Symptoms and General Pathology

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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.

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

Avutometinib

Sameer Farouk Sait, MD

Julia Glade Bender, MD

Jason Fangusaro, MD

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.

A Study of Avutometinib for People With Solid Tumor Cancers

A Multi-Center Phase I Dose Escalation Study of Avutometinib, a RAF/MEK Clamp, in Pediatric Patients With Refractory or Recurrent Solid Tumors Harboring Activating MAPK Pathway Alterations

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

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.

Memorial Sloan Kettering Cancer Center

All Drugs and Chemicals

Amino Acids

Caseins

Phenylalanine

Leucine

A liquid mixed meal are gived adjusted by weight. The meal consists of: Intrinsically labelled D5-Phenylalanine and D3-Leucine labelled casein protein, 13C16palmitate, 13C6-Glucose in a mix of glucose, casein protein and rape seed oil dissolved in water in an energy density of 50% CHO, 35% fat and 15% protein. Blood samples are drawn frequently to measure fat, glucose and protein metabolism.

Meal

Mette Cathrine Ørngreen, MD, DMSc

At the center of pediatric oncology in Copenhagen the investigators experience that the children with brain tumor, more or less have a healthy body with normal skeletal muscle mass and are physical active to the same level as their friends at the same age. The treatment period for brain tumor is approximately two years. After the treatment period, the children are more sedative with less interest in coming out doing physical activities and thus the investigators suspect that they have altered hormonal response, low skeletal muscle mass and perhaps are in risk of developing metabolic syndrome.

By comparing children with newly diagnosed CNS tumor with children finished treated for CNS tumor, we wish to describe the metabolic path during the approximately two years treatment period these children go through. These results will also be compared with results from healthy controls.

The investigators aim to include 10 children (aged 6-18 years) with newly diagnosed CNS tumor, 10 children (aged 6-18 years) finished treated for CNS tumor and 10 healthy controls (aged 6-18 years). By using stable isotope technique the investigators will investigate systemic fat, glucose and protein metabolism together with liver protein degradation and glucose production. Furthermore, by using DXA scan the investigators will describe the quality and distribution of skeletal muscle. Lastly, the investigators will determine the skeletal muscle signal pathway and metabolism in skeletal muscle via the Bergström biopsy technique in vastus lateralis.

By comparing children with newly diagnosed CNS tumor with children finished treated for CNS tumor, the investigators wish to describe the metabolic path during the approximately two years treatment period these children go through. These results will also be compared with results from healthy controls.

Trial design and time frame:

A prospective, non-randomized, cross-sectional study.

There will be three different patient groups included:

* Patient group A: Children with newly diagnosed CNS tumor
* Patient group B: Children finished treated for CNS tumor
* Healthy controls: Children admitted to the hospital at the Epilepsy monitor unit (EMU)

The trial will be conducted over a total of two days and takes place at the Department of Pediatrics and Adolescent Medicine, Rigshospitalet and the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet.

* Study day 1: Is estimated to last approximately 2 hours.
* Study day 2: Is estimated to last approximately 8 hours.

Study Day 1: The children will be DXA-scanned and complete life quality questionnaires and pain scores. In some cases, study day 1 will be done after study day 2, depending on the cancer treatment plan for each patient.

Study Day 2: For the patients newly diagnosed with CNS tumor: The investigators strive to conduct study day 2 within the first week of hospital admission due to newly diagnosed CNS tumor. However, the investigators do accept study day 2 being conducted within the first month after time of diagnose.The subjects will arrive around 08.00, at Copenhagen Neuromuscular Centre (CNMC), Rigshospitalet.

On arrival, EMLA (local anesthetics cream) will be applied on the skin of the children in order to minimize any discomfort that may occur during iv-insertion. Two peripheral venous catheters are inserted, one in the medial cubital vein for infusion of stable isotopes, and one in a dorsal vein of the hand for blood sampling. If the child has a central venous catheter (CVK), we will only insert one peripheral venous catheter, in the medial cubital vein for infusion of the stable isotopes.

After 1 hour and 45 minutes of basal tracer infusion, basal blood samples are drawn (time -15 and 0) for the determination of basal steady state tracer enrichments and hormone concentrations. At time= 0, a liquid mixed meal is provided. Blood samples are drawn frequently for 6 hours relative to start of the test meal (at 0, 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 300 and 360 minutes)\[24\], \[25\]. If the child becomes upset or we for other reasons want to stop earlier than 6 hours, we will use the already obtained results.

