Human Induced Pluripotent Stem Cells Derived Natural Killer Cell(XS005) Injection Combined With Stupp Regimen for Adjuvant Chemotherapy in Subjects With Primary Glioblastoma(GBM)

Study Overview
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Brief Summary
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The main objective of this clinical study is to evaluate the safety of XS005 cell injection and to determine the maximum tolerated dose . Furthermore, initial efficacy will be examined.

Detailed Description
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Treatment on this study includes eight Human Induced Pluripotent Stem Cell derived natural killer cell（ XS005 cell ）infusions over an 16 week period. The study will evaluate the safety, feasibility and maximum tolerated dose (MTD) of XS005 cell using a 3+3 study design . The total study duration will be 2 years.

Official Title
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Clinical Study of Evaluating the Safety and Initial Efficacy of XS005 Cell Injection Combined With Stupp Regimen for Adjuvant Chemotherapy in Subjects With Primary Glioblastoma

Conditions
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Glioblastoma, GBM

Intervention / Treatment
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* Biological: XS005 Cell Injection
* Drug: Temozolomide（TMZ）


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 70 years old (including the threshold), both male and female; GBM (2021 5th Edition of World Health Organization(WHO) Classification of Central nervous System Tumors) diagnosed for the first time by imaging and histopathology; Expected survival ≥6 months; Karnofsky performance status(KPS) score ≥60 before treatment; The level of organ and bone marrow function must meet the following requirements: Bone marrow: Absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90g/L, and no platelet or red blood cell transfusion within 14 days prior to first administration. And did not receive blood transfusion or biological response regulators (such as granulocyte growth factor, erythrocyte growth factor, interleukin-11, etc.) within 14 days before the first administration; Liver function: No history of cirrhosis (Child-Pugh grade B, C). Serum total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN; Renal function: serum creatinine ≤1.5×ULN, or creatinine clearance ≥50ml/min (Cockcroft-Gault formula); Qualitative urine protein ≤1+; If the qualitative urine protein is ≥2+, it is necessary to conduct a quantitative urine protein test for 24 hours. According to the examination results, the researchers made the admission judgment. Coagulation function: prothrombin time (PT) ≤1.5×ULN; International standardized ratio (INR) ≤1.5×ULN, and activated partial thromboplastin time (APTT) ≤1.5×ULN (except those receiving therapeutic anticoagulants); The subjects (including male subjects) have no pregnancy plan and voluntarily take effective contraceptive measures during the screening period and from the beginning of the study administration to the last dose of the study drug within 6 months after the study drug is administered, and have no sperm or egg donation plans, in which the study period should voluntarily take effective contraceptive measures; Able to understand the procedures and methods of this study, willing to sign informed consent and strictly follow the clinical study protocol to complete this study. Exclusion Criteria: Patients who received other anti-tumor drugs (including chemotherapy, targeted drugs other than bevacizumab, immunotherapy, Chinese medicine anti-tumor therapy, etc.) except for patients who received concurrent radiotherapy and chemotherapy for GBM after surgery (TMZ dosage ≤75mg/m2, radiotherapy dose limited to 50-60Gy); Previous or current malignant tumors of other types, except for the following cases: basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin or cervical cancer in situ; Known to be allergic to dacarbazine, temozolomide, the investigational drug, or any of its excipients, or has had a history of unexplained severe allergic reactions; The presence of any contraindications to MRI, such as: use of a pacemaker, infusion pump, or allergy to MRI contrast agents; Receive live attenuated vaccine or vaccine within 4 weeks prior to the first study drug treatment or plan to receive live vaccine during the study period; Subjects with active or pre-existing autoimmune diseases that are likely to recur, or patients at high risk (such as those who have received an organ transplant and require immunosuppressive therapy). Severe cardiovascular and cerebrovascular diseases within 6 months before screening; Patients with sudden lung disease, interstitial lung disease or pneumonia, pulmonary fibrosis, acute lung disease, etc., which cannot be controlled after treatment, except local interstitial pneumonia induced by radiotherapy; A history of infection with human immunodeficiency virus, or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation or stem cell transplantation; Except for those that do not require immunosuppressive therapy, such as corneal transplantation; Evidence of active infection: Hepatitis B (with hepatitis B surface antigen（HBsAg） positive, hepatitis B virus-DNA（HBV-DNA）≥500IU/ml and abnormal liver function); Hepatitis C (hepatitis C antibody（ HCV-Ab） positive, hepatitis C virus-RNA(HCV-RNA) higher than the lower limit of assay and abnormal liver function); Patients with active pulmonary tuberculosis infection found through medical history or CT examination, or a history of active pulmonary tuberculosis infection within 1 year before enrollment, or a history of active pulmonary tuberculosis infection more than 1 year ago without formal treatment; Have a clear history of neurological or psychiatric disorders, or a known history of psychotropic substance abuse, alcohol abuse, or drug use; Received any investigational drug within 4 weeks prior to initial dosing, or participated in another clinical study at the same time; Women who are pregnant or breastfeeding, or who have a positive baseline pregnancy test; Patients deemed unsuitable for inclusion in this study by the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Subjects With Primary Glioblastoma | Biological: XS005 Cell Injection<br>* Treatment on this study includes eight XS005 cell infusions over an 16 week period. Phase 1： dose escalation (3+3); Phase 2 : dose of recommended phase 2 dose(RP2D).<br>* Other names: XS005;Drug: Temozolomide（TMZ）<br>* Patients were given temozolomide on day 1 to day 5 of each cycle, 28 days per cycle, for a total of 4 cycles.<br>* Other names: TMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose-Limiting Toxicities (DLTs) | DLT is defined as a toxic effect in the subject at any dose, cannot be reasonably attributed to the subject's underlying disease, other conditions, and/or concomitants, that the investigator determines to be related (including definitely, likely, or possibly) to the XS005 cell injection. | within 7 days after the the first infusion of XS005. | 
| Incidence of Adverse Events (AEs) | AE is defined as any adverse medical event within 4 months after the the first infusion of XS005. | 4 months | 
| Maximum tolerated dose (MTD) | MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined. | within 7 days after the the first infusion of XS005. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS : defined as the time from the start of treatment until the onset of tumor progression or death from any cause; | From the start of treatment until the time of first disease progression or death , assessed up to 12 months post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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XS005