Inclusion Criteria:

• - 180 days- < 22 years (at time of study enrollment) - Patients with multifocal progressive, relapsed, or recurrent LCH with measurable disease at study entry.

• - Patients must have had histologic verification of LCH (from either original diagnosis or relapse/progression) at the time of study entry (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary) - Tissue confirmation of relapse is recommended but not required.

• - Pathology report must be submitted for central confirmation of diagnosis within 7 days of enrollment.

• - Formalin-fixed paraffin-embedded (FFPE) blocks or unstained slides (initial diagnosis and/or subsequent biopsies) will be required for retrospective central confirmation of diagnosis and molecular studies.

• - Patients with mixed histiocytic disorders (e.g. LCH with juvenile xanthogranuloma) may be included.

• - Patients must have measurable disease, documented by radiographic imaging (LCH- specific response criteria (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary).

• - Patients must have progressive or refractory disease or experience relapse after at least one previous systemic chemotherapy treatment strategy.

• - Pathogenic somatic mutation detected in genes encoding tyrosine kinase receptors (CSFR1, ERBB3 or ALK), RAS or RAF (may be from original or subsequent biopsy or peripheral blood/bone marrow aspirate).

Clinical mutation reports may include quantitative polymerase chain reaction (PCR) (e.g. BRAFV600E) and/or Sanger or next generation sequencing. Immunohistochemistry (e.g. VE1 antibody for BRAFV600E) alone is not sufficient.

• - Participant must be able to take an enteral dose and formulation of medication.

Study medication is only available as an oral suspension or tablet, which may be taken by mouth or other enteral route such as nasogastric, jejunostomy, or gastric tube.

• - Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50% for patients =< 16 years of age.

• - Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2.

Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age.

• - Myelosuppressive chemotherapy: Patients must not have received within 14 days of entry onto this study.

• - Investigational agent or any other anticancer therapy not defined above: Patients must not have received any investigational agent for at least 14 days prior to planned start of tovorafenib (DAY101) - Radiation therapy (RT): Patient must not have received RT within 2 weeks after the last dose fraction of RT.

• - Patients must have fully recovered from any prior surgery.

• - Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy with toxicities reduced to Grade 1 or less (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) - Steroids: < 0.5 mg/kg/day of prednisone equivalent (maximum 20 mg/day) averaged during the month prior to study enrollment is permissible but must be discontinued fourteen (14) days prior to study enrollment.

Patients with documented brain lesions receiving corticosteroids for management of cerebral edema must be on a stable dose for fourteen (14) days prior to study enrollment.

• - Strong inducers or inhibitors of CYP2C8 are prohibited for 14 days before the first dose of tovorafenib (DAY101) and from planned administration for the duration of study participation.

• - Medications that are breast cancer resistant protein (BCRP) substrates that have a narrow therapeutic index are prohibited for 14 days before the first dose of tovorafenib (DAY101) and for the duration of study participation.

• - Peripheral absolute neutrophil count (ANC) >= 750/uL unless secondary to bone marrow involvement, in such cases bone marrow involvement must be documented (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - Platelet count >= 75,000/uL (unsupported/without transfusion within the past 7 days) (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - Patients with marrow disease must have platelet count of >= 75,000/uL (transfusion support allowed) and must not be refractory to platelet transfusions.

Bone marrow involvement must be documented.

• - Hemoglobin >= 8 g/dL (unsupported/without transfusion within the past 7 days).

Patients with marrow disease must have hemoglobin >= 8 g/dL (transfusion support allowed). Bone marrow involvement must be documented.

• - Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta [registered trademark]) or 7 days for short-acting growth factor.

• - A serum creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - Age: 6 months to < 1 year; Maximum Serum Creatinine (mg/dL):= 0.5 mg/dl (male and female) - Age: 1 to < 2 years; Maximum Serum Creatinine (mg/dL): = 0.6 mg/dl (male and female) - Age: 2 to < 6 years; Maximum Serum Creatinine (mg/dL): = 0.8 mg/dl (male and female) - Age: 6 to < 10 years; Maximum Serum Creatinine (mg/dL): = 1.0 mg/dl (male and female) - Age: 10 to < 13 years; Maximum Serum Creatinine (mg/dL): = 1.2 mg/dl (male and female) - 13 to < 16 years; Maximum Serum Creatinine (mg/dL): = 1.5 mg/dl (male) and 1.4 mg/dl (female) - Age: >= 16 years; Maximum Serum Creatinine (mg/dL): = 1.7 mg/dl (male) and 1.4 mg/dl (female) - OR- a 24 hour urine creatinine clearance >= 50 mL/min/1.73 m^2.

• - OR- a glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2.

GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)

• - Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility.

• - Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - Alanine aminotransferase (ALT) =< 3 x ULN for age (must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - Serum albumin >= 2 g/dl must be performed within 7 days prior to enrollment, must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - For patients with liver disease caused by their histiocytic disorder (as evaluated on radiographic imaging or biopsy): patients may be enrolled with abnormal bilirubin, aspartate aminotransferase (AST), ALT and albumin with documentation of histiocytic liver disease.

• - Fractional shortening (FS) of >= 25% or ejection fraction of >= 50%, as determined by echocardiography or multigated acquisition scan (MUGA) within 28 days prior to study enrollment.

Depending on institutional standard, either FS or left ventricular ejection fraction (LVEF) is adequate for enrollment if only one value is measured; if both values are measured, then both values must meet criteria above (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary)

• - No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination; unless it is due to underlying pulmonary LCH.

• - Central Nervous System Function Defined As: - Patients with seizure disorder may be enrolled if well controlled.

• - Central nervous system (CNS) toxicity =< Grade 2.

• - Human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial unless antiretroviral therapy interacts with the metabolism of tovorafenib (DAY101) and cannot safely be changed to antivirals that do not interact with study medication.

Exclusion Criteria:

• - LCH arising along with other hematologic malignancy (e.g. mixed LCH with acute lymphoblastic leukemia) or any history of non-histiocytic malignancy.

• - Disease scenarios as below will be excluded.

• - Skin-limited disease.

• - Single bone lesion.

• - Gastrointestinal (GI) tract involvement only (those that have disease that can be determined by endoscopic biopsies only) - LCH-associated neurodegeneration (LCH-ND) without parenchymal lesions or other systemic lesions.

• - Patients with activating mutations in MAP2K1 are not eligible for this study due to drug target specificity.

Mutation status will be submitted to study team within 7 days of enrollment.

• - Patient must not have received any prior MAPK pathway inhibitor therapy.

• - Refractory nausea and vomiting, malabsorption, or external biliary shunt that would preclude adequate absorption of tovorafenib (DAY101) - Uncontrolled systemic bacterial, viral, or fungal infection.

• - Major surgical procedure or significant traumatic injury within 14 days prior to study enrollment, or anticipation of need for major surgical procedure during the course of the study.

Placement of a vascular access device or minor surgery is permitted within fourteen (14) days of study enrollment (provided that the wound has healed)

• - History of significant bowel resection that would preclude adequate absorption or other significant malabsorptive disease.

• - Ophthalmologic considerations: Patients with known significant ophthalmologic conditions or known risk factors for retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible.

• - History of solid organ or hematopoietic bone marrow transplantation.

• - Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval > 440 ms based on triplicate electrocardiogram (ECG) average.

• - History of Grade >= 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of study entry.

• - History of any drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or Stevens Johnsons syndrome (SJS) or who are allergic to tovorafenib (DAY101) or any of its components.

• - CTCAE version (V).

5.0 Grade 3 symptomatic creatinine kinase (CPK) elevation ( > 5 x ULN)

• - Female patients who are pregnant are ineligible.

A pregnancy test is required for female patients of childbearing potential.

• - Lactating females who plan to breastfeed their infants are ineligible.

• - Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation are ineligible.

Participants (male and female) who are sexually active must use two forms of an acceptable method of birth control (for men, one form must be a barrier method) from start of therapy through 180 days following last dose of tovorafenib (DAY101)

PRIMARY OBJECTIVE:

• I. To determine overall response rate (ORR) for children and young adults with relapsed or refractory Langerhans cell histiocytosis (LCH) treated with tovorafenib (DAY101) after 2 cycles and must be maintained 4 weeks later.

SECONDARY OBJECTIVES:

• I. To determine nature and severity of adverse events in patients treated with tovorafenib (DAY101) for relapsed or refractory LCH.

• II. To describe event-free survival (EFS) at 1 year in children and young adults with relapsed and refractory LCH treated with tovorafenib (DAY 101) for up to 1 year.

• III. To determine durability of response in children and young adults with relapsed or refractory LCH treated with tovorafenib (DAY101) following cessation of therapy in patients with complete response (CR) at 1 year.

• IV. To describe progression-free (and relapse-free) survival (PFS) and overall survival (OS) in children and young adults with relapsed or refractory LCH treated with tovorafenib (DAY101) for up to 1 year.

EXPLORATORY OBJECTIVES:

• I. To determine potential role of pathogenic tumor mutation in response to tovorafenib (DAY101), and to evaluate changes in bone marrow and peripheral blood cell populations carrying pathogenic mutations in response to tovorafenib (DAY101) therapy.

Ia. To define somatic mutations in LCH lesion biopsies; Ib. To determine impact of tovorafenib (DAY101) on bone marrow and blood BRAFV600E+ mononuclear cells; Ic. To determine impact of tovorafenib (DAY101) on cerebral spinal fluid and disease response; Id. To determine the performance of standardized immunohistochemical analysis of LCH lesion biopsies.

• II. To compare performance of LCH-specific response criteria to Response Evaluation Criteria in Solid Tumors (RECIST).

• III. To describe the pharmacokinetics of tovorafenib (DAY101) when administered to pediatric and young adult patients with relapse or refractory LCH.

OUTLINE: This is a dose escalation study of tovorafenib followed by a phase II trial. Patients receive tovorafenib orally (PO) once weekly (QW) on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-gated acquisition (MUGA) or echocardiography (ECHO) scans, and fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) or computed tomography (CT) throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. After completion of study treatment, patients are followed up at 28 days and then every 3, 6, 9, and 12 months.

Arms

Experimental: Treatment (tovorafenib)

Patients receive tovorafenib PO QW on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO scans, and FDG-PET or CT throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up.

Interventions

Procedure: - Biospecimen Collection

Undergo collection of blood samples

Procedure: - Bone Marrow Aspiration

Undergo bone marrow aspiration

Procedure: - Bone Marrow Biopsy

Undergo bone marrow biopsy

Procedure: - Computed Tomography

Undergo CT

Procedure: - Echocardiography

Undergo ECHO

Procedure: - FDG-Positron Emission Tomography and Computed Tomography Scan

Undergo FDG-PET imaging

Procedure: - Lumbar Puncture

Undergo lumbar puncture

Procedure: - Multigated Acquisition Scan

Undergo MUGA

Drug: - Tovorafenib

Given PO