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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether avutometinib is a safe treatment for advanced or recurrent solid tumor cancers in children and young adults. Researchers will look for the highest dose of avutometinib that is safe and cause few or mild side effects.

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.

What data supports the effectiveness of the drug Avutometinib for solid tumors?

The research does not provide direct evidence for Avutometinib, but similar drugs like afatinib have shown effectiveness in treating certain types of lung cancer, suggesting that drugs targeting similar pathways may be beneficial for solid tumors. ^{1 2 3 4 5}

What makes the drug Avutometinib unique for treating solid tumors?

Avutometinib (VS-6766) is unique because it is a dual inhibitor, targeting both RAF and MEK proteins, which are involved in cell growth and survival pathways. This dual action may offer a novel approach compared to other treatments that typically target only one of these pathways. ^{6 7 8 9 10}

Research Team

Sameer Farouk Sait

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. [2019]

3. United States 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. [2022]

4. Switzerland 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. [2018]

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

Real-world experience of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. [2022]

6. Ireland 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. [2022]

7. United States 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. [2023]

8. England 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. [2022]

9. England 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. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. [2022]