Avutometinib for Solid Tumors

Recruiting at 1 trial location

Overseen By Julia Glade Bender, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Rhabdomyolysis, Glaucoma, Uncontrolled diabetes, others

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

Compensation: Varies

Number of Visits: Unknown

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a new drug, avutometinib, for treating advanced or recurring solid tumor cancers in children and young adults. Researchers seek to determine the safest dose that causes few or mild side effects. The trial targets individuals with specific types of tumors, such as certain brain tumors or genetic conditions that lead to tumor growth, who have already tried standard treatments. Those with a recurring tumor that hasn't responded to other therapies might find this trial suitable. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial requires that you avoid certain medications, specifically strong CYP3A4 inhibitors and inducers, within 14 days before starting the trial and during the study. This includes some common medications and herbal supplements, so you should discuss your current medications with the study team.

Is there any evidence suggesting that avutometinib is likely to be safe for humans?

Research has shown that avutometinib has been tested for safety in people with various solid tumors. In earlier studies, researchers combined avutometinib with another drug, defactinib, to observe patient reactions. The results indicated that most patients tolerated the treatment well. While some side effects occurred, they were usually mild or manageable, and serious side effects were less common.

This trial is in its early stages, meaning researchers are still determining the best dose and closely monitoring for any serious side effects. As an early phase study, the focus is on safety and dose optimization rather than the drug's effectiveness. Detailed safety information is still being collected, so participants receive careful monitoring throughout the trial.

Overall, while avutometinib has shown promise in terms of safety in earlier studies, participation in this trial involves close monitoring to quickly address any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Avutometinib is unique because it offers a fresh approach to treating solid tumors by targeting specific pathways involved in cancer cell growth. Unlike standard chemotherapy, which attacks rapidly dividing cells indiscriminately, Avutometinib specifically inhibits certain proteins that are crucial for tumor survival and proliferation. This targeted action not only has the potential to be more effective but also aims to reduce the side effects typically associated with conventional cancer treatments. Researchers are excited about Avutometinib because it represents a promising step towards more personalized and precise cancer therapies.

What evidence suggests that avutometinib might be an effective treatment for solid tumors?

Research has shown that avutometinib, a new treatment for solid tumors, yields promising results. In one study, avutometinib combined with defactinib helped 44% of patients with a specific gene mutation (KRAS-mutant) and 17% of those without the mutation. Another study found that patients with low-grade serous ovarian cancer had a 42.3% positive response, and their cancer did not worsen for an average of 20.1 months. This trial will explore different dosage levels of avutometinib to determine the maximum tolerated dose (MTD) for participants. These findings suggest that avutometinib could be effective for certain solid tumors, but more research is needed to confirm its safety and effectiveness for other types. ^{1 4 5 6 7}

Who Is on the Research Team?

Sameer Farouk Sait

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 3 to 30 with advanced or recurrent solid tumors, including various brain and CNS tumors. Participants must have a confirmed diagnosis with specific genetic alterations or meet certain clinical criteria. They should be able to swallow capsules, have a minimum body surface area, and be past specified recovery periods from previous cancer treatments.

Inclusion Criteria

Fluorescence in situ hybridization (FISH)

total bilirubin ≤ 1.5 × upper limit of normal (ULN) for the institution;

I will provide a blood sample for testing before joining the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Treatment

Participants receive avutometinib at escalating doses to determine the maximum tolerated dose (MTD)

up to 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib

Trial Overview Researchers are testing Avutometinib to determine the highest dose that's safe for treating solid tumor cancers in young patients without causing severe side effects. The study focuses on finding an effective treatment dosage for those who've had standard therapy fail them.

How Is the Trial Designed?

Group I: Dose Level 2 Experimental Treatment 1 Intervention

If 0 of 3-6 or no more than 1 of 6 evaluable participants experience a DLT, then the dose will be escalated to Dose Level 2 and the same approach will be repeated. If 2 or more DLTs are observed on Dose Level 1 in 2-6 subjects, then further enrollment to Dose Level 1 will stop, the dose will be de-escalated to Dose Level -1 and the same approach will be repeated. The MTD will be the highest dose with \<2 DLTs in 6 patients.

Group II: Dose Level 1 Experimental Treatment 1 Intervention

If 0 of 3-6 or no more than 1 of 6 evaluable participants experience a DLT, then the dose will be escalated to Dose Level 2 and the same approach will be repeated. If 2 or more DLTs are observed on Dose Level 1 in 2-6 subjects, then further enrollment to Dose Level 1 will stop, the dose will be de-escalated to Dose Level -1 and the same approach will be repeated. The MTD will be the highest dose with \<2 DLTs in 6 patients.

Group III: Dose Level -1 Experimental Treatment 1 Intervention

If 0 of 3-6 or no more than 1 of 6 evaluable participants experience a DLT, then the dose will be escalated to Dose Level 2 and the same approach will be repeated. If 2 or more DLTs are observed on Dose Level 1 in 2-6 subjects, then further enrollment to Dose Level 1 will stop, the dose will be de-escalated to Dose Level -1 and the same approach will be repeated. The MTD will be the highest dose with \<2 DLTs in 6 patients.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

The Phase III NeoADAURA study is designed to evaluate the effectiveness of neoadjuvant osimertinib, an advanced EGFR inhibitor, in combination with chemotherapy compared to chemotherapy alone in patients with resectable stage II-IIIB N2 EGFR mutation-positive non-small-cell lung cancer (NSCLC).

