Temozolomide for Gastrointestinal Stromal Tumor

Recruiting at 3 trial locations

Overseen By Jason Sicklick, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Adam Burgoyne, MD, PhD

Must not be taking: Antineoplastics

Disqualifiers: Brain metastases, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 6 months

23 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot be on other cancer treatments like chemotherapy or targeted therapy when starting the study. It's best to discuss your specific medications with the trial team.

What evidence supports the effectiveness of the drug Temozolomide for treating gastrointestinal stromal tumors?

Temozolomide has shown effectiveness in treating various types of brain tumors, such as glioblastoma and anaplastic astrocytoma, and has also been used for other cancers like melanoma. While it is not specifically approved for gastrointestinal stromal tumors, its success in treating other cancers suggests it might be beneficial for this condition as well. ^{1 2 3 4 5}

Is Temozolomide generally safe for humans?

Temozolomide is generally well tolerated and safe, with common side effects like fatigue, nausea, and vomiting. However, it can cause serious blood-related issues like myelodysplastic syndrome and aplastic anemia, though these are rare. ^{1 6 7 8 9}

How is the drug Temozolomide unique for treating gastrointestinal stromal tumors?

Temozolomide is unique because it is an alkylating agent that has shown effectiveness in treating various types of tumors, including brain tumors and melanoma, by modifying the DNA of cancer cells to prevent their growth. Its use in gastrointestinal stromal tumors is novel, as it is typically used for other cancers, and there are ongoing studies to explore its potential in this new context. ^{1 2 4 10 11}

What is the purpose of this trial?

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.

Research Team

Jason Sicklick, MD

Principal Investigator

University of California, San Diego

Adam Burgoyne, MD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for male and female patients with a specific type of cancer called SDH-Mutant/Deficient Gastrointestinal Stromal Tumor (GIST) that cannot be removed by surgery or has spread. Participants must have recovered from previous treatments, not have severe diseases like uncontrolled heart conditions, and agree to use contraception. Pregnant or breastfeeding women and those unable to take oral medication are excluded.

Inclusion Criteria

I agree to use contraception during and up to 120 days after the study.

I am a woman who can have children and have a recent negative pregnancy test.

My GIST is confirmed to have an SDH mutation.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I do not have severe or uncontrolled health issues like heart or lung problems.

I cannot swallow pills.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Temozolomide (TMZ) 85 mg/m2 orally for 21 days followed by 7 days without treatment in 28-day cycles, continuing for 6 months or until disease progression or unacceptable toxicity

6 months

Regular evaluations and radiographic imaging every 8 weeks

End of Treatment

An end of treatment visit for clinical evaluations and safety assessments approximately 28 days after the last dose of study drug

4 weeks

1 visit (in-person)

Follow-up

Participants are monitored for disease recurrence and survival every 3-6 months

4 years

Treatment Details

Interventions

• Temozolomide

Trial Overview The study is testing the effectiveness of Temozolomide (TMZ), an FDA-approved drug for certain brain cancers but considered experimental for GIST. The goal is to see if TMZ can improve outcomes in patients with this particular subtype of GIST where other therapies are ineffective.

Participant Groups

Group I: TMZ 85 mg/m2 mg orally Experimental Treatment 1 Intervention

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.

Temozolomide is already approved in European Union, United States for the following indications:

Approved in European Union as Temodal for:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
• Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy

Approved in United States as Temodar for:

• Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
• Newly diagnosed or refractory anaplastic astrocytoma

Who Is Running the Clinical Trial?

Adam Burgoyne, MD, PhD

Lead Sponsor

Trials

1

Recruited

20+

Findings from Research

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

Temozolomide (TMZ) has been established as an effective treatment for primary brain tumors like glioblastoma and oligodendroglioma, and it has also shown efficacy in melanoma, with multiple studies supporting its use as both a monotherapy and adjuvant chemotherapy.

Recent clinical trials suggest that TMZ may be beneficial in treating a variety of other cancers, including brain metastases, lymphomas, and neuroendocrine tumors, indicating its potential as a versatile cancer treatment beyond its formal indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and unusual indications: review of literature. Tatar, Z., Thivat, E., Planchat, E., et al.[2022]

Temozolomide (TMZ) is shown to be more cost-effective than the traditional PCV treatment for glioblastoma multiforme (GBM), with costs of €2367 per extra life-month and €32,471 per quality-adjusted life-year (QALY).

The analysis indicates that TMZ has a high probability (over 60%) of being the most cost-effective treatment option at various willingness-to-pay thresholds, especially when considering quality of life improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. Martikainen, JA., Kivioja, A., Hallinen, T., et al.[2018]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

In a study involving 831 patients across 21 French hospitals, temozolomide (TMZ) prescriptions were found to conform to the French summary of product characteristics (SPC) in 51.9% of cases, indicating a moderate level of adherence to official guidelines.

The study revealed high conformity (91.5%) to the prescription guidebook, with specific adherence rates of 62% for newly diagnosed glioblastoma patients receiving combined treatment with radiotherapy, 72% for maintenance therapy, and 66% for patients with progressive disease, highlighting the overall compliance in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France. Tilleul, P., Brignone, M., Hassani, Y., et al.[2018]

Temozolomide (TMZ) is an effective oral treatment for malignant gliomas, providing significant survival benefits while being generally well tolerated by patients.

While most side effects of TMZ are mild to moderate, there is a risk of severe hematologic adverse events, such as myelodysplastic syndrome and aplastic anemia, which have been documented in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. Scaringi, C., De Sanctis, V., Minniti, G., et al.[2018]

A review of 5,127 reports on temozolomide (TMZ) revealed 112 cases of major hematologic adverse events (HAEs), with a significant number of these cases leading to death, highlighting the serious risks associated with this medication.

Aplastic anemia (AA) and leukemia were the most common major HAEs linked to TMZ, indicating a unique toxicity profile compared to other alkylating agents, and suggesting that patients should be informed about these risks, especially since AA can develop after a short duration of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. Villano, JL., Letarte, N., Yu, JM., et al.[2018]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

Temozolomide (TMZ) is an effective DNA-methylating agent with nearly 100% oral bioavailability, allowing it to cross the blood-brain barrier and be rapidly absorbed, making it a promising treatment for brain tumors.

While TMZ shows limited effectiveness against pediatric brain tumors on its own, combining it with other treatments and assessing the methylation status of specific genes may enhance its efficacy and should be explored in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of temozolomide in pediatric brain tumors. Barone, G., Maurizi, P., Tamburrini, G., et al.[2022]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Temozolomide and unusual indications: review of literature. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. [2019]

5. England pubmed.ncbi.nlm.nih.gov

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Role of temozolomide in pediatric brain tumors. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]