Multiple Drug Therapy for Glioblastoma

Recruiting at 9 trial locations

Overseen By Lisa Doherty, NP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Patrick Y. Wen, MD

Must not be taking: EIAEDs, CYP3A drugs

Disqualifiers: Cardiac disease, Diabetes, Infection, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

460 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores several new drugs to treat glioblastoma, an aggressive brain cancer. The aim is to evaluate the effectiveness of these drugs, either alone or in combination, in slowing or stopping cancer growth. Participants will receive radiation treatment along with medications such as Temozolomide (a chemotherapy drug), Neratinib (a targeted therapy drug), or QBS10072S (an experimental treatment). This trial suits those diagnosed with glioblastoma or gliosarcoma who have not yet received radiation or chemotherapy. Participants must be able to swallow pills and plan to start radiation therapy within a specific time after surgery.

As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in glioblastoma treatment.

Will I have to stop taking my current medications?

Participants must stop taking enzyme-inducing anti-epileptic drugs and drugs that are strong inhibitors or inducers of the CYP3A enzyme at least 7 days before starting the study. Herbal medications and certain citrus fruits should also be avoided. If you are on these medications, you will need to stop them before joining the trial.

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

A previous study found Temozolomide, one of the drugs being tested, safe for treating brain tumors, and the FDA has already approved it for this purpose. This approval indicates thorough research and general safety for many patients.

Research has shown that Neratinib was mostly well-tolerated in trials. Some participants reported side effects, but these were similar to previously observed effects with this drug, with no new or unexpected issues.

For QBS10072S, early findings suggest it was well-tolerated by patients with a specific type of glioblastoma (a kind of brain cancer) when used with radiation therapy. Most patients did not experience severe or unexpected side effects.

Conversely, CC-115 showed higher risks. Studies reported significant side effects in many patients, raising concerns about its safety, indicating it might not be suitable for everyone.

These findings provide an overview of how well these drugs are tolerated, but individual experiences may vary. Always consult a healthcare provider before deciding to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for glioblastoma because they offer new ways to tackle this aggressive brain cancer. Unlike standard treatments that focus mainly on Temozolomide and radiation, Abemaciclib is a CDK4/6 inhibitor that targets cancer cell cycle progression, potentially stopping tumor growth. Neratinib is an irreversible tyrosine kinase inhibitor, which might block signals that glioblastoma cells use to grow. QBS10072S is distinctive because it's being tested to work in synergy with radiation, which could enhance the effectiveness of existing treatments. These novel approaches offer hope for more effective interventions against a cancer that has been notoriously hard to treat.

What evidence suggests that this trial's treatments could be effective for Glioblastoma?

Research has shown that Temozolomide, which participants in this trial may receive, is FDA-approved for treating glioblastoma and has been effective for this condition. In this trial, some participants will receive a combination of Abemaciclib and Temozolomide. Previous studies showed an average survival of 16 months, with 58% living for at least one year, indicating a possible benefit. Another group will receive Neratinib with Temozolomide, which has significantly extended the time patients live without disease progression, especially in those with the EGFR-positive tumor marker. QBS10072S, a new treatment option in this trial, slowed tumor growth in early studies and was well-tolerated when combined with radiation in glioblastoma patients. These findings support further exploration of these drugs for glioblastoma treatment. ^{1 2 3 6 7}

Who Is on the Research Team?

Patrick Wen, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults (18+) with confirmed glioblastoma or gliosarcoma, who can swallow pills and have not had prior systemic or radiation therapy for it. They must have adequate organ function, no severe heart disease, uncontrolled diabetes, active infections, or other serious health issues that could affect study participation. Women of childbearing potential and men must use effective contraception.

Inclusion Criteria

I can swallow pills.

My cancer does not have the IDH1 R132H mutation.

My tumor's MGMT promoter is not methylated.

Exclusion Criteria

I am scheduled for a major surgery.

I have had radiation therapy to my brain before.

I do not have any stomach or intestine problems that could affect how a medicine works in my body.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive daily radiation for a maximum of 49 days

7 weeks

Daily visits for radiation

Treatment

Participants receive investigational drugs post-radiation for up to 6 cycles

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Neratinib
• QBS10072S
• Temozolomide

Trial Overview The trial is testing several investigational drugs including Abemaciclib, Temozolomide (Temodar), Neratinib, CC115, and QBS10072S as possible treatments for Glioblastoma. Participants will be assigned to different treatment groups based on genetic markers related to their cancer.

How Is the Trial Designed?

