFRt+ Tn/Tmem

Group I (lymphodepletion, cellular immunotherapy); Group II (lymphodepletion, cellular immunotherapy)

Bendamustine Hydrochloride DRUG

Given IV

Also known as: Belrapzo, Bendamustin Hydrochloride, Bendeka, Cytostasan Hydrochloride, Levact, Ribomustin, SyB L-0501, Treanda

Group I (lymphodepletion, cellular immunotherapy); Group II (lymphodepletion, cellular immunotherapy)

Cyclophosphamide DRUG

Given IV

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

Group I (lymphodepletion, cellular immunotherapy); Group II (lymphodepletion, cellular immunotherapy)

Etoposide DRUG

Given IV

Also known as: Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16

Group I (lymphodepletion, cellular immunotherapy); Group II (lymphodepletion, cellular immunotherapy)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Group I (lymphodepletion, cellular immunotherapy); Group II (lymphodepletion, cellular immunotherapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Research participants who received memory-enriched CD19R(EQ):CD28:zeta/EGFRt+ on IRB#13277
• Research participants with any uncontrolled illness including ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social situations that would limit compliance with study requirements
• Research participants with known active hepatitis B or C infection; research participants who are human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of screening; research participants with any signs of symptoms of active infection, positive blood cultures or radiological evidence of infections
• Research participants with presence of other active malignancy; however, research participants with history of prior malignancy treated within 2 years with curative intent and in a complete remission are eligible
• Pregnant and lactating women
• Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study
• Research participants with precursor B-cell acute lymphoblastic leukemia/lymphoma or plasma cell dyscrasias
• Any known contraindications to cyclophosphamide, fludarabine, etoposide, bendamustine, cetuximab or tocilizumab
• Dependence on corticosteroids
• Steroid dependence can be defined as a medical need to be greater than 5 mg of prednisone (or equivalent doses of other systemic steroids) a day, chronically; higher doses need to be avoided for at least 3 days prior to leukapheresis and, again, for at least 3 days prior to T cell infusion and up to at least 3 months after T cell infusion unless medically indicated to treat a new toxicity
• Note: topical and inhaled corticosteroids in standard doses and physiologic replacement for subjects with adrenal insufficiency are allowed
• Active autoimmune disease requiring systemic immunosuppressive therapy
• Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

Related Publications (1)

• Siddiqi T, Wang X, Blanchard MS, Wagner JR, Popplewell LL, Budde LE, Stiller TL, Clark MC, Lim L, Vyas V, Brown CE, Forman SJ. CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma. Blood Adv. 2021 Oct 26;5(20):4059-4063. doi: 10.1182/bloodadvances.2020004106.

  PMID: 34492703 DERIVED

MeSH Terms

Conditions

Lymphoma, B-Cell; Leukemia, Prolymphocytic, B-Cell; Burkitt Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Leukemia, Hairy Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Mantle-Cell

Interventions

Bendamustine Hydrochloride; Cyclophosphamide; Etoposide; fludarabine phosphate

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Leukemia, Prolymphocytic; Hematologic Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Tanya Siddiqi

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 30, 2014
• First Posted: June 3, 2014
• Study Start: September 24, 2014
• Primary Completion (Estimated): September 2, 2026
• Study Completion (Estimated): September 2, 2026
• Last Updated: October 6, 2025

Record last verified: 2025-10

Locations

US (1)