Recurrent Glioblastoma IDH Wildtype
Conditions
Brief summary
This is an open-label, single-arm, dose-escalation and expansion Phase 1/2 clinical trial designed to evaluate the safety, tolerability and efficacy of P134 cells in patients with recurrent glioblastoma, to explore the maximum tolerated dose (MTD)and recommended Phase 2 dose (RP2D), and to characterize the cytokinetic profile of CAR-T cells in the cerebrospinal fluid of patients. Eligible participants are adults diagnosed with recurrent or progressive glioblastoma who are confirmed as grade 4 glioblastoma (IDH wild-type) by histopathology or molecular pathology. P134 cells are CD44/CD133 dual-targeting CAR-T cells developed by the research team led by Academician Jiang Tao and Professor Zhang Wei from the Beijing Neurosurgical Institute and the Department of Neurosurgery, Beijing Tiantan Hospital. This study is spearheaded by Professor Zhang Wei of the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China, with scientific oversight and guidance provided by Academician Jiang Tao of the Chinese Academy of Engineering.
Interventions
BIOLOGICALP134 cell injection
In Phase 1 dose-escalation study, P134 cell dosing and safety are evaluated using an accelerated titration initial dose followed by a "3+3" design. The starting dose is 1 × 10⁸ CAR⁺ T cells, administered intratumorally or intraventricularly via an Ommaya reservoir. Three dose levels are planned: Level 1: 1 × 10⁸ CAR⁺ T cells, Q2W. Level 2: 3 × 10⁸ CAR⁺ T cells, Q2W. Level 3: 5 × 10⁸ CAR⁺ T cells, Q2W. The Level 1 adopts accelerated titration, and the Level 2 and Level 3 adopt the "3+3" design. In Phase 2 dose expansion, one or two dose levels will be selected based on integrated safety, efficacy, and other relevant data. Up to 10 participants will be enrolled per dose level (including subjects from the dose-escalation study).Participants will be enrolled sequentially from the lower dose level to the higher dose level: enrollment at the lower dose level will be completed first, followed by enrollment at the higher dose level.
Sponsors
Tasly Pharmaceutical Group Co., Ltd
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntary written informed consent. 2. 18-70 years of age (inclusive), male or female. 3. Recurrent or progressive glioblastoma, histopathologically or molecularly diagnosed consistent with grade 4 glioblastoma (IDH wild-type) (refer to WHO Classification of Central Nervous System Tumors, 5th Edition, 2021). 4. Positive CD44 or CD133 antigen expression in tumor tissue confirmed by IHC, defined as ≥1% of tumor cells showing positive CD44 or CD133 IHC staining, regardless of intensity (applicable only in Phase II dose expansion study). 5. At least one measurable lesion meeting RANO 2.0 criteria and having a radiographically assessed measurable lesion ≤ 3 cm in longest diameter 6. Patient has received prior radiation therapy and/or temozolomide/bevacizumab. 7. The investigator confirmed that the patient was suitable for craniotomy cerebrospinal fluid shunt and accessory (Ommaya reservoir) implantation.
