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Tovorafenib (DAY101) for relapsed or treatment‑resistant Langerhans cell histiocytosis in children and young adults

Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis

Phase 2 Interventional National Cancer Institute (NCI) · NCT05828069

This Phase II trial tests whether tovorafenib (DAY101) can shrink or control progressive, relapsed, or treatment‑resistant Langerhans cell histiocytosis in children and young adults.

Quick facts

PhasePhase 2
Study typeInterventional
Enrollment48 (estimated)
Ages180 Days to 22 Years
SexAll
SponsorNational Cancer Institute (NCI) NIH
Drugs / interventionschemotherapy, immunotherapy, Radiation, prednisone
Locations117 sites (Birmingham, Alabama and 116 other locations)
Trial IDNCT05828069 on ClinicalTrials.gov

What this trial studies

This Phase II, multi‑site trial gives tovorafenib (DAY101) to children and young adults with progressive, relapsed, or refractory Langerhans cell histiocytosis and measures response after two treatment cycles with confirmation four weeks later. Participants are enrolled into separate cohorts based on tumor BRAFV600E mutation status to compare activity in mutation‑positive and mutation‑negative disease. Secondary goals include characterizing side effects, event‑free and progression‑free survival up to one year, and durability of complete responses after stopping therapy. The protocol requires imaging, biopsies, bone marrow sampling, and blood/tissue collection for molecular studies to correlate mutations with response.

Who should consider this trial

Good fit: Children and young adults aged 180 days to under 22 years with histologically confirmed, measurable progressive, relapsed, or refractory LCH who can undergo required biopsies and follow‑up at a participating center are ideal candidates.

Not a fit: Patients without measurable disease, those unable to tolerate required procedures, or patients whose disease biology is unlikely to respond to RAF inhibition may not receive benefit from this treatment.

Why it matters

Potential benefit: If effective, tovorafenib could shrink disease, prolong time without progression, and provide a targeted treatment option for children and young adults whose LCH has returned or not responded to prior therapy.

How similar studies have performed: Other BRAF‑targeted therapies have produced clinical responses in BRAFV600E‑positive LCH, giving precedent for RAF‑directed therapy, although tovorafenib itself has been less extensively studied in LCH.

Eligibility criteria

Show full inclusion / exclusion 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

Where this trial is running

Birmingham, Alabama and 116 other locations

+67 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Recurrent Langerhans Cell HistiocytosisRefractory Langerhans Cell Histiocytosis
Last reviewed 2026-06-10 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.