Clinical Trials /

CAR T Cells After Lymphodepletion for the Treatment of IL13Rα2 Positive Recurrent or Refractory Brain Tumors in Children

NCT04510051

Description:

This phase I trial investigates the side effects of chemotherapy and cellular immunotherapy in treating children with IL13Ralpha2 positive brain tumors that have come back after a period of improvement (recurrent) or do not respond to treatment (refractory). Cellular immunotherapy (IL13(EQ)BBzeta/CD19t+ T cells) are brain-tumor specific cells that may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Many patients with brain tumor respond to treatment, but then the tumor starts to grow again. Giving chemotherapy in combination with cellular immunotherapy may kill more tumor cells and improve the outcome of treatment.

Related Conditions:
  • Malignant Brain Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Chemotherapy and Cellular Immunotherapy for the Treatment of IL13Ralpha2 Positive Recurrent or Refractory Brain Tumors
  • Official Title: Phase I Study of Cellular Immunotherapy Using Memory Enriched T Cells Lentivirally Transduced to Express an IL13Rα2‐Targeting, Hinge‐Optimized, 41BB‐Costimulatory Chimeric Receptor and a Truncated CD19 for Children With Recurrent/Refractory Malignant Brain Tumors

Clinical Trial IDs

  • ORG STUDY ID: 19130
  • SECONDARY ID: NCI-2020-05158
  • SECONDARY ID: 19130
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT04510051

Conditions

  • Malignant Brain Neoplasm
  • Recurrent Malignant Brain Neoplasm
  • Refractory Malignant Brain Neoplasm

Interventions

DrugSynonymsArms
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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (chemotherapy, IL13(EQ)BBzeta/CD19t+ T cells)
FludarabineFluradosaTreatment (chemotherapy, IL13(EQ)BBzeta/CD19t+ T cells)
IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-LymphocytesAutologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T CellsTreatment (chemotherapy, IL13(EQ)BBzeta/CD19t+ T cells)

Purpose

This phase I trial investigates the side effects of chemotherapy and cellular immunotherapy in treating children with IL13Ralpha2 positive brain tumors that have come back after a period of improvement (recurrent) or do not respond to treatment (refractory). Cellular immunotherapy (IL13(EQ)BBzeta/CD19t+ T cells) are brain-tumor specific cells that may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Many patients with brain tumor respond to treatment, but then the tumor starts to grow again. Giving chemotherapy in combination with cellular immunotherapy may kill more tumor cells and improve the outcome of treatment.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the feasibility and safety of lymphodepleting chemotherapy followed by cellular
      immunotherapy utilizing IL13Ralpha2-specific hinge-optimized 41BB-co-stimulatory chimeric
      antigen receptor [CAR] truncated CD19-expressing autologous T-lymphocytes
      (IL13[EQ]BBzeta/CD19t+ Tn/mem cells) administered by intraventricular (ICV) delivery for
      pediatric participants with IL13Ralpha2+ recurrent/refractory brain tumors.

      SECONDARY OBJECTIVES:

      I. To describe persistence and expansion of CAR T cells in peripheral blood (PB) and
      cerebrospinal (CSF).

      II. To describe cytokine levels (PB, and CSF) over the study period.

      III. In research participants who receive the full schedule of 4 CAR T cell cycles:

      IIIa. To estimate 6‐month progression free survival (PFS) rate per disease. IIIb. To estimate
      disease response rates per disease. IIIc. To estimate 1‐year overall survival rate per
      disease. IV. To evaluate the use of circulating tumor deoxyribonucleic acid (ctDNA) to
      evaluate tumor burden.

      V. For study participants who undergo an additional biopsy/resection or autopsy:

      Va. To evaluate CAR T cell persistence in the tumor tissue and the location of the CAR T
      cells with respect to the infusion site. Vb. To evaluate IL13Ralpha2 antigen expression
      levels on tumor tissue pre and post CAR T cell therapy.