Group I: QBS10072S Experimental Treatment 1 Intervention

Daily Radiation for a maximum of 49 days. QBS10072S will be administered on Day 1 of Radiation Treatment QBS10072S will be administered post- radiation for up to 6 cycles

Group II: Neratinib with Temozolomide Experimental Treatment 2 Interventions

* Daily Radiation for a maximum of 49 days. * Temozolomide will be administered orally on a daily dosing schedule * Temozolomide will be administered approximately 2-3 hours before each session of radiotherapy * Neratinib will be taken post radiation at a daily oral pre-determine dose

Group III: CC-115 Experimental Treatment 1 Intervention

* Twice daily oral dosing of CC-115 * Daily Radiation for a maximum of 49 days * CC115 will also be taken twice daily post radiation

Group IV: Abemaciclib with Temozolomide Experimental Treatment 2 Interventions

* Daily Radiation for a maximum of 49 days. * Temozolomide will be administered orally on a daily dosing schedule during radiation * Temozolomide will be administered approximately 2-3 hours before each session of radiotherapy * Abemaciclib will be taken post radiation at a twice daily oral pre-determined dose

Group V: Temozolomide Active Control 1 Intervention

* Daily Radiation for a maximum of 49 days. * Temozolomide will be administered orally on a daily dosing schedule * Temozolomide will be administered approximately 2-3 hours before each session of radiotherapy * Temozolomide will also be administered post radiation for up to 6 cycles (5 days/cycle)

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

Approved in United States as Nerlynx for:

• Extended adjuvant treatment of women with early-stage HER2-positive breast cancer

Approved in European Union as Nerlynx for:

• Extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer

Who Is Running the Clinical Trial?

Patrick Y. Wen, MD

Lead Sponsor

Trials

10

Recruited

990+

Patrick Wen, MD

Lead Sponsor

Trials

3

Recruited

600+

Quadriga Biosciences, Inc.

Industry Sponsor

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3

Recruited

520+

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

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Published Research Related to This Trial

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 phase I/II trial established that the maximum tolerated dose of afatinib is 40 mg/day when combined with temozolomide, with common side effects including diarrhea and rash, affecting 71-82% of participants.

In terms of efficacy, afatinib alone showed limited activity in recurrent glioblastoma, with a 6-month progression-free survival rate of only 3%, while the combination with temozolomide had a slightly better rate of 10%, indicating that temozolomide alone (23%) was more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. Reardon, DA., Nabors, LB., Mason, WP., et al.[2022]

In a study of 20 patients with various types of glioma, the combination of olaparib and temozolomide (TMZ) showed a 50% objective radiographic response rate in patients with recurrent IDH-mutant grade 2-3 gliomas, indicating potential efficacy for this specific group.

While the treatment was generally manageable, common side effects included fatigue and gastrointestinal issues, with 30% of patients requiring dose adjustments due to toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. Schaff, LR., Kushnirsky, M., Lin, AL., et al.[2023]

The heat shock protein 90 inhibitor NVP-AUY922 significantly reduced cell viability and induced cell death in various glioblastoma (GBM) cell lines, including those resistant to temozolomide, suggesting its potential as a treatment for this aggressive cancer.

AUY922 works by promoting apoptosis and autophagy while simultaneously decreasing the expression of key proteins associated with GBM's cellular heterogeneity, such as EGFR, PDGFRA, CDK4, and NF1, which may enhance its efficacy against this challenging tumor type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A heat shock protein 90 inhibitor reduces oncoprotein expression and induces cell death in heterogeneous glioblastoma cells with EGFR, PDGFRA, CDK4, and NF1 aberrations. Ho, KT., Chen, PF., Chuang, JY., et al.[2022]

In a phase II study involving 42 patients with recurrent glioblastoma multiforme, temozolomide (TMZ) demonstrated a progression-free survival rate of 24% at 6 months, indicating its potential efficacy as a second-line treatment.

The study reported a median time to progression of 11.7 weeks, with a response rate of 19% (including complete and partial responses), suggesting that TMZ can be a valid treatment option for patients who have already undergone extensive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study. Brandes, AA., Ermani, M., Basso, U., et al.[2018]

Trotabresib, a BET inhibitor, effectively penetrates the blood-brain-tumor barrier in patients with recurrent high-grade gliomas, showing a brain tumor tissue to plasma concentration ratio of 0.84, which indicates good CNS penetration.

The treatment was well tolerated, with thrombocytopenia being the most common severe side effect, and 12% of patients experienced six-month progression-free survival, suggesting potential efficacy in managing this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: A phase I, "window-of-opportunity" study. Moreno, V., Manuel Sepúlveda, J., Reardon, DA., et al.[2023]

In a study of 31 pretreated patients with non-small cell lung cancer (NSCLC), temozolomide showed minimal efficacy as a salvage therapy, with only 6.5% achieving a partial response and a median survival time of 3.3 months.

