Clinical Trials /

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

NCT02153580

Description:

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.

Related Conditions:
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • Burkitt Lymphoma
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Hairy Cell Leukemia
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Prolymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 13351
  • SECONDARY ID: NCI-2014-01168
  • SECONDARY ID: 13351
  • NCT ID: NCT02153580

Conditions

  • 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

Interventions

DrugSynonymsArms
cyclophosphamideCPM, CTX, Cytoxan, Endoxan, EndoxanaTreatment (lymphodepletion, cellular immunotherapy)
Bendamustine HydrochlorideCytostasan Hydrochloride, Ribomustin, SyB L-0501, TreandaTreatment (lymphodepletion, cellular immunotherapy)
EtoposideEPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213, Demethyl Epipodophyllotoxin Ethylidine GlucosideTreatment (lymphodepletion, cellular immunotherapy)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586Treatment (lymphodepletion, cellular immunotherapy)
Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytesTreatment (lymphodepletion, cellular immunotherapy)

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.

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
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lymphodepletion,cellular immunotherapy)ExperimentalLYMPHODEPLETING 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).
  • cyclophosphamide
  • Bendamustine Hydrochloride
  • Etoposide
  • Fludarabine Phosphate
  • Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes
Treatment (lymphodepletion, cellular immunotherapy)ExperimentalLYMPHODEPLETING 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).
  • cyclophosphamide
  • Bendamustine Hydrochloride
  • Etoposide
  • Fludarabine Phosphate
  • Autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Detection of transferred T cells in the circulation for at least 28 days by quantitative-polymerase chain reaction
Time Frame:28 days
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.
Measure: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
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.
Measure:CD19 B cell aplasia/immunoglobulin G levels
Time Frame:Up to 15 years
Safety Issue:
Description:Normal CD19+ B cell levels and immunoglobulin G levels will be reported over the study period using both descriptive statistics and graphical methods.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

March 11, 2019