This phase I trial studies the side effects and best dose of HER2-CAR T cells in treating patients with cancer that has spread to the brain or leptomeninges and has come back (recurrent). HER2-CAR T cells delivered into the ventricles of the brain may recognize and kill tumor cells.
PRIMARY OBJECTIVES: I. Determine the safety and recommended phase 2 dosing (RP2D) of intraventricularly administered memory-enriched autologous HER2(EQ)BBzeta/CD19t+ T cells (HER2-chimeric antigen receptor \[CAR\] T cells) - either HER2(EQ)BBzeta/CD19t+ TCM in Arm 1, or HER2(EQ)BBzeta/CD19t+ TN/MEM in Arm 2 - in participants with brain and/or leptomeningeal metastases from HER2 positive cancers. SECONDARY OBJECTIVES: I. Assess cerebrospinal fluid (CSF) and peripheral blood for HER2-CAR T cell persistence and endogenous immune system activation. II. Describe changes in cytokine levels in the CSF and peripheral blood. III. Describe changes in circulating tumor cells in the CSF. IV. In study participants who complete at least the first three cycles of HER2-CAR T cell infusions: IVa. Describe the CNS clinical benefit defined as disease response rate based on Response Assessment in Neuro-Oncology Criteria (RANO) criteria (stable disease \[SD\], partial response \[PR\], or complete response \[CR\] in the brain). IVb. Describe the systemic clinical benefit based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. IVc. Estimate the median central nervous system (CNS) progression-free and overall survival rates (mPFS and mOS), (newly diagnosed versus recurrent metastases). V. In study participants who undergo tumor resection or biopsy during or after study treatment or upon autopsy, evaluate the tumor micro-environment for: Va. HER2-CAR T cell persistence. Vb. Immune cell subsets. Vc. Cytokine levels. Vd. HER2 antigen expression levels. VI. Use biomathematical modeling of tumor growth to evaluate benefit of treatment. OUTLINE: This is a dose-escalation study. Patients receive HER2-CAR T cells via intraventricular administration over 5 minutes once weekly for 3 doses in the absence of disease progression or unacceptable toxicity. If patients continue to meet all eligibility criteria, they may receive additional cycles of HER2-CAR T cells at principal investigator's discretion. After completion of study treatment, participants are followed up at 4 weeks, 3, 6, 8, 10, and 12 months, and then for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Given HER2-CAR T cells via intraventricular administration
City of Hope Medical Center
Duarte, California, United States
Incidence of dose limiting toxicities (DLTs)
Rate and associated 90% Clopper and Pearson binomial confidence limits (90% CI) will be estimated for participants' experiencing DLTs at the recommended phase 2 dose schedule.
Time frame: 21 days post T cell infusion
Number of participants with treatment related adverse events
Will be as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
Time frame: Up to 15 years
HER2-CAR T cells cerebrospinal fluid (CSF) and peripheral blood
Statistical and graphical methods will be used to describe the data.
Time frame: Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Endogenous B cells in CSF and peripheral blood
Statistical and graphical methods will be used to describe the data.
Time frame: Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
T cells in CSF and peripheral blood
Statistical and graphical methods will be used to describe the data.
Time frame: Progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Myeloid cells in CSF and peripheral blood
Statistical and graphical methods will be used to describe the data.
Time frame: Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Host immune subsets (e.g. T cell inhibitory/exhaustion markers, activation markers, and effector memory T cells) in CSF and peripheral blood
Statistical and graphical methods will be used to describe the data.
Time frame: Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Cytokine levels in CSF
Statistical and graphical methods will be used to describe the data.
Time frame: Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Cytokine levels in peripheral blood
Statistical and graphical methods will be used to describe the data.
Time frame: Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Circulating tumor cells in the CSF
Statistical and graphical methods will be used to describe the data.
Time frame: Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Disease response in central nervous system (CNS)
Will be evaluated by Response Assessment in Neuro-Oncology (RANO) criteria. Rates and 90% Clopper and Pearson Binomial Confidence limits will be calculated.
Time frame: Progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Systemic disease response
Will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Rates and 90% Clopper and Pearson Binomial Confidence limits will be calculated.
Time frame: Progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Median CNS progression-free survival
Kaplan Meier methods will be used.
Time frame: Progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
Median overall survival
Kaplan Meier methods will be used.
Time frame: From time of surgery up to 15 years
HER2-CAR T cells detected in the tumor micro-environment
Statistical and graphical methods will be used to describe the data.
Time frame: From time of surgery up to 15 years
Immune cell subsets in the tumor micro-environment
Statistical and graphical methods will be used to describe the data.
Time frame: From time of surgery up to 15 years
Cytokine levels in the tumor micro-environment
Statistical and graphical methods will be used to describe the data.
Time frame: From time of surgery up to 15 years
HER2 antigen expression levels
Statistical and graphical methods will be used to describe the data.
Time frame: From time of surgery up to 15 years
Biomathematical modeling of tumor growth: perfusion and growth parameters based on serial brain magnetic resonance imaging
Time frame: Progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.