      OUTLINE: This is a dose-escalation study of IL13(EQ)BBzeta/CD19t+ T cells.

      Patients receive cyclophosphamide intravenously (IV) on days -5 and -4, and fludarabine IV on
      days -5 to -2. Patients then receive autologous IL13(EQ)BBzeta/CD19t+ T cells
      intraventricularly over 5 minutes once a week (QW) on day 0. Treatment with autologous
      IL13(EQ)BBzeta/CD19t+ T cells repeats every 7 days for up to 4 cycles in the absence of
      disease progression or unacceptable toxicity. Patients may receive additional cycles of
      IL13(EQ)BBzeta/CD19t+ T cells as long as they continue to meet eligibility criteria and have
      doses available for infusion.

      After completion of study treatment, patients are followed for up at 30 days, 3, 6, 9, and 12
      months, and then yearly for 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, IL13(EQ)BBzeta/CD19t+ T cells)ExperimentalPatients receive cyclophosphamide intravenously IV on days -5 and -4, and fludarabine IV on days -5 to -2. Patients then receive autologous IL13(EQ)BBzeta/CD19t+ T cells intraventricularly over 5 minutes QW on day 0. Treatment with autologous IL13(EQ)BBzeta/CD19t+ T cells repeats every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of IL13(EQ)BBzeta/CD19t+ T cells as long as they continue to meet eligibility criteria and have doses available for infusion.
  • Cyclophosphamide
  • Fludarabine
  • IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes

Eligibility Criteria

        Inclusion Criteria:

          -  Documented informed consent of the participant and/or legally authorized
             representative.

               -  Assent, when appropriate, will be obtained per institutional guidelines

          -  Agreement to allow the use of archival tissue from diagnostic tumor biopsies

          -  Karnofsky Performance Status (KPS) >= 60% except for loss of mobility due to disease
             involvement; e.g., confinement to a wheelchair due to spinal cord compression

          -  Life expectancy > 4 weeks

          -  Participant has a prior histologically‐confirmed malignant brain neoplasm and has
             progressed after prior conventional therapy

          -  Radiographic evidence of progression/recurrence of the measurable disease more than 12
             weeks after the end of the initial conventional therapy (including initial radiation
             therapy)

          -  City of Hope (COH) clinical pathology confirms IL13Ralpha2+ tumor expression by
             immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease
             (H‐score >= 50)

          -  If the participant has a shunt, it must be programmable and the participant must be
             able to tolerate the shunt being switched off for at least 2 consecutive days

          -  Platelets >= 50,000/mm^3 (performed within 6 weeks of signing the main informed
             consent)

          -  Total bilirubin =< 2 X upper limit of normal (ULN) (unless has Gilbert's disease)
             (performed within 6 weeks of signing the main informed consent)

          -  Aspartate transaminase (AST) =< 2 x ULN (performed within 6 weeks of signing the main
             informed consent)

          -  Alanine transferase (ALT) =< 2 x ULN (performed within 6 weeks of signing the main
             informed consent)

          -  Creatinine clearance of >= 75mL/min/1.73m^2 (performed within 6 weeks of signing the
             main informed consent)

          -  Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo,
             hepatitis C virus (HCV)* and active HBV (surface antigen negative) (performed within 6
             weeks of signing the main informed consent)

               -  If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

          -  Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required (to be performed within 6 weeks of signing the main informed consent)

          -  Agreement by females and males of childbearing potential* to use an effective method
             of birth control or abstain from heterosexual activity for the course of the study
             through at least 6 months after the last dose of protocol therapy.

