Clinical Trials /

CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Children or Young Adults With Recurrent or Refractory CD19 Positive B Acute Lymphoblastic Leukemia

NCT03241940

Description:

This phase I trial studies the best dose and 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 children or young adults with CD19 positive 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 B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, 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 children or young adults with B acute lymphoblastic leukemia.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: PEDSCCT5007
  • SECONDARY ID: NCI-2017-01415
  • SECONDARY ID: PEDSCCT5007
  • SECONDARY ID: P30CA124435
  • NCT ID: NCT03241940

Conditions

  • B Acute Lymphoblastic Leukemia
  • CD19 Positive
  • Minimal Residual Disease
  • Philadelphia Chromosome Positive
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Refractory Acute Lymphoblastic Leukemia

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 best dose and 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 children or young adults with CD19 positive 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 B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, 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 children or young adults with 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 children and young adults with B-cell
      hematologic malignancies following a cyclophosphamide/fludarabine conditioning regimen. The
      following dose escalation will be used in two disease groups: 1) children and young adults
      with relapsed/refractory low disease burden ALL (< 5% blasts), and 2) children and young
      adults with relapsed/refractory high disease burden ALL (≥5% blasts) or lymphoma:

        1. Dose Level -1: 3 x 105 transduced T cells/kg (± 20%)

        2. Dose Level 1: 1 x 106 transduced T cells/kg (± 20%)

        3. Dose Level 2: 3 x 106 transduced T cells/kg (± 20%)

        4. Dose Level 3: 1 x 107 transduced T cells/kg (± 20%)

      SECONDARY OBJECTIVES:

      I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and
      young adults with B-acute lymphoblastic leukemia (ALL).

      TERTIARY OBJECTIVES:

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

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

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

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

      V. Explore the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and
      young adults with refractory B cell lymphoma in a non-statistical cohort due to expectations
      of low accrual.

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

      Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2
      and cyclophosphamide IV over 60 minutes on day -2. 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
      weekly until day 28, at 2 and 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 fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. 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

        1.1 INCLUSION CRITERIA

          1. Diagnosis: ALL In view of the PI and the primary oncologist, there must be no
             available alternative curative therapies or subject has declined to pursue alternative
             therapy; and subjects must be either ineligible for allogeneic stem cell transplant
             (SCT), have refused SCT, recurred after SCT, or have disease activity that prohibits
             SCT at the time of enrollment.

               1. Chemotherapy refractory disease in subjects with B-ALL is defined as progression
                  or stable disease after two lines of therapies

               2. Recurrence of disease after achieving a complete response (CR).

               3. Subjects with persistent or relapsed minimal residual disease (MRD) (by flow
                  cytometry, PCR, FISH, or next generation sequencing) require verification of MRD
                  positivity on two occasions at least 4 weeks apart.

               4. 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).

               5. Subjects with recurrence of isolated CNS relapse after achieving complete
                  remission (CR); if relapsed with MRD, will require verification of MRD positivity
                  on two occasions at least 4 weeks apart.

          2. Diagnosis: Lymphoma Subjects with lymphoma must have progressed, had 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.

          3. CD19 expression CD19 expression is required at any time since diagnosis. If patient
             has received anti-CD19 targeted therapy (i.e. Blinatumomab), then CD19 expression must
             be subsequently demonstrated. CD19 expression. 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.

          4. Subjects who have undergone autologous SCT with disease progression or relapse
             following SCT will be eligible if all other eligibility criteria are met. 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 active GVHD and have been without immunosuppressive agents for at least 30
             days.

          5. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy will be eligible
             if < 5% of circulating levels of CD3+ cells express the previous CAR by flow
             cytometry.

          6. Must have evaluable or measurable disease; subjects with lymphoma must have evaluable
             or measurable disease according to the revised IWG Response Criteria for Malignant
             Lymphoma[66] must be present. Lesions that have been previously irradiated will be
             considered measurable only if progression has been documented following completion of
             radiation therapy.

          7. 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.

             Exceptions:

             f. There is no time restriction with regard to prior intrathecal chemotherapy (incl.
             steroids) provided there is complete recovery from any acute toxic effects of such; g.
             Subjects receiving hydroxyurea may be enrolled provided there has been no increase in
             dose for at least 2 weeks prior to starting apheresis; h. Subjects who are on standard
             ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine or oral methotrexate)
             may be enrolled provided that chemotherapy is discontinued at least 1 week prior to
             apheresis.

             i. Subjects receiving steroid therapy at physiologic replacement doses (≤ 5 mg/day of
             prednisone or equivalent doses of other corticosteroids) only are allowed provided
             there has been no increase in dose for at least 2 weeks prior to starting apheresis;
             j. For radiation therapy: Radiation therapy must have been completed at least 3 weeks
             prior to enrollment, with the exception that there is no time restriction if the
             volume of bone marrow treated is less than 10% and also the subject has
             measurable/evaluable disease outside the radiation port.

