GPC2-targeted CAR T cell therapy for relapsed or refractory medulloblastoma in children and young adults

Phase I Clinical Trial of GPC2 Chimeric Antigen Receptor T (GPC2-CAR T) Cells for Relapsed or Refractory Medulloblastoma in Children and Young Adults

This trial will test whether autologous GPC2-targeted CAR T cells delivered into the brain ventricle are safe and active for children and young adults with relapsed or refractory medulloblastoma or similar CNS embryonal tumors.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Ages: 1 Year to 30 Years
• Sex: All
• Sponsor: Stanford University (Academic / other)
• Drugs / interventions: bevacizumab, CAR T, chimeric antigen receptor, radiation
• Locations: 1 site (Palo Alto, California)
• Trial ID: NCT07087002 on ClinicalTrials.gov

What this trial studies

This is a single-site, open-label Phase 1 trial using autologous CAR T cells that target the GPC2 antigen and are given by intracerebroventricular (ICV) infusion. Patients undergo tumor prescreening with GPC2 immunohistochemistry (H-score ≥100) and receive lymphodepletion with fludarabine and cyclophosphamide before CAR T administration. The primary goals are to test feasibility and safety and to collect preliminary signals of anti-tumor activity in evaluable recurrent or refractory disease. The study enrolls children and young adults with histologically confirmed medulloblastoma or other eligible CNS embryonal tumors at a single pediatric cancer center.

Who should consider this trial

Good fit: Children and young adults with histologically confirmed relapsed or refractory medulloblastoma or selected CNS embryonal tumors who have evaluable disease and tumor GPC2 expression (IHC H-score ≥100) are ideal candidates.

Not a fit: Patients without sufficient GPC2 expression, those with newly diagnosed disease controlled by standard therapy, or those with contraindications to intracerebroventricular procedures or lymphodepletion are unlikely to benefit from this intervention.

Why it matters

Potential benefit: If successful, this approach could offer a targeted immunotherapy option that controls or reduces GPC2-positive tumor growth in patients with few remaining standard treatments.

How similar studies have performed: CAR T cell therapy has shown strong success in some blood cancers but has limited early-phase data and mixed results in primary brain tumors, and GPC2-directed CAR T in CNS tumors is a relatively novel approach with limited prior human experience.

Eligibility criteria

Inclusion Criteria:

1. Diagnosis: Histologically confirmed diagnosis of medulloblastoma or other primary CNS embryonal tumor according to 2021 CNS WHO Classification (5th edition)

   * Other acceptable CNS embryonal tumors include:
   * Embryonal Tumor with Multilayered Rosettes (ETMR)
   * Pineoblastoma
   * Atypical Teratoid/Rhabdoid Tumor (ATRT) of the CNS
   * CNS neuroblastoma, FOXR2-activated
   * CNS Embryonal Tumor NOS
2. Recurrent/Refractory Disease: History of relapsed and/or recurrent disease defined as tumor progression or recurrence following initial diagnosis and upfront treatment with curative intent, or failure to achieve disease control with standard curative-intent therapy.
3. GPC2 Positive: H-score ≥ 100 by IHC staining performed on the (Prescreening Protocol IRB-78780, PI: Katherine Ryan, DO) at Stanford Clinical Anatomic Pathology Lab for GPC2 from a tumor sample any time since initial diagnosis.
4. Evaluable Disease: Evaluable disease as per radiographic findings and/or positive cerebrospinal fluid cytology within 28 days of enrollment.
5. Patients with VP shunts: Patients with pre-existing ventriculo-peritoneal (VP) shunt devices must have a programmable shunt device to enroll on this study. A VP shunt is not a requirement for this study.
6. Prior therapy: No limit to the number of prior treatment regimens. Toxicities due to prior therapy must be stable or recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia, nutritional support measures, electrolyte abnormalities, or those not impacting the investigator's ability to assess treatment emergent toxicities).