               -  Childbearing potential defined as not being surgically sterilized (males and
                  females) or have not been free, once initiated, from menses for > 1 year (females
                  only)

          -  ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR COLLECTION (PBMC) COLLECTION

          -  Research participant must not require more than 0.1mg/kg/day total dose
             (0.03mg/kg/dose three times per day, max of 6mg/day) of Dexamethasone on the day of
             peripheral blood mononuclear cell (PBMC) collection

          -  Research participant must have appropriate venous access

          -  At least 2 weeks must have elapsed since the research participant received his/her
             last dose of prior targeted agents, chemotherapy or radiation

          -  Note: If a research participant weighs less than 50kgs, the study team should provide
             the Donor Apheresis Center (DAC) with the participant's current weight so that
             institutional guidelines can be followed

          -  ELIGIBILITY TO PROCEED WITH INDWELLING CENTRAL NERVOUS SYSTEM (CNS) CATHETER PLACEMENT

          -  Serum creatinine < 1.6 mg/dL

          -  White blood cell (WBC) >= 2,000/dL

          -  Absolute neutrophil count (ANC) >= 1,000

          -  Platelets > 50,000/dL

          -  International normalized ratio =< 1.3

          -  Bilirubin < 1.5 mg/dL

          -  Alanine transferase (ALT) and aspartate transaminase (AST) < 2 x upper limits of
             normal

          -  KPS >= 60% except for loss of mobility due to disease involvement; e.g., confinement
             to a wheelchair due to spinal cord compression

          -  Second‐line radiation therapy (post‐leukapheresis) completed at least 4 weeks prior to
             surgical resection or biopsy/catheter placement

          -  ELIGIBILITY TO PROCEED WITH LYMPHODEPLETION

          -  Pulmonary: Research participant does not require supplemental oxygen to keep
             saturation greater than 95% and/or does not have presence of any radiographic
             abnormalities on chest x‐ray that are progressive

          -  Cardiac: Research participant does not require pressor support and/or does not have
             symptomatic cardiac arrhythmias

          -  Active infection: Research participant does not have a fever exceeding 38.5 degree
             celsius; there is an absence of positive blood cultures for bacteria, fungus, or virus
             within 48‐hours prior to CAR T cell infusion and/or there aren't any indications of
             meningitis

          -  Hepatic: Research participant serum total bilirubin or transaminases does not exceed 2
             x normal limit

          -  Renal: Research participant serum creatinine < 1.8 mg/dL

          -  Neurologic: Research participant does not have uncontrolled seizure activity following
             surgery prior to starting lymphodepletion

          -  ELIGIBILITY TO PROCEED WITH EACH CAR T CELL INFUSION

          -  Research participant has a released cryopreserved T cell product

          -  Research participant does not require supplemental oxygen to keep saturation greater
             than 95% and/or does not have presence of any radiographic abnormalities on chest
             x‐ray that are progressive

          -  Research participant does not require pressor support and/or does not have symptomatic
             cardiac arrhythmias

          -  Research participant does not have a fever exceeding 38.5 degree celsius; there is an
             absence of positive blood cultures for bacteria, fungus, or virus within 48‐hours
             prior to T cell infusion and/or there aren't any indications of meningitis

          -  Research participant serum total bilirubin or transaminases does not exceed 2 x normal
             limit

          -  Research participant serum creatinine < 1.8 mg/dL

          -  Research participant does not have uncontrolled seizure activity

          -  Research participant platelet count must be >= 50,000. However, if platelet level is
             between 25,000‐49,000, then T‐cell infusion may proceed after platelet transfusion is
             given and the post transfusion platelet count is >= 50,000

          -  Research participants must not require more than 0.1mg/kg/day total dose
             (0.03mg/kg/dose three times per day, max of 6mg/day) of dexamethasone during CAR T
             cell therapy

          -  Wash‐out requirements:

               -  At least 6 weeks since the completion of a nitrosourea‐containing chemotherapy
                  regimen;

               -  At least 23 days since the completion of temozolomide and/or 4 weeks for any
                  other non‐nitrosourea-containing cytotoxic chemotherapy regimen. If a patient's
                  most recent treatment was with a targeted agent only, and s/he has recovered from
                  any toxicity of this targeted agent, then a waiting period of only 2 weeks is
                  needed from the last dose

               -  For bevacizumab the wash out period of at least 4 weeks is required before
                  starting study treatment

