RECRUITING

A Study of Avutometinib for People With Solid Tumor Cancers

Conditions

Refractory Cancer CNS Tumors CNS Tumor, Adult CNS Tumor, Childhood MAP Kinase Family Gene Mutation NF1 Plexiform Neurofibroma Low-grade Glioma Optic Pathway Gliomas Neuroblastoma Primary Brain Tumor Solid Tumor Solid Tumor, Adult Solid Carcinoma Central Nervous System Tumor CNS tumor Avutometinib Memorial Sloan Kettering Cancer Center 23-129

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

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

Quick Facts

Study Start:2023-10-20

Study Completion:2029-10-20

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT06104488

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:3 Years to 30 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT

Inclusion Criteria	Exclusion Criteria
* 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: 1. 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. 2. 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. * 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). * Tissue-based or liquid biopsy NGS or quantitative polymerase chain reaction (qPCR) or RNA based fusion detection (ARCHER or other similar platform). * Fluorescence in situ hybridization (FISH) * For subjects enrolled by a liquid biopsy test; blood samples will be required and should be sent prior to enrollment and used for retrospective confirmation in the Sponsor's designated central laboratory (MSKCC). * Patients must meet the following disease status criteria: * Solid tumor: Patients must have either measurable disease as measured by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (Version 1.1) or evaluable disease. * Neuroblastoma subjects are permitted to have evaluable disease only (e.g., bone disease only, evaluable by MIBG or PET). * Primary Brain Tumors: Patients with primary brain tumors are eligible and can either have measurable disease (defined as at least equal or greater than twice the slice thickness in two perpendicular diameters on MRI) OR evaluable disease (clear MRI evidence of disease that may not be measurable in two perpendicular diameters) OR diffuse leptomeningeal disease OR positive CSF cytology alone. * Tumor is refractory or recurrent/progressive after standard therapy (at least one prior standard therapy appropriate for tumor type and stage of disease) unless available standard therapies are considered inadequate for the patient. * Patients must have a body surface area (BSA) ≥ 0.67 m2 for enrollment at dose levels 1 and 2) and BSA ≥ 0.83 m2 for patients enrolling at dose level -1. * Patients must be able to swallow intact capsules. * Patients may have received prior treatment with a RAF inhibitor (1st or 2nd generation) or MEK inhibitor but only as monotherapy (regardless of prior response to therapy). * Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and meet minimum durations (shown below) from prior therapy. 1. Anti-cancer agents not known to be myelosuppressive: ≥ 7 days 2. Anti-cancer and cytotoxic agents known to be myelosuppressive: ≥ 14 days 3. Immunotherapies (including antibodies, interleukins, interferons, etc.): ≥ 21 days 4. Adoptive cellular therapies (including modified T cells, vaccines, etc.): ≥ 42 days 5. Autologous stem cell infusion (boost, no conditioning): ≥ 21 days 6. Autologous stem cell transplantation (with conditioning): ≥ 42 days 7. Allogeneic bone marrow transplantation: ≥ 84 days 8. Focal external beam radiation (e.g., limited sites of disease): ≥ 14 days 9. Substantial external beam radiation (e.g. whole lung or abdomen): ≥ 42 days 10. Radiopharmaceutical therapy (e.g., radiolabeled antibody or MIBG): ≥ 42 days * Adequate hepatic function (within 28 days prior to C1D1), defined as: 1. total bilirubin ≤ 1.5 × upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin \< 3.0 mg/dL (51 μmole/L); 2. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (or \< 5x ULN in patients with liver metastases) 3. Albumin ≥ 3.0 g/dL (451 μmole/L). * Adequate renal function (within 28 days prior to C1D1) defined a maximum serum creatinine for age and gender defined below. Patients that do not meet the criteria in Table 3 but have a 24 hour Creatinine Clearance or absolute GFR (radioisotope or iothalamate) ≥ 85ml/min are eligible. * Adequate hematologic function (within 7 days prior to C1D1), defined as: 1. platelets ≥100,000/mm3; and 2. absolute neutrophil count (ANC) ≥ 1000/mm3. Note: Patients may not receive platelet transfusions nor hematopoietic growth factor support, including granulocyte-colony stimulating factor (e.g. filgrastim) and platelet stimulators (e.g. romiplostim) for at least 7 days prior to demonstrating adequate hematologic function.Patients with known malignant bone marrow infiltration are exempt from the above count requirements but should be discussed with sponsor. * Creatine phosphokinase (CPK) ≤ 2.5 x ULN. * Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2. * Males or females of reproductive potential must agree to use an effective method of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control until one month after the last dose for female patients and 3 months after the last dose for male pts. Male patients should follow the same direction for sperm donation.	* 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: 1. Any history of congestive heart failure 2. 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) 3. 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. * Herbal preparations/medications (except for vitamins) including, but not limited to: * St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone * (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. * Pregnant or breastfeeding women will not be entered on this study because there is yet no available information regarding human fetal or teratogenic toxicities.

