Avutometinib + Defactinib for Glioblastoma

Overseen by Jeffrey J Olson, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Emory University

Must not be taking: Anticoagulants, CYP inhibitors

Disqualifiers: Cardiac disorders, Hepatitis, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests two new drugs, defactinib and VS-6766, for patients with glioblastoma, a type of aggressive brain tumor. These drugs aim to block specific proteins that help the tumor cells grow. The goal is to see how much of the drug reaches the brain and to check if it is safe.

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.

What data supports the effectiveness of the drug Avutometinib + Defactinib for treating glioblastoma?

Research shows that targeting specific mutations in glioblastoma, like the BRAF V600E mutation, with drugs that inhibit the MAPK pathway can help control tumor growth. Additionally, treatments targeting the EGFR pathway, which is often altered in glioblastoma, have shown some promise in improving patient outcomes. ^{1 2 3 4 5}

What makes the drug Avutometinib + Defactinib unique for treating glioblastoma?

Avutometinib (VS-6766) combined with Defactinib is unique because it targets specific pathways involved in tumor growth, potentially offering a new approach for glioblastoma treatment. This combination may be particularly beneficial for patients with specific genetic mutations, such as BRAF V600E, which are actionable targets in other cancers like melanoma. ^{1 5 6 7 8}

Research Team

Jeffrey J Olson, MD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Eligibility Criteria

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

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

I am older than 21 years.

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

Exclusion Criteria

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.

I have an eye condition.

Trial Timeline

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

Treatment Details

Interventions

• Defactinib (Kinase Inhibitor)
• VS-6766 (Kinase Inhibitor)

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.

Participant Groups

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+

Dr. R. Donald Harvey

Emory University

Chief Medical Officer

MD from Emory University School of Medicine

Dr. George Painter

Emory University

Chief Executive Officer since 2013

PhD in Synthetic Organic Chemistry from Emory University

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Dacomitinib: an investigational drug for the treatment of glioblastoma. [2019]

3. United States 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. [2023]

4. Germany 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. [2021]

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

Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: a case report. [2018]

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

Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. [2022]

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

BRAF VE1 immunoreactivity patterns in epithelioid glioblastomas positive for BRAF V600E mutation. [2018]

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

Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma. [2021]