Avutometinib + Defactinib for Glioblastoma

Overseen By Jeffrey J. Olson, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Emory University

Must not be taking: Anticoagulants, CYP inhibitors

Disqualifiers: Cardiac disorders, Hepatitis, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two new drugs, defactinib and avutometinib (also known as VS-6766), in treating glioblastoma, a type of brain cancer. The goal is to determine if these drugs can safely halt or slow the cancer's growth by targeting specific pathways that aid tumor development. Participants with glioblastoma who require surgery may be suitable candidates for this trial. As an Early Phase 1 trial, this research aims to understand how these new treatments work in people, offering participants the opportunity to be among the first to receive potentially groundbreaking therapy.

Do I need to stop my current medications for the trial?

The trial requires that you avoid certain medications, supplements, and foods that could interact with the study drugs within 14 days before starting and during the trial. Specifically, you should not take strong CYP3A4, CYP2C9, and P-glycoprotein inhibitors or inducers. It's best to discuss your current medications with the trial team to see if any need to be stopped.

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

A previous study found defactinib to be well-tolerated at all dose levels tested in an early trial with Japanese patients, indicating that participants generally handled the drug well with few major side effects. The study primarily assessed safety and identified no significant safety concerns. Research on avutometinib, another treatment under investigation, has shown that MEK inhibitors, which block certain cell signals, can be effective alone or with other treatments for various cancers. While this type of drug has been studied for safety in other conditions, specific safety data for avutometinib in glioblastoma is not detailed here.

Since this trial is in its early stages, the main goal is to determine the safety and efficacy of these drugs in the brain. Consequently, there is limited human safety data available for these specific drugs in glioblastoma. However, as the trial progresses, any serious safety issues will continue to be investigated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments Avutometinib and Defactinib for glioblastoma because they offer a novel approach compared to the standard of care, which typically involves surgery, radiation, and chemotherapy. Avutometinib is unique because it targets the RAF/MEK pathway, which is crucial for cancer cell growth, offering a new mechanism of action. Defactinib works by inhibiting focal adhesion kinase (FAK), a protein that helps cancer cells survive and spread. By targeting these specific pathways, both treatments offer potential new avenues for attacking glioblastoma, which could enhance effectiveness and improve outcomes.

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

Research shows that both defactinib and avutometinib may help treat glioblastoma, a type of brain cancer. In this trial, participants will receive either defactinib or avutometinib as separate treatments. Defactinib blocks proteins called FAK and Pyk2, which aid cancer cell growth and spread. Studies have found that it can slow tumor growth and even shrink some tumors. Avutometinib targets a protein called MEK, often overactive in glioblastoma. Early studies in animals and labs suggest these two drugs can work well together, possibly stopping tumor growth more effectively than when used alone. Initial results suggest a promising new way to tackle this challenging cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

Jeffrey J Olson, MD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Are You a Good Fit for This Trial?

Adults over 21 with new or recurrent glioblastoma who are undergoing surgery can join. They must be relatively healthy, with good organ function and blood counts, not have severe heart or lung conditions, no active hepatitis B/C or HIV, and agree to use effective contraception. Pregnant women, prisoners, those on certain drugs that interact with the trial medications, and minors are excluded.

Inclusion Criteria

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 × ULN (or < 5x ULN in patients with liver metastases)

I have a new or returning brain tumor that needs surgery.

I am older than 21 years.

Exclusion Criteria

I have an eye condition.

I had cancer before, but it was either cured or is unlikely to come back.

I have an active hepatitis B, C, or HIV infection needing treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single oral dose of defactinib or avutometinib prior to planned tumor resection

1 day

1 visit (in-person)

Surgery

Participants undergo planned tumor resection and donate resected tumor tissue

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events

Up to 2 weeks post surgery

What Are the Treatments Tested in This Trial?

Interventions

• Defactinib
• VS-6766

Trial Overview The trial is testing how much of two new drugs (Defactinib and VS-6766) gets into the brain and their safety in treating glioblastoma. These drugs target different growth pathways in tumor cells which may help stop tumor growth when used together.

How Is the Trial Designed?

Group I: Arm II (Avutometinib) Experimental Treatment 2 Interventions

Patients receive 1 dose of avutometinib PO while on study, prior to planned tumor resection. Patients undergo blood collection and donate resected tumor tissue while on study.

Group II: Arm I (Defactinib) Experimental Treatment 2 Interventions

Patients receive 1 dose of defactinib PO while on study, prior to planned tumor resection. Patients undergo blood collection and donate resected tumor tissue while on study.

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Epithelioid glioblastomas (E-GBMs) frequently harbor the BRAF V600E mutation, which is present in up to 50% of cases, making BRAF status testing crucial for treatment with targeted therapy like vemurafenib.

The study found a strong correlation between BRAF V600E mutation status and BRAF VE1 immunohistochemistry (IHC) results, although some cases required additional testing due to background staining issues; notably, a patient treated with vemurafenib remained tumor-free for 21 months after initial recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF VE1 immunoreactivity patterns in epithelioid glioblastomas positive for BRAF V600E mutation. Kleinschmidt-DeMasters, BK., Aisner, DL., Foreman, NK.[2018]

A 58-year-old female patient with recurrent glioblastoma multiforme (GBM) showed a remarkable response to treatment with afatinib and temozolomide, surviving approximately 5 years after recurrence, which is significantly longer than the typical prognosis for this condition.

