Clinical Trials /

IL13Ralpha2-Targeted Chimeric Antigen Receptor (CAR) T Cells With or Without Nivolumab and Ipilimumab in Treating Patients With Recurrent or Refractory Glioblastoma

NCT04003649

Description:

This phase I trial studies the side effects and how well IL13Ralpha2-CRT T cells work when given alone or together with nivolumab and ipilimumab in treating patients with glioblastoma that has come back or does not respond to treatment. Biological therapies, such as IL13Ralpha2-CRT T cells, use substances made from living organisms that may attack specific glioma cells and stop them from growing or kill them. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving IL13Ralpha2-CRT T cells and nivolumab together may work better in treating patients with glioblastoma.

Related Conditions:
  • Glioblastoma
  • Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: IL13Ralpha2-Targeted Chimeric Antigen Receptor (CAR) T Cells With or Without Nivolumab and Ipilimumab in Treating Patients With Recurrent or Refractory Glioblastoma
  • Official Title: A Phase 1 Study to Evaluate IL13R-2-Targeted Chimeric Antigen Receptor (CAR) T Cells Combined With Checkpoint Inhibition for Patients With Resectable Recurrent Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 18251
  • SECONDARY ID: NCI-2018-02764
  • SECONDARY ID: 18251
  • NCT ID: NCT04003649

Conditions

  • Recurrent Glioblastoma
  • Refractory Glioblastoma

Interventions

DrugSynonymsArms
IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM CellsIL13 [EQ]BBzeta/truncated CD19[t]+ Naive and Memory T Cells, IL13 [EQ]BBzeta/truncated CD19[t]+ TN/MEM Cells, IL13Ra2-specific-hinge-optimized-4-1BB-CAR/truncated CD19-expressing Autologous TN/MEM LymphocytesArm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells)

Purpose

This phase I trial studies the side effects and how well IL13Ralpha2-CRT T cells work when given alone or together with nivolumab and ipilimumab in treating patients with glioblastoma that has come back or does not respond to treatment. Biological therapies, such as IL13Ralpha2-CRT T cells, use substances made from living organisms that may attack specific glioma cells and stop them from growing or kill them. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving IL13Ralpha2-CRT T cells and nivolumab together may work better in treating patients with glioblastoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To examine and describe the safety and feasibility of nivolumab plus ipilimumab as
      neoadjuvant therapy. (Arm 1) II. To examine and describe the safety and feasibility of
      IL13Ralpha2-CAR T cell plus nivolumab as adjuvant therapy. (Arms 1 and 2) III. In arms
      determined to be safe and feasible, a selection design based on two Southwest Oncology Group
      (SWOG) two stage designs will be used to assess which arm(s) goes on for further study based
      on survival rate at 9 months.

      SECONDARY OBJECTIVES:

      I. Describe persistence, expansion and phenotype of endogenous and IL13Ralpha2-CAR CAR T
      cells in tumor cyst fluid (TCF), peripheral blood (PB), and cerebral spinal fluid (CSF).

      II. Describe cytokine levels (PB, TCF, CSF) over the study period for each arm. (Arm 1 or Arm
      2) III. Estimate disease response rates. IV. Estimate time to progression. V. Estimate median
      overall survival (OS).

      VI. In study participants who have completed the adjuvant dose-limiting toxicity (DLT)
      period:

      VIa. Estimate the mean change from baseline in quality of life using the European
      Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core
      (QLQ-C)30 and EORTC QLQ Brain Cancer Patients (BN-20) survey scale, domain and item scores
      during and post treatment.

      VIb. Assess if the area under the curve (AUC) for CD3 T cells, IFNgamma and IP-10 for the DLT
      period is greater in one arm versus (vs.) the other.

      VII. In study participants who undergo an additional biopsy/resection or autopsy:

      VIIa. Evaluate CAR T cell persistence in the tumor tissue and the location of the CAR T cells
      with respect to the injection, and VIIb. Evaluate IL13Ralpha2 antigen and PD-L1 levels on
      tumor tissue pre and post CAR T cell therapy.

      VIII. Use biomathematical modeling of tumor growth to evaluate benefit of treatment.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over
      90 minutes on day -14. Patients then receive IL13Ralpha2 CAR T cells infusion over 5 minutes
      via Rickham catheter (intracranial intraventricular [ICV]/intracranital intratumoral [ICT])
      every week and nivolumab IV over 60 minutes every other week. Treatment repeats weekly for up
      to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4,
      patients may receive additional CAR T cells weekly and nivolumab IV every other week or
      monthly at the discretion of the principal investigator and oncologist.

