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

NCT06279767 | Recruiting Phase 1 FDA Drug

• 1 other identifier: 2022-SR-557
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Glioblastoma; Cancer; Temozolomide

Keywords

Glioblastoma; Cancer; Temozolomide; 6-mercaptopurine

Outcome Measures

Primary Outcomes (1)

• PFS

  Progression-free survival (PFS), defined as the time from treatment to progression or death, whichever occurs first

  12 months

Secondary Outcomes (2)

• OS

  12 months

• Safety evaluation

  12 months

Study Arms (1)

Treatment with a combination of 6-mercaptopurine and temozolomide

EXPERIMENTAL

Drug: 6-mercaptopurine

Interventions

6-mercaptopurine DRUG

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

Treatment with a combination of 6-mercaptopurine and temozolomide

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 65, no gender restrictions.
• Histologically confirmed glioblastoma as the primary tumor after surgery.
• Patients with recurrent glioblastoma confirmed by MRI after standard treatment (surgery, Stupp regimen) failure, supported by RANO criteria evaluation.
• At least one measurable intracranial tumor lesion according to RANO criteria.
• No prior treatment with 6-mercaptopurine or similar drugs.
• General condition assessed by Karnofsky Performance Status (KPS) score ≥ 60.
• 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.
• Normal organ functions such as heart and lung, and no severe internal diseases.
• Willing to sign an informed consent form, good compliance, able to attend regular follow-ups, and voluntarily agree to comply with the study protocol.

You may not qualify if:

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

Sponsors & Collaborators

• The First Affiliated Hospital with Nanjing Medical University: lead

Study Sites (1)

Department of Neurosurgery of The First Affiliated Hospital of Nanjing Medical University

Nanjing, Jiangsu, 210029, China

RECRUITING

MeSH Terms

Conditions

Glioblastoma; Neoplasms

Interventions

Mercaptopurine

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sulfhydryl Compounds; Sulfur Compounds; Organic Chemicals; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Yongping You, PhD

  The First Affiliated Hospital with Nanjing Medical University

  STUDY DIRECTOR

Central Study Contacts

Yongping You, DD

CONTACT

13770694258; YYPL3@sohu.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2024
• First Posted: February 28, 2024
• Study Start: July 1, 2022
• Primary Completion: July 1, 2025
• Study Completion: July 31, 2025
• Last Updated: February 28, 2024

Record last verified: 2024-02

Locations

CN (1)