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

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.

Study Overview

• Status: Recruiting
• Conditions: Cancer; Glioblastoma; Temozolomide
• Intervention / Treatment: Drug: 6-mercaptopurine

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yongping You, DD; Phone Number: 13770694258; Email: YYPL3@sohu.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • Department of Neurosurgery of The First Affiliated Hospital of Nanjing Medical University
      • Contact: Yongping You, PhD; Phone Number: 13770694258; Email: YYPL3@sohu.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment with a combination of 6-mercaptopurine and temozolomide	Drug: 6-mercaptopurine; 6-mercaptopurine (6-MP) is a crucial drug in the maintenance phase of acute lymphoblastic leukemia treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	Progression-free survival (PFS), defined as the time from treatment to progression or death, whichever occurs first	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety evaluation	Adverse events were assessed according to NCI CTCAE (version 5.0)	12 months
OS	Overall survival (OS), defined as the time from treatment to death	12 months

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Investigators: Study Director: Yongping You, PhD, The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 31, 2025

Study Registration Dates

• First Submitted: January 31, 2024
• First Submitted That Met QC Criteria: February 19, 2024
• First Posted (Estimated): February 28, 2024

Study Record Updates

• Last Update Posted (Estimated): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Cancer; Temozolomide; 6-mercaptopurine; Glioblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Mercaptopurine
• Other Study ID Numbers: 2022-SR-557

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes