Clinical Trials /

CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Patients With Recurrent or Refractory CD19 Positive Diffuse Large B-Cell Lymphoma or B Acute Lymphoblastic Leukemia

NCT03233854

Description:

This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating patients with CD19 positive diffuse large B-cell lymphoma or B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating patients with diffuse large B-cell lymphoma or B acute lymphoblastic leukemia.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Mediastinal Large B-Cell Lymphoma
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Patients With Recurrent or Refractory CD19 Positive Diffuse Large B-Cell Lymphoma or B Acute Lymphoblastic Leukemia
  • Official Title: Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Adults With Recurrent or Refractory B Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: CCT5001
  • SECONDARY ID: 41382
  • NCT ID: NCT03233854

Conditions

  • B Acute Lymphoblastic Leukemia
  • CD19 Positive
  • Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma of the Elderly
  • Minimal Residual Disease
  • Philadelphia Chromosome Positive
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
Chimeric Antigen Receptor T-Cell TherapyCAR T-cell therapyTreatment (CD19/CD22 CAR T cells, chemotherapy)
Cyclophosphamide(-)-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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (CD19/CD22 CAR T cells, chemotherapy)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (CD19/CD22 CAR T cells, chemotherapy)

Purpose

This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating patients with CD19 positive diffuse large B-cell lymphoma or B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating patients with diffuse large B-cell lymphoma or B acute lymphoblastic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the feasibility of producing CD19/CD22-CAR T cells meeting the established
      release criteria.

      II. Assess the safety of administering escalating doses of autologous CD19/CD22-CAR T cells
      that meet established release specifications in adults with hematologic malignancies
      following a cyclophosphamide/fludarabine phosphate (fludarabine) conditioning regimen.

      SECONDARY OBJECTIVES:

      I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in adults with
      B cell malignancies.

      TERTIARY OBJECTIVES:

      I. Evaluate the frequency of CD22+ expression on lymphoma cells, and determine site density
      when possible.

      II. Analyze alterations in early B cell development induced by immune pressure exerted via
      CD19/CD22-CAR T cells.

      III. Evaluate whether subjects receiving CD19/CD22-CAR T cells relapse with loss or
      diminished expression of CD19 and/or CD22, when feasible.

      IV. Measure persistence of CD19/CD22-CAR T cells in the blood, bone marrow and cerebrospinal
      fluid (CSF), and explore correlations between anti CD19/CD22-CAR T cell properties and CAR T
      cell efficacy and persistence.

      V. Establish the utility of chromatin structure and epigenomic technology to characterize CAR
      T cell therapies.

      OUTLINE: This is a dose-escalation study of CD19/CD22-CAR T cells.

      Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine
      phosphate IV over 30 minutes on days -5 to -3. Patients then receive CD19/CD22-CAR T cells IV
      over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T
      cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3
      additional doses of CD19/CD22-CAR T cells.

      After completion of study treatment, patients are followed up daily until day 14, twice per
      week until day 28, at 2 months, at 3 months, every 3 months until month 12, every 6-12 months
      up to year 5, and then annually for years 6-15.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CD19/CD22 CAR T cells, chemotherapy)ExperimentalPatients receive cyclophosphamide IV over 60 minutes and fludarabine phosphate IV over 30 minutes on days -5 to -3. Patients then receive CD19/CD22 CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22 CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22 CAR T cells.
  • Chimeric Antigen Receptor T-Cell Therapy
  • Cyclophosphamide
  • Fludarabine Phosphate

Eligibility Criteria

        Inclusion Criteria:

          -  For diffuse large B-cell lymphoma (DLBCL)

               -  Histologically confirmed aggressive B cell non-Hodgkin lymphoma (NHL) including
                  the following types defined by World Health Organization (WHO) 2008:

                    -  DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma;
                       DLBCL associated with chronic inflammation; Epstein Barr virus (EBV)+ DLBCL
                       of the elderly; OR

                    -  Primary mediastinal (thymic) large B cell lymphoma

                    -  Transformation of follicular lymphoma to DLBCL will also be included

               -  Subjects with DLBCL must have progressed, had stable disease (SD), or recurred
                  after initial treatment regimens that include an anthracycline and an anti CD20
                  monoclonal antibody; subjects who relapse >= 12 months after therapy should have
                  progressed after autologous transplant or been ineligible for autologous
                  transplant

          -  For B acute lymphoblastic leukemia (ALL)

               -  Chemotherapy refractory disease in subjects with B-ALL is defined as progression
                  or stable disease after two lines of standard therapies (two induction regimens),
                  or relapsed disease after 2 established induction regimens

               -  Subjects with persistent or relapsed minimal residual disease (MRD) / next
                  generation sequencing (NGS) relapse require verification of relapse on two
                  occasions at least 4 weeks apart

               -  Subjects with Philadelphia chromosome positive acute lymphoblastic leukemia
                  (Ph+ALL) subjects are eligible if they progressed, had stable disease or relapsed
                  after two lines of therapy, including tyrosine kinase inhibitors (TKIs)

          -  CD19 expression is required and must be detected on greater than 50% of the malignant
             cells by immunohistochemistry or >= 90% by flow cytometry; the choice of whether to
             use flow cytometry or immunohistochemistry will be determined by what is the most
             easily available tissue sample in each subject; in general, immunohistochemistry will
             be used for lymph node biopsies, flow cytometry will be used for peripheral blood and
             bone marrow samples

          -  Subjects who have undergone autologous stem cell transplantation (SCT) with disease
             progression or relapse following SCT are eligible; subjects who have undergone
             allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria,
             they are at least 100 days post transplant, they have no evidence of graft versus host
             disease (GVHD) and have been without immunosuppressive agents for at least 30 days