Exclusion criteria
1. Highly allergic constitution or history of severe allergy, or allergy to related cell products 2. Receipt of biologic anti-tumor therapy (including monoclonal or bispecific antibody-targeted therapy, immune checkpoint inhibitor therapy, etc.) within 6 weeks prior to PBMC collection; receipt of radiotherapy or surgery within 4 weeks prior to PBMC collection (excluding placement of vascular access devices; a 1-week washout period is acceptable for diagnostic biopsy surgeries); receipt of chemotherapy, hormone therapy (excluding hormone replacement therapy), or non-specific immunomodulatory therapy (such as interleukins, interferons, thymosin, cyclophosphamide, methotrexate, tumor necrosis factor, etc.) within 2 weeks prior to PBMC collection; receipt of traditional Chinese medicine therapy with a clear anticancer indication within 1 week prior to PBMC collection. 3. The adverse reactions caused by previous anti-tumor treatment have not recovered to ≤ Grade 1 as evaluated by NCI CTCAE v6.0 (except alopecia, skin pigmentation, leukoplakia, etc. which are assessed as having no safety risk). 4. Tumor metastasis to the brainstem or spinal cord. 5. Suffering from other serious neurological diseases other than brain tumors, such as meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, amyotrophic lateral sclerosis, spinal muscular atrophy, nerve paralysis, uncontrolled epilepsy, etc. 6. Patients with primary immunodeficiency disease, autoimmune diseases requiring medication (such as Crohn 's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus), or previous history of autoimmune diseases of the nervous system (such as multiple sclerosis, Parkinson' s disease). 7. Receiving or requiring long-term use of immunosuppressive agents (except for physiological doses of systemic corticosteroids ≤ 10 mg/day prednisone equivalent, short-term ≤ 7 days corticosteroids for allergies, or topical glucocorticoids). 8. Trial participants who have a previous history of allogeneic bone marrow transplantation or organ transplantation, or are awaiting organ transplantation. 9. HBsAg positive and HBV DNA positive, HCV Ab positive and HCV RNA positive; Treponema pallidum antibody positive; human immunodeficiency virus (HIV) antibody positive. 10. Prior receipt of any gene therapy or cell therapy trial participant. 11. Pregnant or lactating women. 12. History of malignancy other than glioma within 5 years (except for adequately treated carcinoma in situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized prostate cancer, or stage I cervical cancer, which in the opinion of the investigator carries a minimal risk of recurrence).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicities (DLTs) | From the first dose up to Day 28 post-first dose | Proportion of participants with dose-limiting toxicities (DLTs) as assessed by CTCAE version 6.0 in the dose-escalation phase |
| Adverse events (AEs) | Through study completion, an average of two and a half years | Incidence and severity of adverse events (safety and tolerability) as assessed by CTCAE version 6.0 in the dose-escalation phase. |
| Maximum tolerated dose (MTD) | From the first dose up to Day 28 after the first dose. | The highest dose level with less than 33% of participants experiencing dose-limiting toxicities (DLTs) as assessed by CTCAE version 6.0 in the dose-escalation phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) | From study enrollment to Day 28 after the last dose of participants in the dose-escalation phase | The optimal dose level identified based on the safety data (incidence of adverse events, dose-limiting toxicities \[DLTs\]), preliminary efficacy data , and pharmacodynamic data in the dose-escalation phase. |
| Objective Response Rate (ORR) | Through study completion, an average of two and a half years | the proportion of participants who achieve a complete response (CR) or partial response (PR) as assessed by RANO 2.0 criteria. |
| Disease Control Rate (DCR) | Through study completion, an average of two and a half years | the proportion of participants who achieve a complete response (CR), partial response (PR), or stable disease (SD) as assessed by RANO 2.0 criteria. |
| Progression-Free Survival (PFS) | Through study completion, an average of two and a half years | The time from study enrollment to the first occurrence of disease progression (as assessed by RANO 2.0) or death from any cause, whichever occurs first |
| Duration of Response (DOR) | Through study completion, an average of two and a half years | The time from the first documentation of a complete response (CR) or partial response (PR) (as assessed by RANO 2.0) to the first documentation of objective tumor progression or death from any cause, whichever occurs first. |
| Time to Response (TTR) | Through study completion, an average of two and a half years | the time from study enrollment to the first documentation of a complete response (CR) or partial response (PR) as assessed by RANO 2.0 |
| 1-year OS Rate | From study enrollment up to 12 months after study enrollment | the proportion of participants who are still alive 12 months after study enrollment |
| Overall Survival | Through study completion, an average of two and a half years | The time from study enrollment to death from any cause |
Countries
China
Contacts
CONTACTZhang Yuping
PRINCIPAL_INVESTIGATORZhang Wei, Prof.
Beijing Tiantan Hospital, Capital Medical University, Beijing, P.R.China
Outcome results
None listed