Despite its limited effectiveness, the treatment was generally well-tolerated, although there was one toxic death due to severe neutropenia, highlighting the need for careful monitoring of blood cell counts during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a phase II study. Kouroussis, C., Vamvakas, L., Vardakis, N., et al.[2018]

In a study of 21 patients with recurrent glioblastoma, the combination of anlotinib and temozolomide resulted in a high objective response rate of 81% and a median progression-free survival of 7.3 months, indicating significant efficacy in managing this aggressive cancer.

The treatment was generally well-tolerated, with the most common side effects being leukocytopenia and thrombocytopenia, and no treatment-related deaths were reported, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Anlotinib Hydrochloride Plus Temozolomide in Patients with Recurrent Glioblastoma. Xu, Q., Huang, K., Meng, X., et al.[2023]

The combination of AEE788 and RAD001 in glioblastoma patients led to clinically significant thrombocytopenia, indicating potential safety concerns with this treatment regimen.

Despite initial safety issues, a reduced dose of AEE788 (150 mg/day) and RAD001 (5 mg every other day) appeared to be better tolerated, suggesting that dose adjustments may improve the safety profile of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma. Reardon, DA., Cloughesy, T., Rich, J., et al.[2018]

In a phase II study involving 25 patients with recurrent glioblastoma multiforme (GBM), nintedanib showed limited antitumor activity, with only 12% of patients achieving stable disease, and the median progression-free survival was just 1 month.

Despite its limited efficacy, nintedanib was found to have an acceptable safety profile, with no severe adverse events reported, although common side effects included fatigue, loss of appetite, diarrhea, and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. Muhic, A., Poulsen, HS., Sorensen, M., et al.[2021]

In a study involving seven nude rats with gliomas, the combination of the anti-angiogenesis agent cediranib with the chemotherapy drug temozolomide (TMZ) resulted in a slight increase in the intratumoral concentration of TMZ, suggesting improved drug delivery to the tumor.

The MRI results indicated that cediranib treatment led to a normalization of the blood-brain barrier, which may enhance the effectiveness of chemotherapy in treating malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. Grossman, R., Tyler, B., Rudek, MA., et al.[2021]

The study focuses on the treatment of glioblastoma, a highly aggressive brain cancer, and evaluates the efficacy of temozolomide (TMZ) in improving overall survival (OS) and progression-free survival (PFS) in patients.

Data from the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) were analyzed, highlighting the importance of these organizations in cancer research and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Timing of Concurrent Chemoradiation for Newly Diagnosed Glioblastoma: A Critical Review of Current Evidence. Han, SJ., Englot, DJ., Birk, H., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06413706

NCT06413706 | A Study Comparing Abemaciclib Plus ... The purpose of this study is to measure the benefit of adding abemaciclib to the chemotherapy, temozolomide, for newly diagnosed high-grade glioma following ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2073

Combining abemaciclib, temozolomide, and radiation in ... Our study demonstrates that the combination of Abemaciclib, TMZ, and XRT offers a novel, synergistic approach for DIPG, significantly improving survival in ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6808208/

3552 Advancing Glioblastoma (GBM) drug regimen ... RESULTS/ANTICIPATED RESULTS: A PKPD model was developed to predict tumor growth kinetics for TMZ and abemaciclib monotherapy, as well as combination therapy.

4. withpower.com withpower.com/trial/abemaciclib-temozolomide-for-brain-tumors-c6986

Abemaciclib + Temozolomide for Brain Tumors Patients treated with this regimen had a median survival of 16 months, with 58% surviving at one year and 31% at two years, indicating that this treatment may ...

5. onclive.com onclive.com/view/abemaciclib-neratinib-explored-in-glioblastoma-trial

Glioblastoma Platform Trial Investigating Multiple Drugs in ... Temozolomide is FDA approved for the treatment of patients with GBM, while abemaciclib, neratinib, and CC-115 are all currently experimental ...

6. trials.braintumor.org trials.braintumor.org/trials/NCT06413706

A Study Comparing Abemaciclib Plus Temozolomide to ... The purpose of this study is to measure the benefit of adding abemaciclib to the chemotherapy, temozolomide, for newly diagnosed high-grade glioma following ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/26/20/5310/82934/A-Phase-II-Study-of-Abemaciclib-in-Patients-with

A Phase II Study of Abemaciclib in Patients with Brain ... Descriptive statistics summarized safety data. All tests assumed a two-sided ... combination with temozolomide in an intracranial glioblastoma xenograft.