      ARM II: Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter
      (ICV/ICT) every week and nivolumab IV over 60 minutes every other week. Treatment repeats
      weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
      After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every
      other week or monthly at the discretion of the principal investigator and oncologist.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells)ExperimentalPatients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on day -14. Patients then receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/intracranital ICT) every week and nivolumab IV over 60 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.
  • IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
  • Ipilimumab
  • Nivolumab
Arm II (nivolumab, IL13Ra2 CAR T cells)ExperimentalPatients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 60 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.
  • IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
  • Nivolumab

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. If
             unavailable, exceptions may be granted with study principal investigator (PI) approval

          -  Karnofsky performance status (KPS) >= 60%, Eastern Cooperative Oncology Group (ECOG)
             =< 2

          -  Life expectancy >= 4 weeks

          -  Histologically confirmed diagnosis of World Health Organization (WHO) classification
             grade IV glioblastoma (GBM), or has a prior histologically-confirmed diagnosis of a
             grade II or III glioma and now has radiographic progression consistent with a grade IV
             GBM after completing standard therapy.

               -  Note, subjects with leptomeningeal involvement will be excluded from enrollment

          -  Relapsed/refractory disease: radiographic evidence of 1st or 2nd
             recurrence/progression of measurable disease after standard therapy, and >= 12 weeks
             after completion of front?line radiation therapy

          -  Resectable GBM assessed by PI at enrollment with > 75% debulking feasibility

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

          -  White blood cell (WBC) > 2000/dl (or absolute neutrophil count [ANC] >= 1,000/mm^3)
             (to be performed within 14 days prior to leukapheresis unless otherwise stated)

          -  Platelets >= 75,000/mm^3 (to be performed within 14 days prior to leukapheresis unless
             otherwise stated)

          -  Fasting blood glucose within upper limit of normal (ULN) (to be performed within 14
             days prior to leukapheresis unless otherwise stated)

          -  Total bilirubin =< 1.5 ULN (to be performed within 14 days prior to leukapheresis
             unless otherwise stated)

          -  Aspartate aminotransferase (AST) =< 2.5 x ULN (to be performed within 14 days prior to
             leukapheresis unless otherwise stated)

          -  Alanine aminotransferase (ALT) =< 2.5 x ULN (to be performed within 14 days prior to
             leukapheresis unless otherwise stated)

          -  Serum creatinine =< 1.6 mg/dL (to be performed within 14 days prior to leukapheresis
             unless otherwise stated)

          -  Left ventricular ejection fraction (LVEF) >= 50%

               -  Note: To be performed within 28 days prior to day 1 of protocol therapy

          -  Corrected QT interval (QTc) =< 480 ms

               -  Note: To be performed within 28 days prior to start of protocol therapy (Arm 1 is
                  prior to start of neoadjuvant therapy; Arm 2 is prior to start of surgery)

          -  Oxygen (O2) saturation >= 95% on room air (to be performed within 14 days prior to
             leukapheresis unless otherwise stated)

          -  Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo,
             hepatitis C Ab*, active hepatitis B virus (HBV) (surface antigen negative), hepatitis
             A virus IgM antibody (to be performed within 14 days prior to leukapheresis unless
             otherwise stated)

               -  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 14 days prior to leukapheresis unless
             otherwise stated)

          -  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 5 months after the last dose of nivolumab and/or 3 months after the
             last dose of CAR T cells.

               -  Childbearing potential defined as not being surgically sterilized (men and women)
                  or have not been free from menses for > 1 year (women only)

          -  CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participant must not require more
             than 6 mg daily of dexamethasone on the day of PBMC collection

          -  CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participant must have appropriate
             venous access or be willing to undergo central catheter line placement

          -  CRITERIA TO PROCEED WITH PBMC COLLECTION: At least 2 weeks must have elapsed since the
             research participant received his/her last dose of prior chemotherapy or radiation

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): KPS >= 60%

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Creatinine =< 1.6 mg/dL

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): WBC >= 2,000/dl (or ANC >=
             1,000)

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): INR =< 1.3, but may give
             fresh frozen plasma to bring to 1.3

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Bilirubin =< 1.5 ULN

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): ALT and AST =< 2.5 X upper
             limits of normal

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Research participants must
             not require more than < 6 mg daily of dexamethasone during T cell therapy

          -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Washout 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 nonnitrosourea- 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

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: KPS >= 60%

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Creatinine =<
             1.6 mg/dL

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: WBC >=
             2,000/dl (or ANC >= 1,000)

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: INR =< 1.3,
             but may give fresh frozen plasma to bring to 1.3

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Bilirubin =<
             1.5 ULN

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: ALT and AST =<
             2.5 X upper limits of normal

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Second-line
             radiation therapy (post-leukapheresis) within 4 weeks of surgical resection/Rickham
             placement

          -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Washout
             requirements (required for Arm 2 only):

               -  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 nonnitrosourea- 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

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
             has a released cryopreserved CAR T cell product

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Participant has
             completed neoadjuvant therapy (Arm 1 only)

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Participant has
             undergone Rickham catheter placements

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
             does not require supplemental oxygen to keep saturation >= 95% and/or does not have
             presence of any radiographic abnormalities on chest x-ray that are progressive

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
             does not require pressor support and/or does not have symptomatic cardiac arrhythmias

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
             does not have a fever exceeding 38.5 degrees Celsius (C); 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

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Serum total bilirubin
             >= 1.5x ULN.