The primary goal of the study is to assess the major pathological response at the time of surgery, while also examining secondary outcomes such as event-free survival and overall survival, ensuring a comprehensive evaluation of osimertinib's safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Tsuboi, M., Weder, W., Escriu, C., et al.[2022]

A patient with EGFR mutant T790M+ non-small cell lung cancer (NSCLC) developed resistance to osimertinib after 9 months, revealing a significant increase in MET amplification (30 copies) post-treatment.

The use of crizotinib, a MET inhibitor, provided only temporary relief, suggesting that combining osimertinib with a MET inhibitor may be a promising strategy for patients who develop MET amplification after osimertinib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Ou, SI., Agarwal, N., Ali, SM.[2022]

In a patient-derived xenograft mouse model of EGFR mutation-positive non-small cell lung cancer, the combination of osimertinib and savolitinib showed significant antitumor activity, with savolitinib achieving up to 84% tumor regression when combined with a fixed dose of osimertinib.

Savolitinib alone demonstrated substantial antitumor effects, while osimertinib alone had minimal impact, highlighting the potential of savolitinib to overcome resistance mechanisms associated with MET amplification in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model. Jones, RDO., Petersson, K., Tabatabai, A., et al.[2023]

In the AZENT study involving 22 patients with advanced non-small-cell lung cancer (NSCLC) and a specific EGFR mutation, first-line treatment with osimertinib resulted in a high objective response rate of 77.3%, indicating its efficacy in this patient population.

The median progression-free survival (PFS) was 23.1 months, suggesting that osimertinib can provide significant disease control for patients with coexisting low allelic fraction of the EGFR Thr790Met mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line osimertinib in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer and with a coexisting low allelic fraction of Thr790Met. Majem, M., Sullivan, I., Viteri, S., et al.[2022]

Savolitinib, a potent MET receptor inhibitor, demonstrated effective anti-tumour activity in preclinical models, with more frequent dosing schedules leading to better outcomes compared to intermittent dosing.

To achieve optimal anti-tumour effects, sustained high levels of MET inhibition (over 90%) are necessary, and the developed pharmacokinetic-pharmacodynamic model can help translate these findings to guide clinical dosing in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacokinetic-pharmacodynamic model for the MET tyrosine kinase inhibitor, savolitinib, to explore target inhibition requirements for anti-tumour activity. Jones, RDO., Grondine, M., Borodovsky, A., et al.[2022]

Famitinib, a novel oral multitargeting tyrosine kinase inhibitor, was found to be generally well tolerated in a study of 54 patients with advanced solid cancers, with manageable side effects such as hypertension and mild to moderate bone marrow suppression.

The drug demonstrated a wide range of antitumor activities, achieving eight partial responses and stable disease in 14 patients, particularly in renal cell carcinoma and gastrointestinal stromal tumors, suggesting its potential for further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. Zhou, A., Zhang, W., Chang, C., et al.[2019]

Gefitinib, an EGFR inhibitor, was effective in shrinking tumors in two patients with advanced non-small cell lung carcinoma (NSCLC) before they underwent surgery, demonstrating its potential as a preoperative treatment.

Both patients experienced significant tumor reduction and underwent potentially curative surgeries, but they relapsed after stopping adjuvant gefitinib therapy, indicating the need for further research on long-term outcomes and survival benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Down-staging of EGFR mutation-positive advanced lung carcinoma with gefitinib followed by surgical intervention: follow-up of two cases. Levchenko, EV., Moiseyenko, VM., Matsko, DE., et al.[2018]

Afatinib is an effective first-line treatment for advanced EGFR mutation-positive lung adenocarcinoma, showing consistent efficacy regardless of the dosage (40 mg vs < 40 mg) in a study of 140 patients over an 18-month follow-up period.

The study found that significant pretreatment weight loss and the presence of brain metastases were associated with shorter progression-free survival, indicating that these factors may impact treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. Liang, SK., Hsieh, MS., Lee, MR., et al.[2022]

In a study of 188 patients with advanced pulmonary adenocarcinoma, the combination of ficlatuzumab and gefitinib did not show significant improvement in overall response rate or survival compared to gefitinib alone.

However, patients classified as VeriStrat poor experienced significant benefits in progression-free survival and overall survival when treated with the combination therapy, indicating a potential targeted benefit for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase 2 Study Comparing the Combination of Ficlatuzumab and Gefitinib with Gefitinib Alone in Asian Patients with Advanced Stage Pulmonary Adenocarcinoma. Mok, TS., Geater, SL., Su, WC., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05512208

A Phase 2 Study of Avutometinib (VS-6766) Plus Defactinib ... This is a single-stage exploratory, Phase 2, multicenter, parallel cohort, open label study designed to evaluate efficacy and safety of VS-6766 + defactinib.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12393057/

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent ... ORR was 44% in KRAS-mutant and 17% in KRAS wild-type cohorts. The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2) ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT411174

A phase 2 study of avutometinib (VS-6766) ± defactinib in ... The interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status.

4. investor.verastem.com investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-nature-medicine-publication-results

Press Release - Verastem, Inc. FRAME study demonstrated a 42.3% ORR and 20.1 months median PFS for all patients with low-grade serous ovarian cancer (LGSOC), regardless of ...

5. nature.com nature.com/articles/s41591-025-03763-y

Defactinib with avutometinib in patients with solid tumors We describe the first-in-human trial of avutometinib (RAF–MEK clamp) and defactinib (focal adhesion kinase inhibitor) in patients with solid tumors.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00112

Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201 This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05669482

NCT05669482 | Study of Avutometinib (VS-6766) + ... This study will assess the safety and efficacy of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel in patients with ...