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

Recruiting now · Phase 2

Conditions studied: Recurrent Langerhans Cell Histiocytosis, Refractory Langerhans Cell Histiocytosis

In brief

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.

Key facts

Study ID

NCT05828069

Run by

National Cancer Institute (NCI)

People needed

48

Starts

2024-03-28

Expected to finish

2028-09-30

Last updated by the study team

2026-07-29

Who can join

Age: 0 and older, up to 22. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• 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

You may not qualify if…

• 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 it is running

• Arkansas Children's Hospital — Little Rock, Arkansas, United States (enrolling)
• Children's Hospital of Alabama — Birmingham, Alabama, United States (enrolling)
• Loma Linda University Medical Center — Loma Linda, California, United States (enrolling)
• Miller Children's and Women's Hospital Long Beach — Long Beach, California, United States (enrolling)
• Children's Hospital Los Angeles — Los Angeles, California, United States (enrolling)
• Kaiser Permanente Downey Medical Center — Downey, California, United States (enrolling)
• UCSF Benioff Children's Hospital Oakland — Oakland, California, United States (enrolling)
• Kaiser Permanente-Oakland — Oakland, California, United States (enrolling)
• Children's Hospital of Orange County — Orange, California, United States (enrolling)
• Lucile Packard Children's Hospital Stanford University — Palo Alto, California, United States (enrolling)
• UCSF Medical Center-Mission Bay — San Francisco, California, United States (enrolling)
• Children's Hospital Colorado — Aurora, Colorado, United States (enrolling)
• Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center — Denver, Colorado, United States (enrolling)
• Connecticut Children's Medical Center — Hartford, Connecticut, United States (enrolling)
• Yale University — New Haven, Connecticut, United States (enrolling)
• Alfred I duPont Hospital for Children — Wilmington, Delaware, United States (enrolling)
• Children's National Medical Center — Washington D.C., District of Columbia, United States (enrolling)
• Golisano Children's Hospital of Southwest Florida — Fort Myers, Florida, United States (enrolling)
• UF Health Cancer Institute - Gainesville — Gainesville, Florida, United States (enrolling)
• Memorial Regional Hospital/Joe DiMaggio Children's Hospital — Hollywood, Florida, United States (enrolling)
• Nemours Children's Clinic-Jacksonville — Jacksonville, Florida, United States (enrolling)
• University of Miami Miller School of Medicine-Sylvester Cancer Center — Miami, Florida, United States (enrolling)
• Nicklaus Children's Hospital — Miami, Florida, United States (enrolling)
• Arnold Palmer Hospital for Children — Orlando, Florida, United States (enrolling)
• Nemours Children's Hospital — Orlando, Florida, United States (enrolling)

Full record on ClinicalTrials.gov

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