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: AST and ALT do not
             exceed =< 2.5x ULN

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant?s
             serum creatinine =< 1.6 mg/dL

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
             does not have uncontrolled seizure activity following surgery prior to starting the
             first T cell dose

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
             platelet count must be >= 100,000. However, if platelet level is between
             75,000?99,000, then T-cell infusion may proceed if after platelet transfusion the
             count is >= 100,000

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: For cycles 1-4:
             Research participants must not require more than 6 mg daily of dexamethasone during
             CAR T cell therapy

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: For cycles 5+: Research
             participants must not require more than 12 mg daily of dexamethasone during CAR T cell
             therapy

          -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Wash-out requirements
             (standard or investigational):

               -  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 nonnitrosourea- 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 and the start of study treatment, with the exception of
                  bevacizumab where a wash out period of at least 4 weeks is required before
                  starting study treatment

        Exclusion Criteria:

          -  Prior CTLA-4, PD?1 or PD?L1 inhibitor therapy

          -  Participant is steroid?dependent, requiring more than 6 mg of dexamethasone per day

          -  Participant has not yet recovered from toxicities of prior therapy

          -  Uncontrolled seizure activity and/or clinically evident progressive encephalopathy

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to study agent

          -  Active diarrhea

          -  Clinically significant uncontrolled illness

          -  Active infection requiring antibiotics

          -  Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection

          -  Other active malignancy

          -  Females only: Pregnant or breastfeeding

          -  Any other condition that would, in the investigator?s judgment, contraindicate the
             subject?s participation in the clinical study due to safety concerns with clinical
             study procedures

          -  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:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting Toxicities
Time Frame:28-42 days
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits

Secondary Outcome Measures

Measure:T cell levels
Time Frame:Up to 15 years
Safety Issue:
Description:Will assess chimeric antigen receptor (CAR) T and endogenous T cell levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebral spinal fluid (CSF) (absolute number per ul by flow). Statistical and graphical methods will be used to describe persistence and expansion.
Measure:Cytokine (IFN-γ, IL-2, IL-6, TNF-α, and VEGF) levels in TCF, PB, and CSF
Time Frame:Up to 1 years
Safety Issue:
Description:Descriptive statistical and graphical methods will be used to describe cytokine levels over the 1 year period
Measure:Disease response
Time Frame:Up to 15 years
Safety Issue:
Description:By Response Assessment in Neuro-Oncology (RANO) criteria with the need for Avastin as an additional indicator of progression.
Measure:Time to progression
Time Frame:Up to 15 years
Safety Issue:
Description:Progression is defined by RANO with the need for Avastin as an additional indicator of progression.
Measure:Overall survival (OS)
Time Frame:Up to 15 years
Safety Issue:
Description:Kaplan Meier methods will be used to estimate median OS and graph the results.
Measure:Quality of Life Questionnaires
Time Frame:Up to 15 years
Safety Issue:
Description:Will estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the domain scale and items scores from the Quality of Life Questionnaire Brian Tumor Patients 20. Will be estimated for each treatment arm.
Measure:Area under the curve (AUC) for CD3, IFNgamma, and IP-10 levels over time for the DLT evaluation period
Time Frame:Up to 28 days
Safety Issue:
Description:A two-tailed two-sample Students T test with a 0.05 level of significance will be used to determine if the AUCs over the adjuvant treatment DLT period (DLT period 2) for CD3, IFNgamma, and IP-10 are higher in one arm over the other.
Measure:CAR T and endogenous cells detected in tumor tissue
Time Frame:Up to 15 years
Safety Issue:
Description:By immunohistochemistry. Will be described.
Measure:IL13Ralpha2 antigen expression levels in tumor tissue
Time Frame:Up to 15 years
Safety Issue:
Description:By pathology H score. Will be described.
Measure:PD-L1 levels on tumor cells
Time Frame:1 year
Safety Issue:
Description:Change in PD-L1 levels (post -pre) will be presented using means and standard deviations
Measure:Biomathematical modeling of tumor growth
Time Frame:Up to 15 years
Safety Issue:
Description:Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.
Measure:Progression free survival (PFS)
Time Frame:Up to 15 years
Safety Issue:
Description:Kaplan Meier methods will be used to estimate median PFS and graph the results.

Details

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

Last Updated