          -  Must have evaluable or measurable disease according to the revised International
             Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been
             previously irradiated will be considered measurable only if progression has been
             documented following completion of radiation therapy

          -  At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any
             prior systemic therapy at the time the subject is planned for leukapheresis, except
             for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5
             half-lives

          -  Toxicities due to prior therapy must be stable and recovered to =< grade 1 (except for
             clinically non significant toxicities such as alopecia)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, or Karnofsky
             >= 80%

          -  Absolute neutrophil count (ANC) >= 750/uL

          -  Platelet count >= 50,000/uL

          -  Absolute lymphocyte count >= 150/uL

          -  Creatinine =< 2 mg/dL or creatinine clearance (as estimated by Cockcroft Gault
             equation) >= 60 mL/min

          -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 upper
             limit of normal (ULN)

          -  Total bilirubin =< 1.5 mg/dl, except in subjects with Gilbert?s syndrome

          -  Cardiac ejection fraction >= 45%, no evidence of physiologically significant
             pericardial effusion as determined by an echocardiogram (ECHO), and no clinically
             significant electrocardiogram (ECG) findings

          -  No clinically significant pleural effusion

          -  Baseline oxygen saturation > 92% on room air

          -  Central nervous system (CNS) status

               -  Subjects with ALL

                    -  Subjects with the following CNS status are eligible only in the absence of
                       neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

                         -  CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on
                            cytospin preparation, regardless of the number of white blood cells
                            (WBCs);

                         -  CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive
                            for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:

                              -  CNS 2a: < 10/uL red blood cells (RBCs); < 5/uL WBCs and cytospin
                                 positive for blasts;

                              -  CNS 2b: >= 10/uL RBCs; < 5/uL WBCs and cytospin positive for
                                 blasts;

                              -  CNS 2c: >= 10/uL RBCs; >= 5/uL WBCs and cytospin positive for
                                 blasts but negative by Steinherz/Bleyer algorithm

               -  Subjects with DLBCL

                    -  Subjects must have no signs or symptoms of CNS disease or detectable
                       evidence of CNS disease on magnetic resonance imaging (MRI) at the time of
                       screening; subjects who have been previously treated for CNS disease but
                       have no evidence of disease at screening are eligible

          -  Females of childbearing potential must have a negative serum or urine pregnancy test
             (females who have undergone surgical sterilization or who have been postmenopausal for
             at least 2 years are not considered to be of childbearing potential)

          -  Subjects of child bearing or child fathering potential must be willing to practice
             birth control from the time of enrollment on this study and for four (4) months after
             receiving the preparative regimen; females of child bearing potential must have a
             negative pregnancy test

          -  Must be able to give informed consent; subjects unable to give informed consent will
             not be eligible for this study

        Exclusion Criteria:

          -  History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g.
             cervix, bladder, breast) unless disease free for at least 3 years

          -  History of Richter?s transformation of chronic lymphocytic leukemia (CLL)

          -  Presence of fungal, bacterial, viral, or other infection that is uncontrolled or
             requiring IV antimicrobials for management; simple urinary tract infection (UTI) and
             uncomplicated bacterial pharyngitis are permitted if responding to active treatment;
             known history of infection with human immunodeficiency virus (HIV) or hepatitis B
             (hepatitis B surface antigen [HBsAg] positive) or hepatitis C virus (anti hepatitis C
             virus [HCV] positive); a history of hepatitis B or hepatitis C is permitted if the
             viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or
             nucleic acid testing

          -  History or presence of CNS disorder such as seizure disorder, cerebrovascular
             ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS
             involvement

          -  History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or
             other clinically significant cardiac disease within 12 months of enrollment, or have
             cardiac atrial or cardiac ventricular lymphoma involvement

          -  Subjects receiving anticoagulation therapy

          -  Any medical condition that in the judgement of the sponsor investigator is likely to
             interfere with assessment of safety or efficacy of study treatment

          -  History of severe immediate hypersensitivity reaction to any of the agents used in
             this study

          -  Women of child bearing potential who are pregnant or breastfeeding; females who have
             undergone surgical sterilization or who have been postmenopausal for at least 2 years
             are not considered to be of childbearing potential

          -  In the investigators judgment, the subject is unlikely to complete all protocol
             required study visits or procedures, including follow up visits, or comply with the
             study requirements for participation

          -  May not have primary immunodeficiency or history of autoimmune disease (e.g. Crohns,
             rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring
             systemic immunosuppression/systemic disease modifying agents within the last 2 years
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/CD22 chimeric antigen receptor (CAR) T cells
Time Frame:Up to 28 days
Safety Issue:
Description:Safety data will be analyzed per standard methods and interpreted descriptively for each dose cohort. Safety data will be summarized for each dose cohort separately and for all dose cohorts combined. Adverse events will be assessed using the CTCAE version 4.03 for type and severity of event. Serious Adverse Events will be summarized for each dose cohort and for all dose cohorts combined. Reasons for discontinuation of study therapy will be tabulated.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From the start of the preparative regimen until death, assessed for up to 15 years
Safety Issue:
Description:Will be assessed by dose cohort.
Measure:Progression free survival
Time Frame:From the start of the preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first, assessed for up to 15 years
Safety Issue:
Description:Will be assessed by dose cohort.
Measure:The ability to achieve a clinical response after administration of CD19/CD22 chimeric antigen receptor (CAR) T cells
Time Frame:Up to 15 years
Safety Issue:
Description:Will be assessed by the Response Criteria for Lymphoma and the Response Criteria for Acute Lymphoblastic Leukemia.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Crystal Mackall, MD

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