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RECRUITING Phase 2 ClinicalTrials.gov

A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis

Sponsor: National Cancer Institute (NCI) • ClinicalTrials.gov ID: NCT05828069

Registry updated: 2026-10-21
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Description

This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis that is growing, spreading, or getting worse (progressive), has come back (relapsed) after previous treatment, or does not respond to therapy (refractory). Langerhans cell histiocytosis is a type of disease that occurs when the body makes too many immature Langerhans cells (a type of white blood cell). When these cells build up, they can form tumors in certain tissues and organs including bones, skin, lungs and pituitary gland and can damage them. This tumor is more common in children and young adults. DAY101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Using DAY101 may be effective in treating patients with relapsed or refractory Langerhans cell histiocytosis.

Interventions

  • Biospecimen Collection (Procedure)
    Undergo collection of blood and urine samples
  • Bone Marrow Aspiration (Procedure)
    Undergo bone marrow aspiration
  • Bone Marrow Biopsy (Procedure)
    Undergo bone marrow biopsy
  • Computed Tomography (Procedure)
    Undergo CT
  • Echocardiography Test (Procedure)
    Undergo ECHO
  • FDG-Positron Emission Tomography and Computed Tomography Scan (Procedure)
    Undergo FDG-PET imaging
  • Lumbar Puncture (Procedure)
    Undergo lumbar puncture
  • Multigated Acquisition Scan (Procedure)
    Undergo MUGA
  • Tovorafenib (Drug)
    Given PO

Eligibility criteria

Inclusion Criteria: * 180 days- \< 22 years (at time of study enrollment) * Patient must have a body surface area of ≥ 0.3 m\^2 * Patients with 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 * 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 * Patients must have progressive or refractory disease or experience relapse after at least one previous systemic 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 or any other anticancer therapy (including MAPK pathway inhibitor) 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, targeted inhibitor, and/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 * 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/sex 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) * Age: 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 * All patients and/or their parent(s) or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met. 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 * 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 * 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. Women of childbearing potential must use non-hormonal contraception during tovorafenib treatment and for at least 28 days after the last dose. Men should use effective contraception and must not father a child while taking tovorafenib and for 14 days after the last dose

