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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT02153580
First received: May 30, 2014
Last updated: July 29, 2016
Last verified: July 2016
  Purpose
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.

Condition Intervention Phase
Post-transplant Lymphoproliferative Disorder
B-Cell Prolymphocytic Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Hairy Cell Leukemia
B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma
B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
Recurrent Lymphoplasmacytic Lymphoma
Drug: cyclophosphamide
Biological: autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells
Other: laboratory biomarker analysis
Drug: Bendamustine Hydrochloride
Drug: Etoposide
Drug: Fludarabine Phosphate
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study to Evaluate Cellular Immunotherapy Using Central Memory-Enriched T Cells Lentivirally Transduced to Express a CD19-Specific, Hinge-Optimized, CD28-Costimulatory Chimeric Receptor and a Truncated EGFR Following Lymphodepleting Chemotherapy in Adult Patients With CD19+ B-Cell Lymphoproliferative Neoplasms

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Toxicity profile of T-cell infusion as defined by all toxicities associated with T cells at the probably or definite levels [ Time Frame: Up to 15 years ]
    Assessed using Common Terminology Criteria for Adverse Event (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 [ Time Frame: Up to 28 days ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.


Secondary Outcome Measures:
  • Detection of transferred T cells in the circulation for at least 28 days by quantitative-polymerase chain reaction [ Time Frame: 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 (CLL/PLL) and leukemic phase NHL patients by flow cytometry and bone marrow biopsy [ Time Frame: Up to 15 years ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.

  • CD19 B cell aplasia/immunoglobulin G levels [ Time Frame: Up to 15 years ]
    Normal CD19+ B cell levels and and immunoglobulin G levels will be reported over the study period using both descriptive statistics and graphical methods.


Estimated Enrollment: 48
Study Start Date: September 2014
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (lymphodepletion, cellular immunotherapy)
LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising: cyclophosphamide IV on days -4 and/or -3; OR bendamustine hydrochloride IV on days -4 and -3; OR fludarabine phosphate IV and cyclophosphamide IV on days -5 to -3; OR etoposide IV and cyclophosphamide IV on days -5 to -3; OR cyclophosphamide IV on days -7 and -6 followed by etoposide IV on days -5 to -3. CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells 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 Tcm-enriched T cells >= 28 days post T cell infusion.
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Biological: autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells
Given IV
Other Names:
  • CD19-CAR-specific/truncated EGFR lentiviral vector-transduced autologous T cells
  • CD19R:CD28:lentiviral/EGFRt+ T cells
Other: laboratory biomarker analysis
Correlative studies
Drug: Bendamustine Hydrochloride
Given IV
Other Names:
  • Cytostasan Hydrochloride
  • Ribomustin
  • SyB L-0501
  • Treanda
Drug: Etoposide
Given IV
Other Names:
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety of adoptive therapy using ex vivo expanded autologous central memory T cells (Tcm) 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) shortly following lymphodepletion for adults with recurrent/progressive/residual CD19 + B-cell lymphoproliferative neoplasms (stratum 1: non-Hodgkin lymphoma [NHL], stratum 2: 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).

SECONDARY OBJECTIVES:

I. To study antitumor activity of CD19R(EQ)CD28zeta/EGFRt+Tcm (e.g., detection of Tcm, B cells, and tumor burden).

OUTLINE: This is a dose-escalation study of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells (T-cell infusion).

LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising: cyclophosphamide intravenously (IV) on days -4 and/or -3; OR bendamustine hydrochloride IV on days -4 and -3; OR fludarabine phosphate IV and cyclophosphamide IV on days -5 to -3; OR etoposide IV and cyclophosphamide IV on days -5 to -3; OR cyclophosphamide IV on days -7 and -6 followed by etoposide IV on days -5 to -3.

CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells 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 Tcm-enriched T cells >= 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

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 positive must be documented in a pathology report; however, it is not a requirement that the CD19 testing be performed by a COH pathologist

    • Stratum 1 (NHL): 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
    • 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 enrollment
  • 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

PROTOCOL-SPECIFIC CRITERIA:

  • COH pathology review confirms that research participant's diagnostic material is consistent with a lymphoproliferative B-cell neoplasm; additionally, CD19 positivity must be documented in a pathology report; however, it is not a requirement that the CD19 testing be performed by COH pathologist
  • Documentation of recurrence/progression/residual disease following prior therapy
  • Negative serum pregnancy test for women of childbearing potential
  • A pretreatment measured creatinine clearance (absolute value) of >= 60 mL/minute
  • 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)
  • Diffusing capacity of the lung for carbon monoxide (DLCO) or forced expiratory volume in 1 second (FEV1) > 45% predicted

ELIGIBILITY TO UNDERGO LYMPHODEPLETION:

  • Research participant has a released cryopreserved T cell product for T cell infusions on approximately day 0
  • 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
  • Pulmonary: Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air
  • Cardiovascular: Not requiring pressor support, not having symptomatic cardiac arrhythmias
  • Renal Function: Preservation of renal function, serum creatinine did NOT increase by more than 2 fold above the normal range
  • Liver Function: Total bilirubin =< 2.0 mg/dL
  • Neurological: Research participant without clinically significant encephalopathy/new focal deficits
  • Infectious Diseases: No clinical evidence of uncontrolled active infectious process

Exclusion Criteria:

ENROLLMENT EXCLUSION CRITERIA:

  • Research participants who received Tcm-enriched CD19R(EQ):CD28:zeta/EGFRt+ on IRB#13277
  • Research participants with any uncontrolled coexisting 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 enrollment; research participants with any signs of symptoms of active infection, positive blood cultures or radiological evidence of infections
  • Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
  • Research participants with presence of other active malignancy, except non-melanoma skin tumors and in-situ cervical cancer, within 2 years of study entry; participants with history of prior malignancy treated within 2 years with curative intent and in a complete remission are eligible
  • Pregnant and lactating women

STUDY-SPECIFIC EXCLUSIONS:

  • 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 on more 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02153580

Locations
United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Tanya Siddiqi City of Hope Medical Center
  More Information

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02153580     History of Changes
Other Study ID Numbers: 13351
NCI-2014-01168 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
13351 ( Other Identifier: City of Hope Medical Center )
Study First Received: May 30, 2014
Last Updated: July 29, 2016

Additional relevant MeSH terms:
Lymphoma
Leukemia
Lymphoma, Follicular
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Hodgkin Disease
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Large B-Cell, Diffuse
Burkitt Lymphoma
Lymphoproliferative Disorders
Leukemia, Hairy Cell
Leukemia, Prolymphocytic
Waldenstrom Macroglobulinemia
Leukemia, Prolymphocytic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Leukemia, B-Cell
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Neoplasms, Plasma Cell
Hemostatic Disorders

ClinicalTrials.gov processed this record on March 24, 2017