Using GD2 CAR T cells to treat specific brain and spinal tumors in children and young adults

Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR) T Cells (GD2CART) for H3K27M-mutant Diffuse Midline Glioma (DMG)

This study is testing a new type of immune cell treatment for children and young adults with specific brain and spinal tumors to see if it is safe and effective.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 97 (estimated)
• Ages: 2 Years to 60 Years
• Sex: All
• Sponsor: Stanford University (Academic / other)
• Drugs / interventions: chemotherapy, radiation, CAR T, dasatinib, Chimeric Antigen Receptor
• Locations: 1 site (Stanford, California)
• Trial ID: NCT04196413 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the feasibility and safety of using GD2 CAR T cells, which are engineered immune cells, to treat children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) and spinal diffuse midline glioma (DMG). Participants will undergo a process to collect their immune cells, which will then be modified to express a chimeric antigen receptor targeting GD2. The study will assess the maximum tolerated dose of these modified cells after a lymphodepletion regimen and monitor for any potential toxicities. Additionally, the study will explore the preliminary clinical benefits of this treatment approach.

Who should consider this trial

Good fit: Ideal candidates for this study are children and young adults aged 2 to 60 years diagnosed with H3K27M-mutant diffuse midline glioma.

Not a fit: Patients with tumors that do not express the H3K27M mutation or those who are not within the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with aggressive brain and spinal tumors that currently have limited treatment options.

How similar studies have performed: Other studies using CAR T cell therapies have shown promising results in treating various cancers, suggesting potential success for this novel approach.

Eligibility criteria

INCLUSION CRITERIA

1. Disease Status: Diagnosis of H3K27M mutant diffuse midline glioma (DMG)
2. H3K27M or H3K27I mutation. Confirmed by CLIA test.
3. Age: Greater than or equal to 2 year of age and less than or equal to 60 years of age.
4. Prior Therapy:

   * At least 4 weeks following completion of standard upfront radiation therapy.
   * At least 3 weeks post chemotherapy or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy, except for systemic inhibitory/stimulatory immune checkpoint therapy that requires 3 months.
   * Dordaviprone (Modeyso), previously known as ONC201, may be taken as prior therapy but - just as with other anti-cancer medications - administration must cease at least 5 half-lives prior to enrollment
5. Performance Status:

   Subjects \> 16 years of age: Karnofsky ≥ 60% OR Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Subjects ≤ 16 years of age: Lansky scale ≥ 60%.

   Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
6. Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion) i. ANC ≥ 1000/uL ii. Platelet count ≥ 100,000/uL iii. Absolute lymphocyte count ≥ 150/uL iv. Hemoglobin ≥ 8 g/dL v. Adequate renal, hepatic, pulmonary and cardiac function defined as:

   \- Creatinine within institutional norms for age (i.e.

   ≤ 2 mg/dL in adults or according to table below in children \<18 years) OR creatinine clearance (as estimated by Cockcroft Gault Equation) ≥ 60 mL/min

   Serum ALT/AST ≤ 3.0 ULN (grade 1)
   * Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
   * Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an ECHO, and no clinically significant ECG findings
   * Baseline oxygen saturation \> 92% on room air
7. Pregnancy Test Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization are not considered to be of childbearing potential) or NA
8. 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 GD2CART cells are detectable in peripheral blood or CSF.
9. Ability to give informed consent. All subjects ≥ 18 years of age must be able to give informed consent. For subjects \<18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age appropriate discussion and written 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. For Dose Escalation: Bulky tumor involvement of cerebellar vermis or hemispheres (pontocerebellar peduncles involvement is acceptable), or thalamic lesions that in the investigator's assessment place the subject at unacceptable risk for herniation.

   For Dose Expansion: Bulky disease that in the investigator's assessment place the subject at unacceptable risk for herniation. Thalamic DMG is permitted.
2. Clinically significant swallowing dysfunction/dysphagia or prominent medullary dysfunction, as determined by the clinical investigator; or primary cervical cord tumors above C6/7 that represent a high risk of respiratory compromise, as determined by the clinical investigator.
3. Current systemic corticosteroid therapy above physiologic replacement levels.
4. Ongoing use of dietary supplements, alternative therapies or extreme diet modifications or any medication not approved by the investigators
5. Prior CAR therapy.
6. Prior immunomodulatory therapy, except for checkpoint inhibitor therapy after at least 3 month wash-out.
7. Uncontrolled fungal, bacterial, viral, or other infection. Previously diagnosed infection for which the patient continues to receive antimicrobial therapy is permitted if responding to treatment and clinically stable.
8. Diagnosed ongoing infection with:

   * HIV,
   * Hepatitis B (HBsAg positive) or
   * Hepatitis C virus (anti-HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
9. Clinically significant systemic illness or medical condition (e.g. significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.
10. Women who are pregnant or breastfeeding.
11. In the investigator's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.
12. Known sensitivity or allergy to any agents/reagents used in this study.
13. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years

    * All subject files must include supporting documentation to confirm subject eligibility.

The method of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record review.

\*Anyone under 26, please contact Ashley Jacobs and anyone 26 and older, please contact Monica Reddy

Where this trial is running

Stanford, California

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

Study contacts

• Principal investigator: Michelle Monje — Stanford University
• Study coordinator: Ashley Jacobs, RN, BSN

Conditions Glioma of Spinal Cord; Glioma of Brainstem