Conditions

Recurrent Langerhans Cell Histiocytosis Refractory Langerhans Cell Histiocytosis

Locations

  • Children's Hospital of Alabama — Birmingham, Alabama, United States
  • Arkansas Children's Hospital — Little Rock, Arkansas, United States
  • Kaiser Permanente Downey Medical Center — Downey, California, United States
  • Loma Linda University Medical Center — Loma Linda, California, United States
  • Miller Children's and Women's Hospital Long Beach — Long Beach, California, United States
  • Children's Hospital Los Angeles — Los Angeles, California, United States
  • Valley Children's Hospital — Madera, California, United States
  • UCSF Benioff Children's Hospital Oakland — Oakland, California, United States
  • Kaiser Permanente-Oakland — Oakland, California, United States
  • Children's Hospital of Orange County — Orange, California, United States
  • Lucile Packard Children's Hospital Stanford University — Palo Alto, California, United States
  • UCSF Medical Center-Mission Bay — San Francisco, California, United States
  • Children's Hospital Colorado — Aurora, Colorado, United States
  • Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center — Denver, Colorado, United States
  • Connecticut Children's Medical Center — Hartford, Connecticut, United States
  • Yale University — New Haven, Connecticut, United States
  • Alfred I duPont Hospital for Children — Wilmington, Delaware, United States
  • Children's National Medical Center — Washington D.C., District of Columbia, United States
  • Golisano Children's Hospital of Southwest Florida — Fort Myers, Florida, United States
  • UF Health Cancer Institute - Gainesville — Gainesville, Florida, United States
  • Memorial Regional Hospital/Joe DiMaggio Children's Hospital — Hollywood, Florida, United States
  • Nemours Children's Clinic-Jacksonville — Jacksonville, Florida, United States
  • University of Miami Miller School of Medicine-Sylvester Cancer Center — Miami, Florida, United States
  • Nicklaus Children's Hospital — Miami, Florida, United States
  • Arnold Palmer Hospital for Children — Orlando, Florida, United States
  • Nemours Children's Hospital — Orlando, Florida, United States
  • Nemours Children's Clinic - Pensacola — Pensacola, Florida, United States
  • Johns Hopkins All Children's Hospital — St. Petersburg, Florida, United States
  • Saint Joseph's Hospital/Children's Hospital-Tampa — Tampa, Florida, United States
  • Children's Healthcare of Atlanta - Arthur M Blank Hospital — Atlanta, Georgia, United States
  • Memorial Health University Medical Center — Savannah, Georgia, United States
  • Kapiolani Medical Center for Women and Children — Honolulu, Hawaii, United States
  • Lurie Children's Hospital-Chicago — Chicago, Illinois, United States
  • University of Chicago Comprehensive Cancer Center — Chicago, Illinois, United States
  • OSF Children's Hospital of Illinois — Peoria, Illinois, United States
  • Riley Hospital for Children — Indianapolis, Indiana, United States
  • Blank Children's Hospital — Des Moines, Iowa, United States
  • University of Iowa/Holden Comprehensive Cancer Center — Iowa City, Iowa, United States
  • University of Kentucky/Markey Cancer Center — Lexington, Kentucky, United States
  • Children's Hospital New Orleans — New Orleans, Louisiana, United States
  • Ochsner Medical Center Jefferson — New Orleans, Louisiana, United States
  • Sinai Hospital of Baltimore — Baltimore, Maryland, United States
  • Johns Hopkins University/Sidney Kimmel Cancer Center — Baltimore, Maryland, United States
  • Michigan State University — East Lansing, Michigan, United States
  • Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital — Grand Rapids, Michigan, United States
  • Bronson Methodist Hospital — Kalamazoo, Michigan, United States
  • Children's Hospitals and Clinics of Minnesota - Minneapolis — Minneapolis, Minnesota, United States
  • University of Minnesota/Masonic Cancer Center — Minneapolis, Minnesota, United States
  • University of Mississippi Medical Center — Jackson, Mississippi, United States
  • Cardinal Glennon Children's Medical Center — St Louis, Missouri, United States
  • Washington University School of Medicine — St Louis, Missouri, United States
  • Mercy Hospital Saint Louis — St Louis, Missouri, United States
  • Children's Hospital and Medical Center of Omaha — Omaha, Nebraska, United States
  • University of Nebraska Medical Center — Omaha, Nebraska, United States
  • Alliance for Childhood Diseases/Cure 4 the Kids Foundation — Las Vegas, Nevada, United States
  • Summerlin Hospital Medical Center — Las Vegas, Nevada, United States
  • Hackensack University Medical Center — Hackensack, New Jersey, United States
  • Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital — New Brunswick, New Jersey, United States
  • Saint Joseph's Regional Medical Center — Paterson, New Jersey, United States
  • Albany Medical Center — Albany, New York, United States
  • Maimonides Medical Center — Brooklyn, New York, United States
  • The Steven and Alexandra Cohen Children's Medical Center of New York — New Hyde Park, New York, United States
  • Laura and Isaac Perlmutter Cancer Center at NYU Langone — New York, New York, United States
  • Mount Sinai Hospital — New York, New York, United States
  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center — New York, New York, United States
  • Memorial Sloan Kettering Cancer Center — New York, New York, United States
  • NYP/Weill Cornell Medical Center — New York, New York, United States
  • State University of New York Upstate Medical University — Syracuse, New York, United States
  • Montefiore Medical Center - Moses Campus — The Bronx, New York, United States
  • New York Medical College — Valhalla, New York, United States
  • Mission Hospital — Asheville, North Carolina, United States
  • Duke University Medical Center — Durham, North Carolina, United States
  • East Carolina University — Greenville, North Carolina, United States
  • Wake Forest University Health Sciences — Winston-Salem, North Carolina, United States
  • Rainbow Babies and Childrens Hospital — Cleveland, Ohio, United States
  • Nationwide Children's Hospital — Columbus, Ohio, United States
  • Dayton Children's Hospital — Dayton, Ohio, United States
  • University of Oklahoma Health Sciences Center — Oklahoma City, Oklahoma, United States
  • Oregon Health and Science University — Portland, Oregon, United States
  • Geisinger Medical Center — Danville, Pennsylvania, United States
  • Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States
  • Saint Christopher's Hospital for Children — Philadelphia, Pennsylvania, United States
  • Children's Hospital of Pittsburgh of UPMC — Pittsburgh, Pennsylvania, United States
  • Prisma Health Richland Hospital — Columbia, South Carolina, United States
  • BI-LO Charities Children's Cancer Center — Greenville, South Carolina, United States
  • Sanford USD Medical Center - Sioux Falls — Sioux Falls, South Dakota, United States
  • East Tennessee Childrens Hospital — Knoxville, Tennessee, United States
  • The Children's Hospital at TriStar Centennial — Nashville, Tennessee, United States
  • Vanderbilt University/Ingram Cancer Center — Nashville, Tennessee, United States
  • Dell Children's Medical Center of Central Texas — Austin, Texas, United States
  • UT Southwestern/Simmons Cancer Center-Dallas — Dallas, Texas, United States
  • El Paso Children's Hospital — El Paso, Texas, United States
  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center — Houston, Texas, United States
  • UT MD Anderson Cancer Center — Houston, Texas, United States
  • Children's Hospital of San Antonio — San Antonio, Texas, United States
  • Methodist Children's Hospital of South Texas — San Antonio, Texas, United States
  • University of Texas Health Science Center at San Antonio — San Antonio, Texas, United States
  • Scott and White Memorial Hospital — Temple, Texas, United States
  • Primary Children's Hospital — Salt Lake City, Utah, United States
  • University of Virginia Cancer Center — Charlottesville, Virginia, United States
  • Children's Hospital of The King's Daughters — Norfolk, Virginia, United States
  • VCU Massey Comprehensive Cancer Center — Richmond, Virginia, United States
  • Seattle Children's Hospital — Seattle, Washington, United States
  • Providence Sacred Heart Medical Center and Children's Hospital — Spokane, Washington, United States
  • Vandalia Health/CAMC Institute for Academic Medicine — Charleston, West Virginia, United States
  • Saint Vincent Hospital Cancer Center Green Bay — Green Bay, Wisconsin, United States
  • Children's Hospital of Wisconsin — Milwaukee, Wisconsin, United States
  • John Hunter Children's Hospital — Hunter Regional Mail Centre, New South Wales, Australia
  • Sydney Children's Hospital — Randwick, New South Wales, Australia
  • Queensland Children's Hospital — South Brisbane, Queensland, Australia
  • Royal Children's Hospital — Parkville, Victoria, Australia
  • Perth Children's Hospital — Perth, Western Australia, Australia
  • University of Alberta Hospital — Edmonton, Alberta, Canada
  • British Columbia Children's Hospital — Vancouver, British Columbia, Canada
  • IWK Health Centre — Halifax, Nova Scotia, Canada
  • McMaster Children's Hospital at Hamilton Health Sciences — Hamilton, Ontario, Canada
  • Children's Hospital — London, Ontario, Canada
  • Hospital for Sick Children — Toronto, Ontario, Canada
  • Centre Hospitalier Universitaire Sainte-Justine — Montreal, Quebec, Canada
  • Centre Hospitalier Universitaire de Sherbrooke-Fleurimont — Sherbrooke, Quebec, Canada
  • CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL) — Québec, Canada
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Official Source

Data sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

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