Temozolomide + Tuvusertib for Cancer

Recruiting at 19 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Proton-pump inhibitors

Disqualifiers: Uncontrolled illness, Pregnancy, Ataxia telangiectasia, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

58 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of two drugs, temozolomide and M1774, in patients with advanced cancer that has spread. Temozolomide damages cancer cell DNA, while M1774 blocks growth enzymes. The goal is to find a more effective treatment for these patients.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot take proton-pump inhibitors (PPIs) while on M1774. H-2 receptor antagonists and antacids are allowed with timing restrictions around M1774 doses.

What data supports the effectiveness of the drug Temozolomide + Tuvusertib for cancer?

Temozolomide has shown effectiveness in treating various types of brain cancers, like glioblastoma, and has potential for other cancers due to its ability to damage cancer cell DNA. It is often used in combination with other treatments to improve its effectiveness and overcome resistance. ^{1 2 3 4 5}

Is the combination of Temozolomide and Tuvusertib generally safe for humans?

Temozolomide is generally well tolerated, with common side effects like fatigue, nausea, and low blood cell counts. However, it can sometimes cause serious blood-related issues like myelodysplastic syndrome and aplastic anemia, especially with long-term use. ^{5 6 7 8 9}

What makes the drug Temozolomide + Tuvusertib unique for cancer treatment?

Temozolomide is unique because it is an oral drug that works by damaging the DNA of cancer cells, making it effective in treating various cancers, including those not typically treated with this drug. Its combination with Tuvusertib may offer a novel approach by potentially enhancing its effectiveness or overcoming resistance seen in some cancers. ^{1 3 10 11 12}

Research Team

Michael Cecchini

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

Adults with advanced metastatic cancer, particularly colorectal cancer that's stable and has not spread widely after certain treatments. They must have tried all beneficial therapies or be unable to tolerate them. Those with specific blood levels, organ function, and no severe allergies to trial drugs can join. Pregnant women and individuals with uncontrolled illnesses or recent adverse reactions from past cancer treatments are excluded.

Inclusion Criteria

I am 18 years old or older.

My cancer can be measured on scans according to specific criteria.

My cancer is advanced and has spread, confirmed by lab tests.

Exclusion Criteria

Patients with a Fridericia's correction formula (QTcF) > 480 ms.

Pregnant women or breastfeeding mothers.

I cannot stop taking my acid reflux medication while on M1774.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tuvusertib orally once daily on days 1-7 and temozolomide orally once daily on days 1-5 of each 28-day cycle. Patients undergo CT scan, MRI, and blood sample collection throughout the trial.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits at 4 weeks, and then every 3 months for up to 2 years.

Up to 2 years

Treatment Details

Interventions

• Temozolomide
• Tuvusertib

Trial Overview The trial is testing the combination of Temozolomide (a DNA-damaging agent) and M1774 (an enzyme blocker) on patients with advanced cancers to see if this combo is safer or more effective than current treatments. It includes imaging tests like MRI/CT scans and biopsies for monitoring responses.

Participant Groups

Group I: Treatment (tuvusertib, temozolomide) Experimental Treatment 6 Interventions

Patients receive tuvusertib PO QD) on days 1-7 and temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI as well as collection of blood samples throughout the trial. Patients also undergo a biopsy at baseline and may undergo one on study and/or at time of progression.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II trial involving 26 patients with advanced mycosis fungoides/Sézary syndrome, temozolomide (TMZ) showed an overall response rate of 27%, with 8% achieving complete remission and 19% partial remission, indicating its potential efficacy in this patient population.

Despite the low levels of MGMT in malignant CD4(+) T cells, which suggested sensitivity to TMZ, the study found that pretreatment levels of MGMT and mismatch repair proteins did not predict treatment response, indicating that other resistance mechanisms may be at play.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. Querfeld, C., Rosen, ST., Guitart, J., et al.[2021]

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]

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]

Temozolomide (TMZ) is an effective oral anticancer drug for treating newly diagnosed glioblastoma and shows comparable efficacy to dacarbazine for metastatic melanoma, making it a promising option for various cancers.

Resistance to TMZ is a common challenge that limits its effectiveness, prompting ongoing research into combination therapies with DNA repair inhibitors and other treatments to enhance its efficacy and overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent approaches to improve the antitumor efficacy of temozolomide. Tentori, L., Graziani, G.[2019]

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) 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]

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]

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), a treatment for malignant glioma, can lead to therapy-induced myelodysplasia (T-MDS) in patients, with a cumulative dose threshold of approximately 18,000 to 20,000 mg/sq m identified as a risk factor.

Despite its effectiveness, TMZ is considered potentially leukemogenic, similar to other alkylating agents, highlighting the need for careful monitoring during long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced myelodysplasia. Natelson, EA., Pyatt, D.[2020]

In a Phase II study involving 26 chemotherapy-naive patients with brain metastases from metastatic melanoma, the combination of temozolomide and thalidomide showed activity, with 12% of patients achieving a complete or partial response in brain tumors.

The treatment was associated with significant safety concerns, as 11 patients discontinued due to serious adverse events, including intracranial hemorrhage and pulmonary embolism, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. Hwu, WJ., Lis, E., Menell, JH., et al.[2018]

Temozolomide (TMZ) is commonly used as an adjuvant therapy for malignant glioma, but in this case study, a patient developed treatment-related acute myeloid leukemia (t-AML) after receiving 15 cycles of TMZ, highlighting a rare but serious complication.

The case raises questions about the duration of TMZ therapy, as the patient showed no tumor progression but still developed t-AML, suggesting a need for better guidelines to balance treatment benefits and risks in long-term TMZ use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma. Kosugi, K., Saito, K., Takahashi, W., et al.[2018]

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]

References

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

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. [2021]

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

Future directions for temozolomide therapy. [2019]

3. 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]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Recent approaches to improve the antitumor efficacy of temozolomide. [2019]

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

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

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

Temozolomide-related hematologic toxicity. [2018]

7. England pubmed.ncbi.nlm.nih.gov

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

8. Germany pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. [2018]

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

Temozolomide-induced myelodysplasia. [2020]

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

Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. [2018]

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

A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma. [2018]

12. Netherlands pubmed.ncbi.nlm.nih.gov

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