Temozolomide (TMZ) In Advanced Succinate Dehydrogenase (SDH)-Mutant/Deficient Gastrointestinal Stromal Tumor (GIST)

An Open-Label, Phase 2 Efficacy Study of Temozolomide (TMZ) In Advanced Succinate Dehydrogenase (SDH)-Mutant/Deficient Gastrointestinal Stromal Tumor (GIST)

Funding Source - FDA OOPD

FDA-approved products for patients with unresectable or metastatic GIST include therapies such as imatinib and sunitinib. Although there are FDA-approved products for the treatment of advanced/metastatic GIST, these therapies are known to be ineffective in the SDH-mutant/deficient subtype and no known effective therapies exist.

The purpose of this study is to investigate SDH-Mutant/Deficient Gastrointestinal Stromal cancer's response to the drug Temozolomide (TMZ) and aim to improve patient outcomes.

Temozolomide is approved by the FDA for the treatment of newly diagnosed glioblastoma multiforme (GBM) and refractory anaplastic astrocytoma cancers.

Temozolomide is considered experimental because it is not approved by the FDA for the treatment of SDH-Mutant/Deficient Gastrointestinal Stromal Tumor.

Study Overview

• Status: Active, not recruiting
• Conditions: Cancer; Gastrointestinal Stromal Tumors; GIST; Sdh
• Intervention / Treatment: Drug: Temozolomide

Detailed Description

This oncology study will be a phase 2 study for patients with advanced or metastatic GIST. This study will determine overall response rate at 6 months for TMZ therapy in patients with SDH-mutant/deficient GIST.

Treatment will continue for 6 months (with option to continue if benefiting treatment) or until disease progression or unacceptable toxicity (whichever occurs first). All patients will have regular evaluations for assessment of safety parameters. Temozolomide dose may be held and/or modified for the management of adverse treatment effects according to pre-specified criteria. Patients will have radiographic imaging (CT or MRI) every 8 weeks to assess tumor resection.

An end of treatment visit for clinical evaluations and safety assessments will be performed approximately 28 days (7 days) after the last dose of study drug. Patients discontinuing study treatment will be followed every 3-6 months for disease recurrence and survival.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patient has pathologically confirmed SDH-mutant/deficient GIST.
2. Has recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy.
3. Patient has an ECOG Performance Status of 0-2.
4. Patient has adequate hematologic, hepatic and renal function.
5. Female patient of childbearing potential has a negative serum or urine pregnancy within 72 hours prior to receiving the first dose of study medication.
6. Female patient of childbearing potential agrees to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.
7. Male patient with a partner of childbearing potential agrees to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
8. Has measurable or evaluable disease as per RECIST v1.1 (Appendix B).
9. Life expectancy of >12 weeks.

Exclusion Criteria:

1. Patients who have had major surgery within 4 weeks of initiation of study medication.
2. Patients who are receiving other concurrent anti-neoplastic therapy (e.g., chemotherapy, targeted therapy, immunotherapy, or radiotherapy) at the start of study treatment.
3. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
4. Evidence of severe or uncontrolled systemic diseases [e.g., unstable or uncompensated respiratory, cardiac (including life threatening arrhythmias)].
5. Unresolved toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy except alopecia (if applicable) unless agreed that the patient can be entered after discussion with the Medical Monitor.
6. Presence of cardiac impairment class III and IV definitions; OR history of myocardial infarction/active ischemic heart disease within one year of study entry; OR uncontrolled dysrhythmias; OR poorly controlled angina.
7. Pregnant or breast-feeding females.
8. Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
9. Any concurrent condition which in the investigator's opinion makes it undesirable for the subject to participate in this trial or which would jeopardize compliance with the protocol.
10. Patients who cannot swallow oral formulations of the agent

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: TMZ 85 mg/m2 mg orally; TMZ 85 mg/m2 mg orally once for 21 days followed by 7 days without treatment in 28 day cycles. Treatment will continue for 6 months (with option to continue if benefiting treatment) or until disease progression or unacceptable toxicity (whichever occurs first). All patients will have regular evaluations for assessment of safety parameters. Temozolomide dose may be held and/or modified for the management of adverse treatment effects according to pre-specified criteria. Patients will have radiographic imaging (CT or MRI) every 8 weeks to assess tumor resection. An end of treatment visit for clinical evaluations and safety assessments will be performed approximately 28 days after the last dose of study drug. Patients discontinuing study treatment will be followed every 3-6 months for disease recurrence and survival.

Drug: Temozolomide; Temozolomide 85 mg/m2 will be administered orally for 21 days followed by 7 days without treatment in 28 day cycles. Treatment will continue for 6 months (with option to continue if benefiting treatment) or until disease progression or unacceptable toxicity (whichever occurs first). All patients will have regular evaluations for assessment of safety parameters; Other Names: TEMODAR®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	To determine overall response rate at 6 months for TMZ therapy in patients with SDH-mutant/deficient GIST	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		4 years
Progression-free survival		4 years
Adverse events related to TMZ	Description, grade [CTCAE v4.03], and seriousness	6 months

Collaborators and Investigators

• Sponsor: Adam Burgoyne, MD, PhD
• Investigators: Principal Investigator: Adam Burgoyne, MD, PhD, University of California, San Diego; Principal Investigator: Jason Sicklick, MD, University of California, San Diego

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2018
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: June 1, 2018
• First Submitted That Met QC Criteria: June 12, 2018
• First Posted (Actual): June 14, 2018

Study Record Updates

• Last Update Posted (Actual): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: cancer; Temozolomide; GIST; SDH; SDH-Mutant/Deficient; Succinate Dehydrogenase
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Neoplasms, Connective Tissue; Gastrointestinal Stromal Tumors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: 180114; FD-R-6334 (Other Grant/Funding Number: FDA OOPD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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