        Exclusion Criteria:

          -  Pulmonary: Research participant requires supplemental oxygen to keep saturation
             greater than 95% and the situation is not expected to resolve within 2 weeks

          -  Cardiac: Research participant requires pressor support and/or has symptomatic cardiac
             arrhythmias

          -  Renal: Research participant requires dialysis

          -  Neurologic: Research participant has uncontrolled seizure activity and/or clinically
             evident progressive encephalopathy

          -  Failure of research participant to understand the basic elements of the protocol
             and/or the risks/benefits of participating in this phase I study. A legal guardian may
             substitute for the research participant

          -  Research participant with any non‐malignant intercurrent illness which is either
             poorly controlled with currently available treatment, or which is of such severity
             that the study team deems it unwise to enter the research participant on protocol
             shall be ineligible

          -  Research participant with any other active malignancies

          -  Research participant being treated for severe infection or recovering from major
             surgery is ineligible until recovery is deemed complete by the study team

          -  Research participant with any uncontrolled illness including ongoing or active
             infection. Research participant with known active hepatitis B or C infection; research
             participant with any signs or symptoms of active infection, positive blood cultures or
             radiological evidence of infections

          -  Research participant who has confirmed HIV positivity within 4 weeks of enrollment

          -  Females only: Pregnant or breastfeeding

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:4 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 1 year after the last chimeric antigen response (CAR) T cell infusion
Safety Issue:
Description:Will assess the incidence of grade 3 toxicities, dose limiting toxicities, and all other toxicities. Toxicity and adverse events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 and the revised cytokine release syndrome (CRS) grading system. Symptoms and toxicities will be evaluated by physical exam and blood chemistry/hematology results and adverse event reporting. Rate and associated 90% Clopper and Pearson binomial confidence limits (90% CI) will be estimated for participants experiencing dose limiting toxicities. Tables will be created to summarize all toxicities and side effects by time post treatment, organ, severity and disease subgroup.

Secondary Outcome Measures

Measure:Persistence and expansion of CAR T cells
Time Frame:Up to 1 year after the last CAR T cell infusion
Safety Issue:
Description:Will assess CAR T cells detected in peripheral blood and cerebrospinal fluid (CSF). Descriptive statistical and graphical methods will be used to describe persistence and expansion of the CAR T cells (peripheral blood [PB] and CSF).
Measure:Peripheral blood and CSF cytokine levels
Time Frame:Up to 1 year after the last CAR T cell infusion
Safety Issue:
Description:Descriptive statistical and graphical methods will be used to describe cytokine levels (PB and CSF).
Measure:Peripheral blood and CSF immune cell characterization
Time Frame:Up to 1 year after the last CAR T cell infusion
Safety Issue:
Description:
Measure:Progression free survival
Time Frame:From time of lymphodepletion to the event date (progression or death), assessed at 6 months
Safety Issue:
Description:
Measure:Overall survival
Time Frame:From time of lymphodepletion to date of death, assessed at 1 year after the last CAR T cell infusion
Safety Issue:
Description:
Measure:Disease response
Time Frame:Up to 1 year after the last CAR T cell infusion
Safety Issue:
Description:Will estimate the rate (90% confidence interval [CI]) of disease response Disease status will be assessed by the grading of the tumor responses performed according to the Response Assessment in Neuro-Oncology Criteria (RANO) criteria.
Measure:CAR T cells detected in tumor tissue
Time Frame:Up to 1 year after the last CAR T cell infusion
Safety Issue:
Description:
Measure:IL13Ralpha2 antigen expression levels in tumor tissue
Time Frame:Up to 1 year after the last CAR T cell infusion
Safety Issue:
Description:
Measure:Circulating tumor deoxyribonucleic acid (ctDNA) assessments
Time Frame:Up to 1 year after the last CAR T cell infusion
Safety Issue:
Description:Descriptive statistical and graphical methods will be used to describe ctDNA.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

August 10, 2020