The patient's tumor had multiple epidermal growth factor receptor (EGFR) abnormalities, suggesting that these genetic factors may contribute to the effectiveness of afatinib, an irreversible ErbB family blocker, in her treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: a case report. Alshami, J., Guiot, MC., Owen, S., et al.[2018]

Dacomitinib, a second-generation pan-HER tyrosine kinase inhibitor, has shown promising antiglioma activity in preclinical models and was tested in a phase II trial for patients with recurrent glioblastoma (GB) with EGFR amplification.

Although the phase II trial results for Dacomitinib in recurrent GB were generally poor, some patients experienced significant benefits, highlighting the need to better understand resistance mechanisms to EGFR inhibitors in GB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dacomitinib: an investigational drug for the treatment of glioblastoma. Sepúlveda, JM., Sánchez-Gómez, P., Vaz Salgado, MÁ., et al.[2019]

Dacomitinib, a pan ERBB inhibitor, effectively reduced phosphorylated EGFR levels in various glioblastoma multiforme (GBM) cell lines, but did not consistently decrease cell viability, indicating potential resistance mechanisms in GBM.

Combining dacomitinib with the PI3K/mTOR inhibitor PF-05212384 significantly enhanced the inhibition of cell proliferation and apoptosis in GBM lines, suggesting that targeting both pathways may be a more effective treatment strategy for patients with specific molecular profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple lesions in receptor tyrosine kinase pathway determine glioblastoma response to pan-ERBB inhibitor PF-00299804 and PI3K/mTOR dual inhibitor PF-05212384. Zhu, Y., Shah, K.[2023]

In a study of 66 patients with recurrent glioblastoma (rGBM) and EGFR amplification, depatuxizumab mafodotin (depatux-m) showed a 6-month progression-free survival rate of 28.8% and an overall survival rate of 72.5%, indicating potential efficacy in this difficult-to-treat population.

The treatment was associated with frequent ocular adverse events, primarily Grade 1/2, such as blurred vision and dry eye, but these were manageable and typically resolved after stopping the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study. van den Bent, M., Gan, HK., Lassman, AB., et al.[2021]

In two young adults with BRAFV600E mutant glioblastoma, treatment with BRAF and MEK inhibitors as a primary therapy resulted in significant tumor regression and clinical improvement, despite the patients' critical conditions.

The rapid development of drug resistance limited the duration of disease control, highlighting the need for BRAFV600E mutation testing in young GBM patients, particularly those with aggressive disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of BRAF V600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases. Woo, PYM., Lam, TC., Pu, JKS., et al.[2023]

In a study of 28 heavily pretreated patients with recurrent malignant gliomas, the combination of EGFR inhibitors (gefitinib or erlotinib) and the mTOR inhibitor sirolimus was reasonably well tolerated, indicating a favorable safety profile for this treatment approach.

The treatment resulted in a 19% partial response rate and 50% of patients achieving stable disease, with a 25% six-month progression-free survival rate specifically for glioblastoma patients, suggesting potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Doherty, L., Gigas, DC., Kesari, S., et al.[2022]

In a phase II trial involving 15 patients with bevacizumab-refractory glioblastoma, ponatinib showed minimal activity, with a 3-month progression-free survival rate of 0% and a median overall survival of only 98 days.

The treatment led to significant increases in various plasma biomarkers related to angiogenesis and inflammation, suggesting that the lack of efficacy may be linked to an increase in inflammatory cytokines, which could contribute to resistance against ponatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma. Lee, EQ., Muzikansky, A., Duda, DG., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12295435/

MEK Inhibition in Glioblastoma: Current Perspectives and ... MEK inhibitors have shown efficacy in pre-clinical investigations as well as some promise in clinical trials which have demonstrated improved overall and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05798507

Study Details | NCT05798507 | Identification of Treatment ... This early phase I trial tests brain concentration level and safety of defactinib or VS-6766 for the treatment of patients with glioblastoma.

3. platform.mytomorrows.com platform.mytomorrows.com/trial-details/NCT06630260

A Phase 1/2 Trial of the Doublet Combination ... The purpose of this clinical trial is to evaluate the safety and tolerability of avutometinib and defactinib and to determine the ...

4. alliance.rcm.upr.edu alliance.rcm.upr.edu/wp-content/uploads/2023/05/29-Emely-Morales-poster.pdf

a dose response study of raf/mek inhibitor avutometinib ... The purpose of the study was to determine effective doses of Avutometinib and Defactinib on glioblastoma cell viability. Glioblastoma (GBM) is ...

5. trialx.com trialx.com/clinical-trials/listings/295169/5g-ruby-avutometinib-and-defactinib-in-malignant-brain-tumours/

Avutometinib and Defactinib in Malignant Brain Tumours The purpose of this clinical trial is to evaluate the safety and tolerability of avutometinib ... Glioblastoma Multiforme (GBM), Glioblastoma ...

6. mdpi.com mdpi.com/1422-0067/26/14/6875

MEK Inhibition in Glioblastoma: Current Perspectives and ... MEK inhibitors have shown promise in combating tumorigenesis as both monotherapy and combined therapy in several malignancies.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2025/219616Orig1s000MultidisciplineR.pdf

219616Orig1s000 - accessdata.fda.gov The available therapy ORR ranges represent data from trials specifically in patients with LGSOC, except for the data on chemotherapy in.