Temozolomide + Tuvusertib for Cancer

Recruiting at 26 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, temozolomide and tuvusertib (also known as M1774), to treat advanced cancer that has spread from its original site. Temozolomide damages the DNA of cancer cells, potentially killing them or slowing their growth. Tuvusertib blocks enzymes that cancer cells need to grow, and researchers hope that combining it with temozolomide will prove more effective than temozolomide alone. This trial may suit individuals with advanced cancer who have already tried other treatments. Participants must have a type of cancer that is advanced and can be biopsied safely.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that temozolomide is usually easy for people to handle. Common side effects include fatigue, nausea, and low blood cell counts. Occasionally, it causes more serious side effects, but these are less common.

Early results for tuvusertib, when used alone, also show it is generally well tolerated. Participants in earlier studies found the side effects manageable.

When these drugs are used together, the goal is to find the best dose that minimizes side effects. The trials aim to determine how well these drugs work together and ensure their safety. Currently, researchers closely monitor the combination for any dose-related problems, but more information on the safety of using them together is still being collected. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of temozolomide and tuvusertib because it offers a novel approach to cancer treatment. While temozolomide is a well-known chemotherapy drug used in standard care, tuvusertib introduces a new mechanism by targeting specific pathways that may enhance the effectiveness of temozolomide. This combination aims to improve treatment outcomes by potentially overcoming resistance mechanisms that limit the efficacy of existing therapies. Additionally, the unique administration schedule, which includes oral dosing on specific days of a 28-day cycle, might provide a more manageable option for patients compared to some existing treatments.

What evidence suggests that temozolomide and tuvusertib might be effective treatments for advanced cancer?

Research has shown that temozolomide effectively treats certain brain cancers, such as glioblastoma. It damages the DNA of cancer cells, which can kill them or slow their growth. In this trial, participants will receive a combination of temozolomide and tuvusertib (also known as M1774). Tuvusertib is a newer treatment that prevents cancer cells from obtaining the enzymes they need to grow. Early studies suggest that combining tuvusertib with temozolomide may shrink or stabilize tumors longer than temozolomide alone. This combination might be particularly useful for cancers that have spread. ^{1 2 3 5 6}

Who Is on the Research Team?

Michael Cecchini

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

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

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

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

My brain scans show no cancer growth 4 weeks after treatment for brain metastases.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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 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]

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]

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 (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) 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05691491

Study Details | NCT05691491 | Testing the Combination of ... This phase I/II trial studies the side effects and best dose of temozolomide and M1774 and how well they works in treating patients with cancer that has ...

2. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/temozolomide?pn=1

Clinical Trials Using Temozolomide - NCI NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying temozolomide.

3. withpower.com withpower.com/trial/phase-2-neoplasms-3-2023-6ae2d

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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11094421/

First-in-Human Study of the Ataxia Telangiectasia and Rad3 ... This first-in-human study demonstrates that ataxia telangiectasia and Rad3-related inhibitor tuvusertib as monotherapy is well tolerated, has a manageable ...

5. aacrjournals.org aacrjournals.org/mct/article/23/7/911/746064/The-Novel-ATR-Inhibitor-Tuvusertib-M1774-Induces

The Novel ATR Inhibitor Tuvusertib (M1774) Induces ... Together, these results demonstrate that M1774-induced cancer cell death in combination results from lack of cell cycle arrest and persistent DNA replication, ...

6. clin.larvol.com clin.larvol.com/trial-detail/NCT05691491

Testing the Combination of the Anti-Cancer Drugs ... Dose limiting toxicity for temozolomide in combination with M1774 and the maximum tolerated dose or maximum safe dose. Will consider ten dose levels (dose level ...