GPC3 CAR T Cells With IL-15 and IL-21 for Recurrent ATRT and CNS Rhabdoid Tumors (RADIANT)

Phase 1Not Yet RecruitingNCT07513194

Baylor College of Medicine21 enrolled

Overview

This study is being conducted in patients with GPC3-positive brain tumors that have recurred or have not responded to standard therapy. Atypical teratoid rhabdoid tumors (ATRT) are aggressive tumors with poor outcomes and limited treatment options, particularly in young children. There is a need for new therapies that can improve outcomes while minimizing toxicity. This study evaluates a new experimental treatment using genetically engineered T cells (RADIANT-T cells) that target glypican-3 (GPC3), a protein expressed on tumor cells. These T cells are modified to express a chimeric antigen receptor (CAR) targeting GPC3, along with IL-15 and IL-21 to enhance their persistence and activity. The cells also include an inducible safety mechanism (iCasp9) that allows them to be eliminated if necessary. The purpose of this study is to determine the highest safe dose of RADIANT-T cells, evaluate their safety and side effects, assess how long they persist in the body, and determine whether they show anti-tumor activity in patients with GPC3-positive brain tumors.

This is a Phase 1 dose-escalation study conducted at Texas Children's Hospital to evaluate RADIANT-T cells in patients with GPC3-positive brain tumors. Approximately 15-24 subjects will participate in the treatment portion of the study. Autologous T cells are collected from the patient and genetically engineered using a retroviral vector to express a GPC3-specific chimeric antigen receptor along with IL-15 and IL-21. The modified T cells are expanded and tested for activity against GPC3-positive tumor cells prior to administration. Patients receive a single dose of RADIANT-T cells administered intracavitarily during a planned surgical resection. Prior to administration, patients may receive premedication to reduce the risk of infusion reactions. During surgery, an Ommaya reservoir is placed to allow monitoring and management of potential treatment-related effects. This is a dose-escalation study in which groups of patients receive increasing dose levels of RADIANT-T cells to determine the maximum tolerated dose. The dose administered to each patient depends on prior patient outcomes at lower dose levels. Patients undergo clinical evaluations before treatment, including physical examination, laboratory testing, and imaging studies. After treatment, patients are monitored with physical exams, laboratory tests, cerebrospinal fluid assessments, and imaging to evaluate safety and tumor response. Tumor assessments are performed by MRI at approximately 1 week and 4-6 weeks after treatment. Patients are followed longitudinally to assess safety, persistence of the modified T cells, and clinical outcomes. Long-term follow-up continues for up to 15 years after infusion, with more frequent visits early after treatment and less frequent visits over time.

Eligibility

Sex: ALLMin age: 1 YearMax age: 21 Years

Medical Language ↔ Plain English

Procurement Inclusion Criteria: * 1\) Diagnosis of GPC3-positive recurrent ATRT. * 2\) Age ≥ 6 months * 3\) Karnofsky/Lansky score ≥ 60% * 4\) Informed consent explained to, understood by, and signed by patient/guardian; copy provided * 5\) GPC3 expression by immunohistochemistry with extent score ≥ Grade 2 (\>25% positive tumor cells) and intensity score ≥ 2 (scale 0-4) Procurement Exclusion Criteria: * 1\) No history of organ transplantation * 2\) No known HIV positivity * 3\) No active bacterial, fungal, or viral infection (except Hepatitis B or Hepatitis C virus infections) * 4\) No other risk factors in which administration of the investigational agent is deemed not in the patient's best interest, in the opinion of the investigator Treatment Inclusion Criteria: * 1\) Age ≥ 6 months * 2\) Diagnosis of treatment refractory or unresectable ATRT after standard of care therapy * 3\) Lansky/Karnofsky score ≥ 60% * 4\) Stable neurologic exam for 7 days prior to enrollment * 5\) Stable or decreasing dose of steroids over past 7 days prior to surgery and administration of therapy (max allowable dose is 0.1mg/kg dexamethasone or equivalent per day) * 6\) Not receiving any concurrent anti-cancer therapy. * 7\) At least 6 weeks following craniospinal radiation therapy. * 8\) At least 14 days wash-out needed following small volume radiotherapy (i.e., Stereotactic Radiosurgery (SRS)). * 9\) At least 21 days or 5 half-lives (whichever is shorter) must have elapsed since any prior systemic therapy * 10\) Received any other forms of immunotherapy ≤ 42 days before administration of investigational agent * 11\) At least 28 days following bevacizumab * 12\) Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min * 13\) Total bilirubin \< 3 times ULN for age * 14\) INR ≤ 1.7 * 15\) Absolute neutrophil count \> 500/μl * 16\) Platelet count \> 100,000/μl (can be transfused but must be achieved prior to enrollment) * 17\) Hgb ≥ 7.0 g/dl (can be transfused) * 18\) Pulse oximetry \> 90% on room air * 19\) Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study * 20\) Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion. * 21\) Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent Treatment Exclusion Criteria: * 1\) Pregnancy or lactation (for women at child-bearing age, birth control is required) * 2\) Uncontrolled infection * 3\) Known HIV positivity * 4\) Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections) * 5\) History of organ transplantation

Outcomes

Primary Outcomes

Number of Participants with Dose-Limiting Toxicity

DLT will be defined as any of the following that may be considered possibly, probably, or definitely related to the 21.15.GPC3-CAR T cells: Any Grade 5 event, Non-hematologic dose-limiting toxicity (any Grade 4 non-hematologic toxicity that fails to return to Grade 2 within 72 hours), Grade 4 allergic reaction to CAR T cell administration, Grade 4 reactions due to CRS and neurotoxicity (rarely seen with the use of CAR-based immunotherapy), Grade 3 cytokine release syndrome (CRS) infusion reactions and neurologic toxicity that fail to return to Grade 1 within 72 hours, Grade 4 CRS and neurologic toxicities

Time frame: 4 weeks after CAR T-cell administration

Secondary Outcomes

Maximum Tolerated Dose (MTD) of intratumoral and/or ICV injection of 21.15.GPC3-CAR T cells in treating patients with GPC3-positive recurrent or incompletely resected ATRT.

Once dose escalation is finished and all patients are evaluable for DLT, we will determine the MTD based on isotonic regression, specifically, the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there is no DLT that determine a MTD, the maximum dose level will be declared as the MTD. In case the lowest dose level is determined to be too toxic and the elimination boundary is reached, no MTD will be defined for the trial.

Time frame: 28 days

Response Rate

Response rates will be estimated as the percent of patients whose best response is either complete response or partial response by combining the data from lesions recorded via imaging for each patient pre- and post- 21.15.GPC3-CAR T-cell intratumoral and/or ICV injection. Per immunotherapy response assessment for neuro-oncology (iRANO) criteria: * Complete Response (CR): Disappearance of all enhancing disease for ≥4 weeks; no new lesions; stable or improved T2/FLAIR; no more than physiological steroids; clinically stable or improved. * Partial Response (PR): ≥50% decrease in the sum of biperpendicular diameters of enhancing disease for ≥4 weeks; no new lesions; stable or improved T2/FLAIR; stable or decreased steroid dose; clinically stable or improved.

Time frame: 4-6 weeks after CAR T-cell administration

GPC3 CAR T Cells With IL-15 and IL-21 for Recurrent ATRT and CNS Rhabdoid Tumors (RADIANT)

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts