Trial Summary
What is the purpose of this trial?This trial is testing Peposertib combined with radiation therapy in patients with hard-to-treat brain tumors. Radiation kills the tumor cells, and Peposertib stops them from growing.
Do I have to stop taking my current medications for this trial?The trial protocol does not specify if you need to stop taking your current medications. However, you cannot receive other chemotherapy, immunotherapy, or radiotherapy while participating in the study, except for standard care for GBM. It's best to discuss your specific medications with the trial team.
What data supports the idea that Peposertib + Radiation + Temozolomide for Glioblastoma/Gliosarcoma is an effective treatment?The available research does not provide specific data on the effectiveness of Peposertib combined with Radiation and Temozolomide for treating Glioblastoma/Gliosarcoma. However, it does mention other treatments like Temozolomide combined with radiation, which is a common approach for this condition. For example, one study showed that Temozolomide with radiation had a median overall survival of 17.9 months for patients with newly diagnosed glioblastoma. This suggests that Temozolomide is a key component in treating this type of cancer, but there is no direct data on the combination with Peposertib.157911
Is the drug Nedisertib, combined with radiation therapy and Temozolomide, a promising treatment for glioblastoma or gliosarcoma?Yes, the combination of Nedisertib, radiation therapy, and Temozolomide is promising for treating glioblastoma or gliosarcoma. Temozolomide is known to help kill cancer cells, and when used with radiation, it can enhance the treatment's effectiveness. Studies have shown that similar combinations improve survival rates and control tumor growth.245611
What safety data exists for the treatment of Peposertib, Radiation, and Temozolomide for glioblastoma?The provided research does not directly address the safety data for the combination of Peposertib, Radiation, and Temozolomide. However, it includes studies on similar treatments involving radiation and Temozolomide, such as the safety of nivolumab plus radiotherapy with or without Temozolomide, and galunisertib with Temozolomide-based radiochemotherapy. These studies generally focus on determining safe and tolerable doses, with some reporting comparable safety profiles across treatment arms. For specific safety data on Peposertib, further research or clinical trial results would be needed.3781012
Eligibility Criteria
This trial is for adults with newly diagnosed MGMT unmethylated glioblastoma or gliosarcoma who have had surgery but no other treatments. They must be able to follow the study plan, have proper kidney and liver function, normal blood counts, and a stable condition on low-dose steroids. Women of childbearing age need a negative pregnancy test and agree to use birth control; men also need to use contraception.Inclusion Criteria
I've had a brain MRI within the last 14 days and am on a low or reducing dose of steroids.
My GBM is MGMT unmethylated according to a certified lab test.
I am a woman who could still become pregnant.
My kidney function is within the required range for the study.
I am using two forms of birth control or am surgically sterile.
My brain tumor is a grade IV glioma or gliosarcoma, IDH wild-type.
I can care for myself and perform daily activities.
I've had a brain MRI within the last 2 weeks and am on a low or reducing dose of steroids.
I can care for myself but may not be able to do active work.
My GBM is MGMT unmethylated according to a certified lab test.
My brain tumor is a grade IV glioma or gliosarcoma, IDH wild-type.
I've had brain surgery or a biopsy and no treatments after that.
Exclusion Criteria
I had surgery to remove a brain tumor and no visible tumor remains, or it's in a place that can't be surgically removed.
I am not taking drugs that strongly affect certain liver enzymes or specific drug transporters.
I have been treated with drugs that target cancer cell DNA repair mechanisms.
I have a history of HIV infection.
I have a history of long QT syndrome.
I have issues swallowing or a gut condition that affects medication absorption.
My cancer's MGMT status has been tested and is methylated.
Treatment Details
The trial tests Peposertib combined with radiation therapy followed by Temozolomide chemotherapy in patients with specific brain tumors. It aims to find the best dose of Peposertib that can be given safely and see if this combination works better than standard treatment alone.
2Treatment groups
Experimental Treatment
Group I: Stage II (Peposertib, Radiation, Temozolomide, Surgery)Experimental Treatment4 Interventions
CONCURRENT: Patients receive Peposertib and undergo standard of care radiation therapy as in Stage I. Within 1-14 days after the completion of radiation therapy, patients undergo surgical resection.
ADJUVANT: Patients receive temozolomide as in Stage I.
Group II: Stage I (Peposertib, Radiation therapy, Temozolomide)Experimental Treatment3 Interventions
CONCURRENT: Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive Peposertib PO on each day of radiation therapy and given 1-2 hours before each treatment fraction. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.
ADJUVANT: Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Find a clinic near you
Research locations nearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who is running the clinical trial?
M.D. Anderson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Pilot study of estramustine added to radiosurgery and radiotherapy for treatment of high grade glioma. [2019]Patients with high grade glioma generally have poor prognoses. Addition of radiosensitizing agents might improve the response to irradiation. The chemotherapeutic agent estramustine sensitizes experimental gliomas to radiation. Gliomas express estramustine binding proteins, and cytotoxic concentrations of estramustine metabolites are found in gliomas after oral administration. Twenty three patients, aged 25-78, with new or recurrent high grade glioma were treated with estramustine and radiosurgery and/or radiotherapy. Patients with recurrent tumors were treated with estramustine and Gamma Knife stereotactic radiosurgery; eligible tumors were limited to 4 cm maximal diameter. Patients with newly diagnosed tumors were treated with estramustine and fractionated radiotherapy, with radiosurgery also performed if the tumor was less than 4 cm maximal diameter. Estramustine (16 mg/kg per day orally) was started three days prior to radiosurgery, or, if only radiotherapy was performed, on the first day of radiotherapy. Estramustine was continued until the completion of radiosurgery and/or radiotherapy (72 Gy, 60 fractions, 1.2 Gy bid over 6 weeks). Of the 13 patients treated for newly diagnosed glioblastoma, median survival was 16 months with 38% 2-year survival. Of five patients treated for recurrent glioblastoma, survival was 3, 8, 9, 15, and 23 + months. Two patients with recurrent anaplastic astrocytoma survived for 24 and 48+ months. One patient with recurrent anaplastic mixed glioma survived 5+ months. Two patients with newly diagnosed anaplastic oligodendroglioma survived 20 and 42+ months. Four of the new glioblastoma patients developed deep vein thrombosis. The results of this pilot study indicate some benefit, and further investigation incorporating estramustine into clinical trials is suggested.
Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study. [2021]We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCbeta] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status > or =60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m(2) daily) followed by adjuvant temozolomide (200 mg/m(2)) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if
A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma. [2021]To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ.
Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma. [2022]This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.
Net clinical benefit analysis of radiation therapy oncology group 0525: a phase III trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma. [2022]Radiation Therapy Oncology Group trial 0525 tested whether dose-intensifying temozolomide versus standard chemoradiotherapy improves overall survival (OS) or progression-free survival (PFS) in newly diagnosed glioblastoma. Tests of neurocognitive function (NCF) and symptoms (using the MD Anderson Symptom Inventory-Brain Tumor module; MDASI-BT) and of quality of life (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ] -C30/BN20) examined the net clinical benefit (NCB) of therapy.
In Vitro Radiosensitizing Effects of Temozolomide on U87MG Cell Lines of Human Glioblastoma Multiforme. [2020]Glioma is the most common primary brain tumor with poor prognosis. Temozolomide (TMZ) has been used with irradiation (IR) to treat gliomas. The aim of the present study was to evaluate the cytotoxic and radiosensitizing effect of TMZ when combined with high-dose and high-dose rate of gamma irradiation in vitro.
Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma. [2021]Purpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.
Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. [2021]Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).
Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. [2021]Radiotherapy may synergize with programmed cell death 1 (PD1)/PD1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high-grade gliomas (HGGs).
Radiation treatment planning study to investigate feasibility of delivering Immunotherapy in Combination with Ablative Radiosurgery to Ultra-High DoSes (ICARUS). [2021]Label="PURPOSE" NlmCategory="OBJECTIVE">Immune checkpoint inhibitors improve survival in metastatic diseases for some cancers. Multisite SBRT with pembrolizumab (SBRT + Pembro) was shown to be safe with promising local control using biologically effective doses (BEDs) = 95-120 Gy. Increased BED may improve response rate; however, SBRT doses are limited by surrounding organs at risk (OARs). The purpose of this work was to develop and validate methods for safe delivery of ultra-high doses of radiation (BED10  > 300) to be used in future clinical trials.
Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]Glioblastoma is one of the most radioresistant cancers. It is suggested that combination of radiotherapy with other cancer treatment modalities may increase control of tumor. Temozolomide (TMZ) is one of the most known drugs for glioblastoma. It has shown that TMZ via induction of mutation and cell death can kill glioma cells.
Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. [2023]The phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma.