Efficacy and Safety of TMZ Plus 6-MP in the Patients With Recurrent Glioblastoma

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Efficacy and Safety of TMZ Plus 6-MP in the Patients With Recurrent Glioblastoma

Study Purpose

Glioblastoma, the most prevalent malignant tumor in the central nervous system, is characterized by high invasiveness and a propensity to recur, contributing to a relatively elevated mortality rate. Patients diagnosed with high-grade glioblastomas typically experience a median survival period of less than 14 months. Presently, the standard treatment for glioblastoma involves surgical resection combined with postoperative radiotherapy and chemotherapy, with postoperative chemotherapy playing a pivotal role in enhancing patient prognosis. Temozolomide (TMZ), a cutting-edge oral alkylating agent known for its advantageous properties, including easy traversal of the blood-brain barrier, induces DNA alkylation in tumor cells, fostering apoptosis. Currently, it serves as a frontline medication for postoperative chemotherapy in glioblastoma. However, clinical resistance to TMZ chemotherapy significantly hampers its efficacy in later stages. We have recently discovered and validated that 5-aminoimidazole-4-carboxamide (AICA), derived from TMZ, can transform into 5-aminoimidazole-4-carboxamide ribonucleotide-5-phosphate (AICAR) in GBM cells. Hypoxanthine phosphoribosyltransferase 1 (HPRT1) has been identified as the catalyst for the AICA reaction, generating AICAR. AICAR acts as an endogenous activator of AMP-activated protein kinase (AMPK), fostering chemoresistance in glioblastoma through the activation of the AMPK signaling pathway. 6-mercaptopurine (6-MP) competes effectively to inhibit HPRT1 activity, thereby impeding TMZ-induced AMPK activation and significantly heightening glioblastoma cell sensitivity to TMZ. In this project, we propose an innovative strategy involving the combination of 6-MP with TMZ for the treatment of glioblastoma.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 65 Years
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

1. Age between 18 and 65, no gender restrictions. 2. Histologically confirmed glioblastoma as the primary tumor after surgery. 3. Patients with recurrent glioblastoma confirmed by MRI after standard treatment (surgery, Stupp regimen) failure, supported by RANO criteria evaluation. 4. At least one measurable intracranial tumor lesion according to RANO criteria. 5. No prior treatment with 6-mercaptopurine or similar drugs. 6. General condition assessed by Karnofsky Performance Status (KPS) score ≥ 60. 7. Normal bone marrow function: white blood cell count ≥ 3.5 × 10^9/L, neutrophil count ≥ 2.0 × 10^9/L, hemoglobin count ≥ 90 g/L, platelet count ≥ 80 × 10^9/L. 8. Normal organ functions such as heart and lung, and no severe internal diseases. 9. Willing to sign an informed consent form, good compliance, able to attend regular follow-ups, and voluntarily agree to comply with the study protocol.

Exclusion Criteria:

1. Participants who do not consent. 2. Vulnerable populations such as pregnant women, children, and adolescents. 3. No history of or concurrent malignancy within the past 5 years. 4. Abnormal liver function (total bilirubin > 1.5 times the upper limit of normal, ALT/AST > 2 times the upper limit of normal). 5. Impaired kidney function (serum creatinine > 1.5 times the upper limit of normal). 6. Presence of organic heart disease leading to clinical symptoms or cardiac dysfunction (NYHA ≥ Grade 2). 7. Factors significantly affecting oral drug absorption, such as difficulty swallowing, intestinal obstruction, etc.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06279767
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1/Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	The First Affiliated Hospital with Nanjing Medical University
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Yongping You, PhD
Principal Investigator Affiliation	The First Affiliated Hospital with Nanjing Medical University
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	China
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioblastoma, Cancer, Temozolomide

Arms & Interventions

Arms

Experimental: Treatment with a combination of 6-mercaptopurine and temozolomide

Interventions

Drug: - 6-mercaptopurine

6-mercaptopurine (6-MP) is a crucial drug in the maintenance phase of acute lymphoblastic leukemia treatment.

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