Anti-GARP Chimeric Antigen Receptor T Cell Therapy for the Treatment of Recurrent Grade III or IV Gliomas

Description

PRIMARY OBJECTIVE:

I. To assess the safety and feasibility of a CAR T targeting GARP for glioma by defining rate, frequency, and severity of dose limiting toxicities (DLT) following intracavity administration to patients with recurrent glioma, to determine recommended phase II dose (RP2D).

SECONDARY OBJECTIVES:

I. To describe the adverse event profile of anti-GARP CAR T cell therapy. II. To describe the cytokine levels and immunophenotype in cerebrospinal fluid (CSF) during and following anti-GARP CAR T cell therapy.

III. To describe the duration of anti-GARP CAR T cell persistence and phenotype in CSF.

IV. To describe anti-tumor activity of anti-GARP CAR T cell therapy based on objective response rate (ORR), as measured by established radiological criteria.

V. To estimate the progression-free survival (PFS) and overall survival (OS) of patients receiving anti-GARP CAR T cell therapy.

VI. For research participants with tumor specimens from primary resections and/or autopsy, describe GARP expression levels pre- and post-treatment and correlate with outcomes.

VII. To describe the frequency and phenotype of anti-GARP CAR T cells and describe GARP expression in resected post-treatment tumor tissue at progression (for patients in whom surgical resection is indicated).

EXPLORATORY OBJECTIVES:

I. To assess peripheral blood (mononuclear cells, plasma) and CSF for biomarkers that may be associated with response to anti-GARP CAR T cell therapy.

II. To assess archival tissues (primary resection), recurrent tumor, and/or autopsy specimens for biomarkers that may be associated with response to anti-GARP CAR T cell therapy.

III. To assess baseline genetic markers that may be associated with response to anti-GARP CAR T cell therapy.

OTHER EFFICACY OBJECTIVES:

I. Best overall response, determined via response assessment in neuro-oncology (RANO) criteria.

II. Clinical benefit rate that includes all subjects receiving 5 doses of anti-GARP CAR T cell therapy who demonstrate a complete response (CR), partial response (PR), or stable disease (SD) of at least 6 months duration.

III. Duration of response, calculated as the time from which a response is first observed (CR or PR) until progression or death, whichever occurs first.

IV. Overall survival (OS), calculated from first administration of study drug until death for up to two years after receiving the drug.

OUTLINE: This is a dose-escalation study.

Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients are followed up at 2 weeks then at 3, 4, 6, 8, 12 and 24 months then annually for at least 15 years.