The tracers: In this study, the investigators will intravenously infuse small amounts of metabolites labelled with stable isotopes in primed continuous intravenous infusions of: D8-Phenylalanine, D2-Tyrosine, 13C18-Oleate acid, D2-Glucose, D5-Glycerol. This method is well-established at both CIMT and CNMC and has been used investigating several of patients categories before: Neonates (ongoing study), gastric sleeve, elderly and neuromuscular patients.

The tracers are prepared from the hospital pharmacy. All tracers are purchased from Cambridge Isotope Laboratories, Andover, MA, USA suitable for human use. Stable isotopes are non-radioactive and naturally occurring in food (e.g. in corn).

Food intervention: At time= 0 (120 minutes after infusion), a liquid mixed meal adjusted by weight is given. The meal consists of: Intrinsically labelled D5-Phenylalanine and D3-Leucine labelled casein protein, 13C16palmitate, 13C6-Glucose in a mix of glucose, casein protein and rape seed oil dissolved in water in an energy density of 50% CHO, 35% fat and 15% protein. Intrinsically labeled caseinate was produced via an infusion of \[D5\]-phenylalanine and \[D3\]leucine into a lactating cow to obtain enriched milk Foulumn, Arhus University, from which the caseinate fraction was isolated at Arla Foods according to Good Manufacturing Practice (GMP) and safety checked an store under appropriate regulatory conditions until use (Nørre Vium, Denmark) following a previously described procedure.

Analyses of blood samples:The samples will be collected in syringes containing 10μL EDTA/mL to prevent coagulation. The blood is immediately centrifuged at 4oC to separate plasma from red blood cells. The samples will be frozen in coded tubes and stored at -80C until analysis.

Routine blood samples: Will be analysed immediately at the Department of Clinical Biochemistry, Rigshospitalet:

- Blood samples include: Insulin, HbA1C, Cholesterol, HDL, LDL, triglycerides

Glucose and lactate: will be analyzed (ABL 700) immediately as the blood is drawn.

Specific blood samples:

* Free fatty acids: will be analyzed using fluorometry.
* Hormones (catecholamines, insulin, incretins and glucagon): will be analyzed using RIA and Elisa Methods respectively.
* Stable isotope enrichments in blood: will be analyzed using Liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) (Thermo Scientific, Palo Alto, CA, USA and Bremen, Germany).

Calculations: Whole body metabolite quantitative kinetics will be calculated using Steele's equation for non-steady state adapted for analysis of stable isotopes under the post-absorptive conditions.

Whole Body Metabolism in Children Before and After Treatment of CNS Tumor

Phenylalanine Rate of appearance micro mol/kgFFM/min

Phenylalanine Rate of disappearance micro mol/kgFFM/min

Nutritional, meal, absorption kinetics of proteins, carbohydrates and fat including first bypass losses (interstitial and liver). In case of fat that included synthesis rates of chylomicrons and their breakdown rate by determining the overflow of the nutritional fatty acids into the main circulation.

Dual-energy X-ray absorptiometry (DEXA) scan

Blood, mainly liver, proteins synthesis rate and liver function parameter from, A. liver glucose; B. VLDL-TAG production rate; C. phenylalanine hydroxylation rates

Life quality score by using PedsQL (0-100)

Muscle morphology, muscle fiber type and size, atrophy protein markers (MuRF1, MAFbx, FoxO) muscle generating markers (Myo D, Myogenin, IGF1), muscle growth regulating protein (myostatin).

HDL , LDL, total cholesterol, TAG (mmol/L)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Avutometinib for People With Solid Tumor Cancers	NCT06104488	Refractory Canc... CNS Tumors CNS Tumor, Adul... CNS Tumor, Chil... MAP Kinase Fami... NF1 Plexiform Neuro... Low-grade Gliom... Optic Pathway G... Neuroblastoma Primary Brain T... Solid Tumor Solid Tumor, Ad... Solid Carcinoma Central Nervous...	Avutometinib	3 Years - 30 Years	Memorial Sloan Kettering Cancer Center
Whole Body Metabolism in Children Before and After Treatment of CNS Tumor	NCT06380387	CNS Tumor, Chil...	Meal	6 Years - 18 Years	Rigshospitalet, Denmark

Spots Global Cancer Trial Database for cns tumor, childhood