A Study of Avutometinib for People With Solid Tumor Cancers

NCT06104488 | Recruiting Phase 1 FDA Drug

• 1 other identifier: 23-129
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Refractory Cancer; CNS Tumors; CNS Tumor, Adult; CNS Tumor, Childhood; NF1; Plexiform Neurofibroma; Low-grade Glioma; Optic Pathway Gliomas; Neuroblastoma; Primary Brain Tumor; Solid Tumor; Solid Tumor, Adult; Solid Carcinoma; Central Nervous System Tumor; MAP Kinase Family Gene Mutation

Keywords

Refractory Cancer; Central nervous system tumor; CNS tumor; Plexiform Neurofibroma; Low-grade Glioma; Optic Pathway Gliomas; Neuroblastoma; Primary Brain Tumor; Solid Tumor; Solid Carcinoma; Avutometinib; Memorial Sloan Kettering Cancer Center; 23-129

Outcome Measures

Primary Outcomes (1)

• Safety of avutometinib

  The primary objective is to assess the safety of avutometinib in the pediatric population. CTCAE Version 5 will be utilized for toxicity evaluation. Adverse Events should be recorded from treatment start through 30 days after the last dose of study drug.

  up to 12 months

Study Arms (3)

Dose Level -1

EXPERIMENTAL

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.

Drug: Avutometinib

Dose Level 1

EXPERIMENTAL

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.

Drug: Avutometinib

Dose Level 2

EXPERIMENTAL

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.

Drug: Avutometinib

Interventions

Avutometinib DRUG

Participants will receive oral avutometinib once daily twice a week, three weeks on/ 1week off, for a period of 28 days per cycle

Dose Level -1; Dose Level 1; Dose Level 2

Eligibility Criteria

• Age: 3 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age ≥ 3 year and ≤ 30 years at the time of informed consent. \*Patients over 18 years of age will be treated at the adult RP2D. The accrual for patients \>18 and ≤ 30 years will be limited to no more than 5 patients overall and will not participate in the dose escalation.
• All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age.
• Participants must have one of the following:
• Histologically confirmed diagnosis of a pediatric tumor including CNS tumors with activating MAP kinase pathway alterations including but not limited to BRAF/ARAF/CRAF fusions or mutations, KRAS/NRAS/HRAS alterations, PTPN11 or SOS1/2 mutations and/or loss of function alterations in NF1. This will be performed at the enrolling institution and central review is not required OR
• Participants with a clinical or molecularly confirmed (germline alteration positive) diagnosis of NF1 with symptomatic inoperable plexiform neurofibromas and recurrent/progressive low-grade gliomas are eligible and may enroll without tissue/biopsy confirmation.
• Patients with recurrent optic pathway gliomas are eligible if they have clinical progression (defined as new or worsening neurologic symptoms including visual dysfunction, as defined below):
• Visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year (by examination or history); OR - Significant visual dysfunction (defined as VA worse than normal for age by 0.6 logMAR \[20/80, 6/24, or 2.5/10\] or more in one or both eyes).
• OR d) Participants with a confirmed diagnosis of neurofibromatosis 2 schwannomatosis (NF2-SWN) based on revised consensus 2021 criteria \[61\] with a target NF2-related tumor (vestibular schwannoma, non-vestibular schwannoma, meningioma) with documented radiographic progression defined as either:
• ≥ 20% increase in volume of enhancing tumor
• ≥ 2mm increase in greatest linear dimension of enhancing tumor Participants with diagnosis of NF2-SWN may enroll without tissue/biopsy confirmation. Genetic variants are classified as benign (B), likely benign (LB), likely pathogenic (LP), pathogenic (P), or variant of uncertain clinical significance (VUS) according to the standards and guidelines developed by the American College of Medical Genetics and Genomics, the Association for Molecular Pathology, and the College of American Pathologists \[62\]. Only patients with pathogenic and likely pathogenic variants in NF2 will be permitted to enroll \[61\].
• Molecular testing requirements: Genetic alterations (SNVs or fusions) may be identified through local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) (CLIA certified) by using molecular assays on any tumor samples (either at initial diagnosis or recurrence). Only the following test modalities are permitted:
• Tissue-based or liquid biopsy NGS or quantitative polymerase chain reaction (qPCR) or RNA based fusion detection (ARCHER or other similar platform).
• The reports should be collected for any participants who have completed Next Generation Sequencing (NGS) at any point prior to or during study participation
• Fluorescence in situ hybridization (FISH)

You may not qualify if:

• History of rhabdomyolysis.
• Concurrent ocular disorders:
• Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes.
• Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure \> 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
• Patients with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions.
• Patients with a history of hypersensitivity to any of the inactive ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational product.
• Ongoing active diarrhea requiring medication (e.g., loperamide, bile acid sequestrant such as cholestyramine) within 7 days.
• Clinically significant cardiac disease or risk factors at screening including any of the following:
• Any history of congestive heart failure
• Left ventricular ejection fraction (LVEF) \< 50% or below the institutional standard lower limit, whichever is higher, as determined by multiple gated acquisition (MUGA) scan or Trans-thoracic echocardiography (TTE)
• QTc \> 470 msec regardless of sex (using Bazett formula) on screening ECG (using triplicate ECGs), history of Torsades de Pointes, or a history of congenital long QT syndrome.
• Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active and/or requires therapy.
• Exposure to strong CYP3A4 inhibitors and inducers within 14 days prior to the first dose and during the course of therapy (see appendix A).
• Known strong and moderate inducers or inhibitors of CYP3A4/5, including enzyme-inducing anti-convulsant drugs (EIACDs), grapefruit, echinacea, grapefruit hybrids, pummelos, starfruit, and Seville oranges.
• Substrates of CYP3A4/5 with a narrow therapeutic index.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead

Study Sites (2)

Children's Healthcare of Atlanta (Data Collection Only)

Atlanta, Georgia, 30322, United States

RECRUITING

Memorial Sloan Kettering Cancer Center (All Protocol Activities)

New York, New York, 10065, United States

RECRUITING

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Neoplasms; Central Nervous System Neoplasms; Neurofibroma, Plexiform; Neuroblastoma; Brain Neoplasms

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Peripheral Nervous System Neoplasms; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Brain Diseases; Central Nervous System Diseases

Study Officials

• Sameer Farouk Sait, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sameer Farouk Sait, MD

CONTACT

212-639-3449; faroukss@mskcc.org

Julia Glade Bender, MD

CONTACT

212-639-6729; gladebej@mskcc.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2023
• First Posted: October 27, 2023
• Study Start: October 20, 2023
• Primary Completion (Estimated): October 20, 2029
• Study Completion (Estimated): October 20, 2029
• Last Updated: February 25, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

US (2)