   At time of enrollment, subjects are on track to meet the required therapy wash out period(s) prior to apheresis.

   a. At least 6 weeks following craniospinal radiation therapy. i. At least 14 days wash-out needed following small volume radiotherapy (i.e., Stereotactic Radiosurgery (SRS)).

   b. At least 21 days or 5 half-lives (whichever is shorter) must have elapsed since any prior systemic therapy, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives.

   c. At least 28 days following bevacizumab treatment. d. At least 30 days following any investigational drug. e. At least 12 weeks following systemic inhibitory or stimulatory immune checkpoint therapy.
7. Age: ≥ 12 months to ≤ 30 years of age at time of enrollment The first 3 subjects treated with GPC2-CAR T cells must be ≥ 3 years old at time of infusion
8. Performance Status: Subjects ≥ 16 years of age must have Karnofsky ≥ 60%. Subjects \< 16 years of age must have Lansky scale 60%; or ECOG performance status ≤ 2 (see Section 11.3).
9. Normal Organ and Marrow Function \[supportive care is allowed per institutional standards, i.e., filgrastim, transfusion\]

   1. Hemoglobin ≥ 8 g/dL
   2. Absolute Neutrophil Count (ANC) ≥ 1,000/μL
   3. Platelet count ≥ 75,000/μL, with no platelet transfusion within 96 hours prior to enrollment
   4. Absolute lymphocyte count (ALC) ≥ 150/μL
   5. PT/INR, PTT ≤ 1.5 x ULN for age

      Adequate renal, hepatic, cardiac, and pulmonary function defined as:
   6. Serum creatinine \< 1.5 x ULN for age and gender, OR creatinine clearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2
   7. Serum ALT or AST ≤ 3x ULN
   8. Total bilirubin ≤ 1.5 mg/dL, unless subject has Gilbert's Syndrome
   9. Cardiac ejection fraction ≥ 45%
   10. No evidence of physiologically significant pericardial effusion as determined by an ECHO
   11. No clinically significant ECG findings
   12. No clinically significant pleural effusion
   13. Pulse oximetry ≥ 92% on room air, OR forced vital capacity ≥ 50% of predicted value
10. Not Pregnant: Females of childbearing potential must have a negative pregnancy test.
11. Contraception: Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative regimen or for as long as CAR T cells are detectable in peripheral blood.
12. Must provide informed consent. All subjects ≥ 18 years of age must be able to give informed consent. For subjects \<18 years old or adults with limited decision-making capacity, their legal authorized representative (LAR) (i.e., parent or guardian) must give informed consent. Pediatric subjects will be included in age-appropriate discussion and assent will be obtained for those \> 7 years of age, when appropriate. If a minor becomes of age during participation of this study, he/she will be asked to reconsent as an adult.

Exclusion Criteria

1. Any patient with metastatic disease OUTSIDE the CNS.
2. Unwilling or unable, in the investigator's judgement, to have a CSF reservoir (Ommaya or Rickham) placed. Does not apply to subjects who have a pre-existing device suitable for ICV delivery of CAR T cells and ICP monitoring.
3. Clinical evidence of active/on-going significant increased intracranial pressure (i.e., impending herniation) or uncontrolled seizures.
4. Prior receipt of a chimeric antigen receptor (CAR)-based therapy.
5. Currently receiving anticoagulation therapy.
6. Known history of infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive).

   EXCEPTION: A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
7. Pregnancy or breastfeeding in a postpartum female.
8. Known sensitivity or allergy to any agents/reagents used in this study.
9. History of prior other malignancy. EXCEPTION: Previously diagnosed and definitively treated more than 5 years prior to enrollment or whose prognosis is deemed good enough to not warrant surveillance.
10. Primary immunodeficiency or history of autoimmune disease (e.g., Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
11. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
12. Significant medical diseases or poorly controlled conditions that, in the judgement of the investigator, put the subject at an unacceptable risk of complications, including but not limited to: uncontrolled diabetes mellitus, chronic obstructive pulmonary disease, pulmonary fibrosis, clinically significant inflammatory disorders, immunodeficiency (e.g., HIV infection), immunocompromised for reasons other than malignancy (e.g., chronic corticosteroid therapy or other immunosuppressive therapy), renal failure including patients requiring dialysis, or clinically significant liver dysfunction.
13. In the Investigator's judgment, the subject or parents/caregivers (as required) will not be able to comply with the study procedures outlined in the study protocol including follow-up visits.

Where this trial is running

Palo Alto, California

• Lucile Packard Children's Hospital Stanford — Palo Alto, California, United States (Recruiting)

Study contacts

• Principal investigator: Katherine Ryan, DO — Stanford University
• Study coordinator: Mariah Duncan

Conditions Medulloblastoma; Central Nervous System Embryonal Tumor; Refractory Medulloblastoma; Recurrent Medulloblastoma; Pediatric Brain Tumor; Embryonal Tumor With Multilayered Rosettes; Pineoblastoma; Atypical Teratoid/Rhabdoid Tumor of the CNS