IL13Ra2-CAR T Cells with or Without Nivolumab and Ipilimumab in Treating Patients with GBM
- Conditions
- Refractory GlioblastomaRecurrent Glioblastoma
- Interventions
- Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM CellsOther: Quality-of-Life AssessmentOther: Questionnaire Administration
- Registration Number
- NCT04003649
- Lead Sponsor
- City of Hope Medical Center
- Brief Summary
This phase I trial studies the side effects and how well IL13Ralpha2-CAR T cells work when given alone or together with nivolumab and ipilimumab in treating patients with glioblastoma that has come back (recurrent) or does not respond to treatment (refractory). Biological therapies, such as IL13Ralpha2-CAR 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-CAR 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. To provide IL13Rα2-CAR T cell therapy for subjects who are unable to wait for randomization into Arms 1 and 2. This arm will provide additional safety data provided in COH IRB 13384 for the set dose schedule. (Arm 3) 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 \[ICV\]/intracranial intratumoral \[ICT\]) every week and nivolumab IV over 30 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 30 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 III: Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (intracranial intraventricular \[ICV\]/intracranial intratumoral \[ICT\]) every 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 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 60
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm II (nivolumab, IL13Ra2 CAR T cells) Nivolumab Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 30 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 I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells) Questionnaire Administration 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 30 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 I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells) Quality-of-Life Assessment 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 30 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 (nivolumab, IL13Ra2 CAR T cells) IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 30 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 (nivolumab, IL13Ra2 CAR T cells) Quality-of-Life Assessment Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 30 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 III (IL13Ra2 CAR T cells) IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every 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 at the discretion of the principal investigator and oncologist. Arm III (IL13Ra2 CAR T cells) Questionnaire Administration Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every 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 at the discretion of the principal investigator and oncologist. Arm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells) Ipilimumab 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 30 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 I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells) IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM 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 30 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 III (IL13Ra2 CAR T cells) Quality-of-Life Assessment Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every 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 at the discretion of the principal investigator and oncologist. Arm II (nivolumab, IL13Ra2 CAR T cells) Questionnaire Administration Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 30 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 I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells) Nivolumab 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 30 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.
- Primary Outcome Measures
Name Time Method Incidence of adverse events Up to 15 years Will assess dose limiting toxicity and all toxicities. Toxicity is the primary endpoint and will be assessed using the National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Rates and associated 95% Clopper and Pearson binomial confidence limits (95% confidence interval \[CI\]) will be estimated for participants' experiencing dose limiting toxicity (DLT) during neoadjuvant treatment period (DLT period 1), during adjuvant treatment period (DLT period 2), neo-adjuvant and adjuvant feasibility, as well as survival at 9 months. All toxicities and side effects will be summarized in tables by dose, time period, organ, and severity.
Feasibility (adjuvant therapy) Up to 28 days Defined as the ability of patients to complete 4 cycles of CAR T infusions (\> 80% of the assigned dose) and 2 doses of nivolumab.
Feasibility (neoadjuvant therapy) Up to 14 days As measured by the ability of patients receive ipilimumab/nivolumab (\> 80% of the assigned doses) and undergo undergo surgery so that they can go on to receive the first dose of CAR T cells.
Overall Survival At 9 months The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.
Dose-limiting toxicity (DLT) Up to 28 days A toxicity that causes side effects that are serious enough to prevent an increase in dose or level of that treatment.
- Secondary Outcome Measures
Name Time Method IL13Ralpha2 antigen expression levels in tumor tissue Up to 15 years By pathology H score.
Area under the curve (AUC) for CD3, IFNgamma, and IP-10 levels over time for the DLT evaluation period 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.
T cell levels 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.
Cytokine levels in TCF, PB, and CSF Up to 15 years Statistical and graphical methods will be used to describe persistence and expansion.
Biomathematical modeling of tumor growth Up to 15 years Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.
Progression free survival (PFS) Up to 15 years Kaplan Meier methods will be used to estimate median PFS and graph the results.
Disease response Up to 15 years By Response Assessment in Neuro-Oncology (RANO) criteria with the need for Avastin as an additional indicator of progression.
Time to progression Up to 15 years Progression is defined by RANO with the need for Avastin as an additional indicator of progression.
Overall survival (OS) Up to 15 years Kaplan Meier methods will be used to estimate median OS and graph the results.
Quality of life (QOL) 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.
CAR T and endogenous cells detected in tumor tissue Up to 15 years By immunohistochemistry.
PD-L1 levels on tumor cells Pre- and post-therapy By flow cytometry
Trial Locations
- Locations (1)
City of Hope Medical Center
🇺🇸Duarte, California, United States