Temozolomide + Tuvusertib for Cancer
Recruiting in Palo Alto (17 mi)
+19 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Proton-pump inhibitors
Disqualifiers: Uncontrolled illness, Pregnancy, Ataxia telangiectasia, others
No Placebo Group
Approved in 2 Jurisdictions
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.
12345Is 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.
56789What 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.
13101112Eligibility 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.
+10 more
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.
+6 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (tuvusertib, temozolomide)Experimental Treatment6 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Siteman Cancer Center-South CountySaint Louis, MO
Smilow Cancer Hospital Care Center-TrumbullTrumbull, CT
Washington University School of MedicineSaint Louis, MO
University of Kansas Cancer Center at North Kansas City HospitalNorth Kansas City, MO
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. [2021]Temozolomide (TMZ) is an oral derivative of dacarbazine that induces DNA damage by methylating nucleotide bases. Resistance has been associated with high levels of O⁶-methylguanine-DNA methyltransferase (MGMT). Malignant CD4(+) T cells of patients with mycosis fungoides/Sézary syndrome (MF/SS) have been shown to have low levels of MGMT and may be particularly sensitive to this methylator.
Future directions for temozolomide therapy. [2019]Although the initial indications of temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) therapy are for refractory central nervous system malignancies (anaplastic astrocytoma in the United States and Europe, glioblastoma multiforme in Europe), a number of clinical trials are planned or ongoing to evaluate the efficacy and safety of temozolomide in newly diagnosed glioma, oligodendroglioma, pediatric glioma, brain metastases, metastatic melanoma, and other systemic tumors. Also under investigation are modifications to the temozolomide dosing schedule, other routes of administration, and treatment regimens that include temozolomide in combination with other chemotherapeutic and biologic agents. Temozolomide has the potential to be a useful agent in the treatment of a variety of cancers.
Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]Temozolomide (TMZ) is a newly approved alkylating agent for the treatment of malignant gliomas. To investigate resistance mechanisms in a multidrug therapeutic approach, a TMZ-resistant human glioma cell line, SF188/TR, was established by stepwise exposure of human SF188 parental cells to TMZ for approximately 6 months. SF188/TR showed 6-fold resistance to TMZ and cross-resistance to a broad spectrum of other anticancer agents that included 3-5-fold resistance to melphalan (MEL), gemcitabine (GEM), paclitaxel (PAC), methotrexate (MTX), and doxorubicin (DOX), and 1.6-2-fold resistance to cisplatin (CDDP) and topotecan (TPT). Alkylguanine alkyltransferase (AGT) activity was increased significantly in the resistant cell line compared with the parental cell line (P
Recent approaches to improve the antitumor efficacy of temozolomide. [2019]Temozolomide (TMZ) is an oral anticancer agent approved for the treatment of newly diagnosed glioblastoma in combination with radiotherapy. Moreover, TMZ has shown comparable efficacy with respect to dacarbazine, the reference drug for metastatic melanoma. Due to its favorable toxicity and pharmacokinetic profile, TMZ is under clinical investigation for brain metastasis from solid tumors and refractory leukemias. TMZ interacts with DNA generating a wide spectrum of methyl adducts mainly represented by N-methylpurines. However, its antitumor activity has been mainly attributed to O(6)-methylguanine, since tumor cell sensitivity inversely correlates with the levels of O(6)-alkylguanine DNA alkyltransferase and requires an intact mismatch repair system. Therefore, an increasing number of studies have been performed in order to identify patients who will benefit from TMZ treatment on the basis of their molecular/genetic profile. Unfortunately, resistance to the methylating agent occurs relatively often and strongly affects the rate and durability of the clinical response in cancer patients. Thus, different approaches have been developed to abrogate resistance or to increase the efficacy of TMZ and for many of them investigation is still underway. Herein, we provide an overview on the recent findings of preclinical and clinical studies on TMZ in combination with inhibitors of DNA repair, chemotherapeutic drugs with different mechanisms of action or radiotherapy, anti-angiogenic agents and other biological modulators.
Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma.
Temozolomide-related hematologic toxicity. [2018]Temozolomide (TMZ) is an oral alkylating agent used for the treatment of recurrent or newly diagnosed malignant gliomas with significant survival benefit. TMZ is generally well tolerated and safe. The most common side effects are mild to moderate, and are represented by fatigue, nausea, vomiting, thrombocytopenia, and neutropenia. However severe hematologic adverse events (HAEs), including myelodysplastic syndrome and aplastic anemia, have also been reported. In this review we present an overview of the available literature of HAEs after exposure to TMZ.
Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]Temozolomide (TMZ) is an oral alkylating agent principally indicated for neurological malignancies including glioblastoma (GBM) and astrocytoma. Most common side effects are mild to moderate, and include fatigue, nausea, vomiting, thrombocytopenia and neutropenia. Severe or prolonged myelosuppression, causing delayed treatment or discontinuation, is uncommon. Major haematological adverse effects such as myelodysplastic syndrome or aplastic anaemia (AA) have rarely been reported.
Hematologic adverse events associated with temozolomide. [2018]Temozolomide (TMZ) is a widely used oral alkylating agent that has been associated with the development of severe hematologic adverse events (HAEs). Limited clinical information about HAEs is available.
Temozolomide-induced myelodysplasia. [2020]A patient who had received temozolomide (TMZ) as a single agent in treatment of malignant glioma developed therapy-induced myelodysplasia (T-MDS). TMZ is an orally active imidazotetrazine which methylates guanine residues in DNA, ultimately causing single and double-strand DNA breaks leading to apoptotic cell death. TMZ does not chemically cross-link DNA and is considered a nonclassical alkylating agent, similar in structure and activity to dacarbazine. Observations on this patient, and on similarly treated others, suggest that the cumulative dose threshold (CDT) for TMZ that predisposes to T-MDS and which may potentially lead to acute myeloid leukemia (T-AML) is around 18000 to 20000 mg/sq m. Although the incidence of T-MDS and the predisposing CDT of TMZ may differ from that of other potentially leukemogenic compounds currently and formerly used as chemotherapeutic agents, all alkylating agents, including TMZ, should be considered potentially leukemogenic when administered long term.
Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. [2018]Temozolomide plus thalidomide is a promising oral combination regimen for the treatment of metastatic melanoma. The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases.
A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma. [2018]Temozolomide (TMZ) is now standard adjuvant therapy in combination with radiotherapy for patients with newly diagnosed malignant glioma. Treatment-related myelodysplastic syndrome and acute treatment-related leukemia (t-AML) associated with TMZ chemotherapy for patients with glioma is quite a rare complication.
Temozolomide and unusual indications: review of literature. [2022]Temozolomide (TMZ) was first known to be useful as a radiosensitiser in both primary brain tumours like glioblastoma multiforme and oligodendroglioma. Later, TMZ proved its efficacy in the treatment of melanoma. Multiple publications have demonstrated the benefit of TMZ in terms of efficacy and tolerance (used as mono-therapy or as adjuvant chemotherapy) compared to the "gold standard" treatment of this kind of tumours. Furthermore, several recent clinical trials have shown the particular importance of TMZ in other types of cancer. This publication deals with the use of TMZ in cancers which are not formal indications for TMZ (excluding glioblastoma multiforme, oligodendroglioma and melanoma). It also includes a necessary review of recent literature about the role of TMZ in the treatment of brain metastases, lymphomas, refractory leukaemia, neuroendocrine tumours, pituitary tumours, Ewing's sarcoma, primitive neuroectodermal tumours, lung cancer and other tumours.