The Efficacy and Safety of Temozolomide in SDH-deficient GIST (GIST)

A Phase 2 Study to Evaluate the Efficacy and Safety of Temozolomide in Advanced Gastrointestinal Stromal Tumor Patients With SDH Deficiency

The goal of this clinical trial is to investigate the efficacy and safety of temozolomide in SDH deficiency GIST patients.

Study Overview

• Status: Recruiting
• Conditions: Gastrointestinal Stromal Tumors
• Intervention / Treatment: Drug: Temozolomide capsule

Detailed Description

Wild type GISTs are less responsive to imatinib with a response rate of 23.1-44.6% and a median progressiion-free survival of 12.3-12.8 months. The efficacy of imatinib is limited in particular in SDH deficienctGIST with a reported response of 2%. Therefore, the development of a new therapeutic agents is urgently needed.

Recently, a study of TKI-resistant SDH-deficient preclinical model showed that temozolomide, an alkylating agent, promotes DNA damage in tumor cells, leading to tumor cell killing. In a retrospective analysis, 2 out of 5 SDH deficient GIST patients treated with temozolomide showed partial response, suggesting its efficacy in this patient population.

Based on these findings,The goal of this clinical trial is to investigate the efficacy and safety of temozolomide in SDH deficiency GIST patients. In addition, for exploratory purposes, aim to investigate the efficacy and safety of temozolomide in KIT and PDGFRA wild-type GIST without SDH deficiency.

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Min-Hee Ryu, MD, PhD; Phone Number: 82-2-3010-5936; Email: miniryu@amc.seoul.kr
• Study Contact Backup: Name: Hyung-Don Kim, MD, PhD; Phone Number: 82-2-3010-0236; Email: kimhdmd@amc.seoul.kr

Study Locations

• South Korea
  • Seoul
    • Seoul, Seoul, South Korea, 138-736
      • Recruiting
      • Asan Medical Center, University of Ulsan College of Medicine
      • Contact: Min-Hee Ryu, MD, PhD; Phone Number: +82-2-3010-5935; Email: miniryu@amc.seoul.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 20 years or older, at the time of acquisition of informed consent
2. Histologically confirmed GIST with CD117(+), DOG-1(+)
3. Wild type GIST without KIT or PDGFRα gene mutations determined by Sanger sequencing and panel sequencing
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 ~ 2
5. Resolution of all adverse events with prior treatments to grade 0 or 1 by NCI-CTCAE version 5.0
6. At least one measurable lesion by RECIST version 1.1.

7. Adequate bone marrow, hepatic, renal, and other organ functions, before adjuvant imatinib treatment

   • Neutrophil >1,500/mm3
   • Platelet > 100,000/mm3
   • Hemoglobin >8.0 g/dL
   • Total bilirubin < 1.5 x upper limit of normal (ULN)
   • AST/ALT < 2.5 x ULN
   • Creatinine <1.5 x ULN
8. Life expectancy ≥12 weeks
9. Disease progression or discontinuation of treatment due to intolerable toxicity at least with palliative 1st line imatinib .
10. Washout period of previous TKIs or chemotherapy for more than 4 times the half life ((Imitinib and regorafenib need 1 week and sunitinib need 2 weeks.)
11. Provision of a signed written informed consent

Exclusion Criteria:

1. Confirmed GIST with KIT or PDGFRα gene mutations determined by Sanger sequencing and panel sequencing
2. Women of child-bearing potential who are pregnant or breast feeding
3. Women or men who are not willing to use effective contraception entering the study period or until at least 6 months after the last study drug administration
4. If any of the following applies within ≤ 6 months prior to starting study enrollment : Myocardial Infarction, severe instable angina, coronary/peripheral bypass, NYHA class III or IV congestive heart failure, stroke or transient ischemic attack, treatment required severe arrhythmia
5. Uncontrolled infection
6. Acute and chronic liver disease and all chronic liver impairment.(But Patients with stable chronic hepatitis B are eligible
7. Acute, or chronic medical or psychiatric condition or laboratory abnormality such as active uncontrolled infection that difficult to study participation in the judgment of the investigator
8. Known diagnosis of HIV infection (HIV testing is not mandatory).
9. History of another primary malignancy that is currently clinically significant or currently requires active intervention.
10. Alcohol or substance abuse disorder
11. The patients with NTRK fusion

5)

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: temozolomide treatment	Drug: Temozolomide capsule; Temozolomide 200 mg/m2 is administered orally for 1-5 days of each cycle, and then canceled for 23 days (a total of 28 days is 1 cycle)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective respone rate in SDH deficiency wild type GIST	complet response+partial response defined by RECIST v1.1	up to 4 years

Collaborators and Investigators

• Sponsor: Asan Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: December 14, 2022
• First Submitted That Met QC Criteria: December 14, 2022
• First Posted (Actual): December 22, 2022

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Gastrointestinal Stromal Tumors; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Dacarbazine; Triazenes; Imidazoles; Temozolomide
• Other Study ID Numbers: AMC2203

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No