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

Trial Summary

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.

What data supports the effectiveness of the drug combination for glioblastoma?

Temozolomide, a key drug in the combination, has shown effectiveness in treating glioblastoma, especially in patients who have relapsed after initial treatments. Additionally, combining temozolomide with other drugs like afatinib has been explored, suggesting potential benefits in managing recurrent glioblastoma. ^{1 2 3 4 5}

Is the combination of multiple drugs, including temozolomide, safe for treating glioblastoma?

Temozolomide has been studied in combination with other drugs for treating glioblastoma and other cancers. Common side effects include fatigue, gastrointestinal issues, and blood-related toxicity, with some patients needing dose adjustments or stopping treatment due to these effects. ^{2 5 6 7 8}

What makes the drug combination of Neratinib, QBS10072S, and Temozolomide unique for treating glioblastoma?

This drug combination is unique because it targets multiple pathways involved in glioblastoma, which is a highly diverse and aggressive brain tumor. By using a multitarget approach, it aims to address the tumor's heterogeneity, potentially improving treatment effectiveness compared to single-drug therapies. ^{3 9 10 11 12}

What is the purpose of this trial?

This research study is studying several investigational drugs as a possible treatment for Glioblastoma (GBM). The drugs involved in this study are : * Abemaciclib * Temozolomide (temodar) * Neratinib * CC115 * QBS10072S

Research Team

Patrick Wen, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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: 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

Trials

3

Recruited

520+

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

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Jay Backstrom

Celgene

Chief Medical Officer since 2016

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Mark Alles

Celgene

Chief Executive Officer since 2016

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Puma Biotechnology, Inc.

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Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

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Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study. [2018]

2. England 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. [2022]

3. Netherlands 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. [2022]

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

Impact of Timing of Concurrent Chemoradiation for Newly Diagnosed Glioblastoma: A Critical Review of Current Evidence. [2018]

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

Future directions for temozolomide therapy. [2019]

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

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]

7. England 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. [2023]

8. Switzerland 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. [2018]

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

Safety and Efficacy of Anlotinib Hydrochloride Plus Temozolomide in Patients with Recurrent Glioblastoma. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma. [2018]

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

Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. [2021]

12. Germany 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. [2021]