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

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ClinicalTrials.gov Identifier: NCT04003649
Recruitment Status : Recruiting
First Posted : July 1, 2019
Last Update Posted : October 16, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Recurrent Glioblastoma Refractory Glioblastoma Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells Biological: Ipilimumab Biological: Nivolumab Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : December 1, 2019
Estimated Primary Completion Date : January 22, 2022
Estimated Study Completion Date : January 22, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells)
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 (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.
Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
Given ITV/ITC
Other Names:
  • IL13 [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 Lymphocytes

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Experimental: Arm II (nivolumab, IL13Ra2 CAR T cells)
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.
Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
Given ITV/ITC
Other Names:
  • IL13 [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 Lymphocytes

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Dose limiting Toxicities [ Time Frame: 28-42 days ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits

  2. Cytokine Release Syndrome based on (Appendix C) [ Time Frame: 28-42 days ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits.

  3. All other toxicities will be assessed using the NCI's Common Terminology Criteria for Adverse Events (CTCAE v5.0, released on 11/27/2017). [ Time Frame: up to 15 years ]
    All toxicities and side effects will be summarized in tables by dose, time period, organ, and severity

  4. Feasibility of participants to either (i) receive Ipi/Nivo followed by 4 weekly CAR T cell with alternating weeks of Nivo infusions OR (ii) 4 weekly CAR T cell with alternating weeks of Nivo infusions [ Time Frame: 14- 28 days ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits

  5. Survival at 9 months [ Time Frame: Up to 9 months ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits


Secondary Outcome Measures :
  1. T cell levels [ Time Frame: Up to 15 years ]
    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.

  2. Cytokine (IFN-γ, IL-2, IL-6, TNF-α, and VEGF) levels in TCF, PB, and CSF [ Time Frame: Up to 1 years ]
    Descriptive statistical and graphical methods will be used to describe cytokine levels over the 1 year period

  3. Disease response [ Time Frame: Up to 15 years ]
    By Response Assessment in Neuro-Oncology (RANO) criteria with the need for Avastin as an additional indicator of progression.

  4. Time to progression [ Time Frame: Up to 15 years ]
    Progression is defined by RANO with the need for Avastin as an additional indicator of progression.

  5. Overall survival (OS) [ Time Frame: Up to 15 years ]
    Kaplan Meier methods will be used to estimate median OS and graph the results.

  6. Quality of Life Questionnaires [ Time Frame: Up to 15 years ]
    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.

  7. 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 ]
    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.

  8. CAR T and endogenous cells detected in tumor tissue [ Time Frame: Up to 15 years ]
    By immunohistochemistry. Will be described.

  9. IL13Ralpha2 antigen expression levels in tumor tissue [ Time Frame: Up to 15 years ]
    By pathology H score. Will be described.

  10. PD-L1 levels on tumor cells [ Time Frame: 1 year ]
    Change in PD-L1 levels (post -pre) will be presented using means and standard deviations

  11. Biomathematical modeling of tumor growth [ Time Frame: Up to 15 years ]
    Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.

  12. Progression free survival (PFS) [ Time Frame: Up to 15 years ]
    Kaplan Meier methods will be used to estimate median PFS and graph the results.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04003649


Locations
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United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Behnam Badie    626-359-8111    bbadie@coh.org   
Principal Investigator: Behnam Badie         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Behnam Badie City of Hope Medical Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT04003649     History of Changes
Other Study ID Numbers: 18251
NCI-2018-02764 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
18251 ( Other Identifier: City of Hope Comprehensive Cancer Center )
First Posted: July 1, 2019    Key Record Dates
Last Update Posted: October 16, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents