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

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ClinicalTrials.gov Identifier: NCT02153580
Recruitment Status : Recruiting
First Posted : June 3, 2014
Last Update Posted : March 13, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

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.

Condition or disease Intervention/treatment 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 Other: laboratory biomarker analysis Drug: Bendamustine Hydrochloride Drug: Etoposide Drug: Fludarabine Phosphate Biological: Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes Phase 1

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 naïve and memory T-cells [Tn/mem]) that are enriched and genetically modified to express a CD19-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 OBJECTIVES:

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).

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 or 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 Tcm-enriched T cells or 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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study to Evaluate Cellular Immunotherapy Using 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
Study Start Date : September 24, 2014
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: Treatment (lymphodepletion,cellular immunotherapy)

LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of, and not limited to, any of the following agents: 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 cells >= 28 days post T cell infusion.

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

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

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

Biological: Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
Given IV

Experimental: Treatment (lymphodepletion, cellular immunotherapy)

LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and extent of disease comprising of, and not limited to, any of the following agents: 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).

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

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

Biological: Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
Given IV




Primary Outcome Measures :
  1. 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.

  2. 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 :
  1. 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.

  2. 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.

  3. CD19 B cell aplasia/immunoglobulin G levels [ Time Frame: 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.



Information from the National Library of Medicine

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

    • 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), 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
  • 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:

SCREENING EXCLUSION CRITERIA:

  • 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

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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02153580


Locations
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United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Tanya Siddiqi    800-826-4673      
Principal Investigator: Tanya Siddiqi         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tanya Siddiqi City of Hope Medical Center

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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 )
First Posted: June 3, 2014    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: August 2018
Additional relevant MeSH terms:
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Burkitt Lymphoma
Lymphoma
Leukemia
Lymphoma, Follicular
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Leukemia, Hairy Cell
Leukemia, Prolymphocytic
Waldenstrom Macroglobulinemia
Leukemia, Prolymphocytic, B-Cell
Lymphoproliferative Disorders
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
Vascular Diseases
Cardiovascular Diseases