Inclusion Criteria

Exclusion Criteria

* 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:
1. 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.
2. 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.
* 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).
* Tissue-based or liquid biopsy NGS or quantitative polymerase chain reaction (qPCR) or RNA based fusion detection (ARCHER or other similar platform).
* Fluorescence in situ hybridization (FISH)
* For subjects enrolled by a liquid biopsy test; blood samples will be required and should be sent prior to enrollment and used for retrospective confirmation in the Sponsor's designated central laboratory (MSKCC).
* Patients must meet the following disease status criteria:
* Solid tumor: Patients must have either measurable disease as measured by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (Version 1.1) or evaluable disease.
* Neuroblastoma subjects are permitted to have evaluable disease only (e.g., bone disease only, evaluable by MIBG or PET).
* Primary Brain Tumors: Patients with primary brain tumors are eligible and can either have measurable disease (defined as at least equal or greater than twice the slice thickness in two perpendicular diameters on MRI) OR evaluable disease (clear MRI evidence of disease that may not be measurable in two perpendicular diameters) OR diffuse leptomeningeal disease OR positive CSF cytology alone.
* Tumor is refractory or recurrent/progressive after standard therapy (at least one prior standard therapy appropriate for tumor type and stage of disease) unless available standard therapies are considered inadequate for the patient.
* Patients must have a body surface area (BSA) ≥ 0.67 m2 for enrollment at dose levels 1 and 2) and BSA ≥ 0.83 m2 for patients enrolling at dose level -1.
* Patients must be able to swallow intact capsules.
* Patients may have received prior treatment with a RAF inhibitor (1st or 2nd generation) or MEK inhibitor but only as monotherapy (regardless of prior response to therapy).
* Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and meet minimum durations (shown below) from prior therapy.
1. Anti-cancer agents not known to be myelosuppressive: ≥ 7 days
2. Anti-cancer and cytotoxic agents known to be myelosuppressive: ≥ 14 days
3. Immunotherapies (including antibodies, interleukins, interferons, etc.): ≥ 21 days
4. Adoptive cellular therapies (including modified T cells, vaccines, etc.): ≥ 42 days
5. Autologous stem cell infusion (boost, no conditioning): ≥ 21 days
6. Autologous stem cell transplantation (with conditioning): ≥ 42 days
7. Allogeneic bone marrow transplantation: ≥ 84 days
8. Focal external beam radiation (e.g., limited sites of disease): ≥ 14 days
9. Substantial external beam radiation (e.g. whole lung or abdomen): ≥ 42 days
10. Radiopharmaceutical therapy (e.g., radiolabeled antibody or MIBG): ≥ 42 days
* Adequate hepatic function (within 28 days prior to C1D1), defined as:
1. total bilirubin ≤ 1.5 × upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin \< 3.0 mg/dL (51 μmole/L);
2. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (or \< 5x ULN in patients with liver metastases)
3. Albumin ≥ 3.0 g/dL (451 μmole/L).
* Adequate renal function (within 28 days prior to C1D1) defined a maximum serum creatinine for age and gender defined below. Patients that do not meet the criteria in Table 3 but have a 24 hour Creatinine Clearance or absolute GFR (radioisotope or iothalamate) ≥ 85ml/min are eligible.
* Adequate hematologic function (within 7 days prior to C1D1), defined as:
1. platelets ≥100,000/mm3; and
2. absolute neutrophil count (ANC) ≥ 1000/mm3. Note: Patients may not receive platelet transfusions nor hematopoietic growth factor support, including granulocyte-colony stimulating factor (e.g. filgrastim) and platelet stimulators (e.g. romiplostim) for at least 7 days prior to demonstrating adequate hematologic function.Patients with known malignant bone marrow infiltration are exempt from the above count requirements but should be discussed with sponsor.
* Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
* Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2.
* Males or females of reproductive potential must agree to use an effective method of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control until one month after the last dose for female patients and 3 months after the last dose for male pts. Male patients should follow the same direction for sperm donation.

* 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:
1. Any history of congestive heart failure
2. 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)
3. 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.
* Herbal preparations/medications (except for vitamins) including, but not limited to:
* St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone
* (DHEA), yohimbe, saw palmetto, black cohosh and ginseng.
* Pregnant or breastfeeding women will not be entered on this study because there is yet no available information regarding human fetal or teratogenic toxicities.

Contacts and Locations

Study Contact

Sameer Farouk Sait, MD

CONTACT

212-639-3449

faroukss@mskcc.org

Julia Glade Bender, MD

CONTACT

212-639-6729

gladebej@mskcc.org

Principal Investigator

Sameer Farouk Sait, MD

PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Study Locations (Sites)

Children's Healthcare of Atlanta (Data Collection Only)

Atlanta, Georgia, 30322

United States

Memorial Sloan Kettering Cancer Center (All Protocol Activities)

New York, New York, 10065

United States

Collaborators and Investigators

Sponsor: Memorial Sloan Kettering Cancer Center

Sameer Farouk Sait, MD, PRINCIPAL_INVESTIGATOR, Memorial Sloan Kettering Cancer Center

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-10-20

Study Completion Date2029-10-20

Study Record Updates

Study Start Date2023-10-20

Study Completion Date2029-10-20

Terms related to this study

Keywords Provided by Researchers

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

Additional Relevant MeSH Terms

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