          8. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for
             clinically non-significant toxicities, such as alopecia, nutritional support measures,
             electrolyte abnormalities, or those not impacting the investigator's ability to assess
             treatment emergent toxicities)

          9. Age Greater than or equal to 1 year of age and less than or equal to 30 years of age
             at time of enrollment; must meet parameters for apheresis per institutional
             guidelines. NOTE: The first subject in the first dose cohort must be ≥ 18 years of age
             if an adult has not been treated at that dose cohort on the companion Stanford
             protocol "Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T
             Cells in Adults with Recurrent or Refractory B Cell Malignancies" and undergone safety
             evaluation at Day 28 without evidence of DLT.

         10. Performance Status: Subjects > 10 years of age: Karnofsky ≥ 50%; Subjects ≤ 10 years
             of age: Lansky scale ≥ 50% (See Appendix B Section 14.2)

         11. Normal Organ and Marrow Function (supportive care is allowed per institutional
             standards, i.e. filgrastim, transfusion)

               1. ANC ≥750/uL*

               2. Platelet count ≥50,000/uL*

               3. Absolute lymphocyte count ≥150/uL*

               4. Adequate renal, hepatic, pulmonary and cardiac function defined as:

                    -  Serum ALT/AST ≤10 ULN (unless elevated ALT/AST is attributed to leukemia or
                       lymphoma involvement of the liver, in which case this criterion will be
                       waived and not disqualify a patient).

                    -  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 ECHO, and no clinically significant
                       ECG findings

                    -  No clinically significant pleural effusion

                    -  Baseline oxygen saturation >92% on room air at rest

                    -  creatinine: within age adjusted normal institutional limits (see table
                       below) OR

                    -  creatinine clearance ≥60 mL/min/1.73 m2 (as estimated by Cockcroft Gault
                       Equation) for subjects with creatinine levels above institutional normal.

             Age (Years) Maximum Serum Creatinine (mg/dL)

             ≤5 0.8 5 < age ≤ 10 1.0 >10 1.2

             * if these cytopenias are not judged by the investigator to be due to underlying
             disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not
             be excluded because of pancytopenia ≥ Grade 3 if it is due to disease, based on the
             results of bone marrow studies.

         12. CNS Status

               1. 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 WBCs;

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

                         -  CNS 2a: <10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;

                         -  CNS 2b: ≥10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;

                         -  CNS 2c: ≥10/µL RBCs; ≥5/µL WBCs and cytospin positive for blasts but
                            negative by Steinherz/Bleyer algorithm.

               2. Subjects with lymphoma

             Subjects must have no signs or symptoms of CNS disease or detectable evidence of CNS
             disease on MRI at the time of screening. Subjects who have previously been treated for
             CNS disease and who have the following CNS status will be eligible:

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

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

                    -  CNS 2a: < 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;

                    -  CNS 2b: ≥ 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts;

                    -  CNS 2c: ≥ 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts but
                       negative by Steinherz/Bleyer algorithm.

         13. 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)

         14. Contraception 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 because of the
             potentially dangerous/unknown effects on the fetus.

         15. Ability to give informed consent. All subjects ≥ 18 years of age must be able to give
             informed consent. For subjects <18 years old their legal authorized representative
             (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be
             included in age appropriate discussion and verbal assent will be obtained for those >
             7 years of age, when appropriate.

        1.2 EXCLUSION CRITERIA

        Subjects meeting any of the following criteria are not eligible for participation in the
        study:

          1. Recurrent or refractory ALL limited to isolated testicular.

          2. Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of ≥
             5/µL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic
             lumbar puncture] and/or clinical signs of CNS leukemia).

          3. Hyperleukocytosis (≥ 50,000 blasts/µL) or rapidly progressive disease that in the
             estimation of the investigator and sponsor would compromise ability to complete study
             therapy.

          4. 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.

          5. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or
             requiring IV antimicrobials for management. Simple UTI and uncomplicated bacterial
             pharyngitis are permitted if responding to active treatment.

             Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus
             (anti-HCV positive) as the immunosuppression contained in this study will pose
             unacceptable risk. A history of hepatitis B or hepatitis C is permitted if the viral
             load is undetectable per quantitative PCR and/or nucleic acid testing.

          6. CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar
             disease, or autoimmune disease with CNS involvement that in the judgment of the
             investigator may impair the ability to evaluate neurotoxicity.

          7. 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.

          8. Subjects receiving anticoagulation therapy.

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

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

         11. Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the conditioning lymphodepletion chemotherapy on the
             fetus or infant. Females who have undergone surgical sterilization or who have been
             postmenopausal for at least 2 years are not considered to be of childbearing
             potential.

         12. In the investigator's 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.

         13. May not have primary immunodeficiency or history of systemic 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:30 Years
Minimum Eligible Age:1 Year
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:Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined.

Secondary Outcome Measures

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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