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

• ClinicalTrials.gov Identifier: NCT03556384
• Recruitment Status: Recruiting
• First Posted: June 14, 2018
• Last Update Posted: October 4, 2022
• Sponsor: Adam Burgoyne, MD, PhD
• Information provided by (Responsible Party): Adam Burgoyne, MD, PhD, University of California, San Diego

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Gastrointestinal Stromal Tumors; Sdh; GIST; Cancer	Drug: Temozolomide	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Phase 2 Efficacy Study of Temozolomide (TMZ) In Advanced Succinate Dehydrogenase (SDH)-Mutant/Deficient Gastrointestinal Stromal Tumor (GIST)
• Actual Study Start Date: September 12, 2018
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: June 2025

Arms and Interventions

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 Name: TEMODAR®

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate [ Time Frame: 6 months ]
   To determine overall response rate at 6 months for TMZ therapy in patients with SDH-mutant/deficient GIST

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Adam M Burgoyne, MD, PhD; (858) 657-1276 ext 5; aburgoyne@health.ucsd.edu

Contact: Jason Sicklick, MD; 858-822-6173; jsicklick@health.ucsd.edu

Locations

United States, California

UC San Diego Moores Cancer Center; Recruiting

La Jolla, California, United States, 92093

Contact: Gabriel Baker 858-246-3628 gbaker@health.ucsd.edu

Principal Investigator: Adam M Burgoyne, MD, PhD

Sub-Investigator: Jason K Sicklick, MD

United States, Florida

University of Miami; Recruiting

Miami, Florida, United States, 33136

Contact: Yvonne Enriquez-Nunez 305-243-0864 YXE97@med.miami.edu

Principal Investigator: Jonathan Trent, MD, PhD

United States, Massachusetts

Dana-Farber Cancer Institute; Withdrawn

Boston, Massachusetts, United States, 02215

United States, Oregon

Oregon Health & Science University; Recruiting

Portland, Oregon, United States, 97239

Contact: Tracy Havnaer 503-346-1183 walkertr@ohsu.edu

Principal Investigator: Michael Heinrich, MD

United States, Pennsylvania

Fox Chase Cancer Center; Recruiting

Philadelphia, Pennsylvania, United States, 19111

Contact: Megan Villarin 215-728-4091 Megan.Villarin@fccc.edu

Principal Investigator: Margaret von Mehren, MD

Sponsors and Collaborators

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

More Information

• Responsible Party: Adam Burgoyne, MD, PhD, Associate Professor of Medicine, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT03556384
• Other Study ID Numbers: 180114; FD-R-6334 ( Other Grant/Funding Number: FDA OOPD )
• First Posted: June 14, 2018
• Last Update Posted: October 4, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adam Burgoyne, MD, PhD, University of California, San Diego:

cancer; Temozolomide; GIST; SDH-Mutant/Deficient; SDH; Succinate Dehydrogenase

Additional relevant MeSH terms:

Gastrointestinal Stromal Tumors; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Temozolomide; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents