A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis
Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis
3 other identifiers
interventional
48
3 countries
115
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_2
Started Mar 2024
Typical duration for phase_2
115 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 21, 2023
CompletedFirst Posted
Study publicly available on registry
April 25, 2023
CompletedStudy Start
First participant enrolled
March 28, 2024
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 30, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
September 30, 2028
April 16, 2026
January 1, 2026
4.5 years
April 21, 2023
April 15, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
Frequency of dose limiting toxicity (dose finding phase)
Will be analyzed descriptively.
Up to 28 days
Overall response rate (phase II)
Will be assessed using minimax Simon's two-stage designs in each of the BRAFV600E and non-BRAFV600E cohorts separately. The two arms will not be directly compared. The 95% confidence interval for the overall response rate will be adjusted for the two-stage design.
After 2 cycles of therapy (each cycle is 28 days)
Secondary Outcomes (4)
Event free survival rate
At 1 and 2 years
Progression free survival rate
Up to 2 years
Duration of response rate
After 12 months of therapy. From the scan confirming the complete response or partial response (whichever is recorded first), until the first occurrence of recurrent or progressive disease or death (event) or last known status on trial
Overall survival rate
Up to 2 years
Other Outcomes (1)
Percent peripheral blood mononuclear cells with mutated allele
Up to 2 years
Study Arms (1)
Treatment (tovorafenib)
EXPERIMENTALPatients 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 and urine 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
Undergo ECHO
Undergo MUGA
Given PO
Undergo FDG-PET imaging
Undergo collection of blood and urine samples
Undergo bone marrow biopsy
Undergo CT
Eligibility Criteria
You may qualify if:
- 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
- +35 more criteria
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
- +4 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (115)
Children's Hospital of Alabama
Birmingham, Alabama, 35233, United States
Arkansas Children's Hospital
Little Rock, Arkansas, 72202-3591, United States
Kaiser Permanente Downey Medical Center
Downey, California, 90242, United States
Loma Linda University Medical Center
Loma Linda, California, 92354, United States
Children's Hospital Los Angeles
Los Angeles, California, 90027, United States
Valley Children's Hospital
Madera, California, 93636, United States
UCSF Benioff Children's Hospital Oakland
Oakland, California, 94609, United States
Kaiser Permanente-Oakland
Oakland, California, 94611, United States
Children's Hospital of Orange County
Orange, California, 92868, United States
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, 94304, United States
UCSF Medical Center-Mission Bay
San Francisco, California, 94158, United States
Children's Hospital Colorado
Aurora, Colorado, 80045, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver, Colorado, 80218, United States
Connecticut Children's Medical Center
Hartford, Connecticut, 06106, United States
Yale University
New Haven, Connecticut, 06520, United States
Alfred I duPont Hospital for Children
Wilmington, Delaware, 19803, United States
Children's National Medical Center
Washington D.C., District of Columbia, 20010, United States
Golisano Children's Hospital of Southwest Florida
Fort Myers, Florida, 33908, United States
UF Health Cancer Institute - Gainesville
Gainesville, Florida, 32610, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
Hollywood, Florida, 33021, United States
Nemours Children's Clinic-Jacksonville
Jacksonville, Florida, 32207, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136, United States
Nicklaus Children's Hospital
Miami, Florida, 33155, United States
Arnold Palmer Hospital for Children
Orlando, Florida, 32806, United States
Nemours Children's Hospital
Orlando, Florida, 32827, United States
Nemours Children's Clinic - Pensacola
Pensacola, Florida, 32504, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa, Florida, 33607, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta, Georgia, 30329, United States
Memorial Health University Medical Center
Savannah, Georgia, 31404, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois, 60611, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637, United States
Saint Jude Midwest Affiliate
Peoria, Illinois, 61637, United States
Riley Hospital for Children
Indianapolis, Indiana, 46202, United States
Blank Children's Hospital
Des Moines, Iowa, 50309, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536, United States
Children's Hospital New Orleans
New Orleans, Louisiana, 70118, United States
Ochsner Medical Center Jefferson
New Orleans, Louisiana, 70121, United States
Sinai Hospital of Baltimore
Baltimore, Maryland, 21215, United States
Michigan State University
East Lansing, Michigan, 48823, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
Grand Rapids, Michigan, 49503, United States
Bronson Methodist Hospital
Kalamazoo, Michigan, 49007, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis, Minnesota, 55404, United States
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, 55455, United States
University of Mississippi Medical Center
Jackson, Mississippi, 39216, United States
Cardinal Glennon Children's Medical Center
St Louis, Missouri, 63104, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Mercy Hospital Saint Louis
St Louis, Missouri, 63141, United States
Children's Hospital and Medical Center of Omaha
Omaha, Nebraska, 68114, United States
University of Nebraska Medical Center
Omaha, Nebraska, 68198, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
Las Vegas, Nevada, 89135, United States
Summerlin Hospital Medical Center
Las Vegas, Nevada, 89144, United States
Hackensack University Medical Center
Hackensack, New Jersey, 07601, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
New Brunswick, New Jersey, 08903, United States
Saint Joseph's Regional Medical Center
Paterson, New Jersey, 07503, United States
Albany Medical Center
Albany, New York, 12208, United States
Maimonides Medical Center
Brooklyn, New York, 11219, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park, New York, 11040, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016, United States
Mount Sinai Hospital
New York, New York, 10029, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032, United States
Memorial Sloan Kettering Cancer Center
New York, New York, 10065, United States
NYP/Weill Cornell Medical Center
New York, New York, 10065, United States
State University of New York Upstate Medical University
Syracuse, New York, 13210, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467, United States
New York Medical College
Valhalla, New York, 10595, United States
Mission Hospital
Asheville, North Carolina, 28801, United States
Duke University Medical Center
Durham, North Carolina, 27710, United States
East Carolina University
Greenville, North Carolina, 27834, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157, United States
Rainbow Babies and Childrens Hospital
Cleveland, Ohio, 44106, United States
Nationwide Children's Hospital
Columbus, Ohio, 43205, United States
Dayton Children's Hospital
Dayton, Ohio, 45404, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
Oregon Health and Science University
Portland, Oregon, 97239, United States
Geisinger Medical Center
Danville, Pennsylvania, 17822, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104, United States
Saint Christopher's Hospital for Children
Philadelphia, Pennsylvania, 19134, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224, United States
Prisma Health Richland Hospital
Columbia, South Carolina, 29203, United States
BI-LO Charities Children's Cancer Center
Greenville, South Carolina, 29605, United States
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, 57117-5134, United States
East Tennessee Childrens Hospital
Knoxville, Tennessee, 37916, United States
The Children's Hospital at TriStar Centennial
Nashville, Tennessee, 37203, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232, United States
Dell Children's Medical Center of Central Texas
Austin, Texas, 78723, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390, United States
El Paso Children's Hospital
El Paso, Texas, 79905, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas, 77030, United States
M D Anderson Cancer Center
Houston, Texas, 77030, United States
Children's Hospital of San Antonio
San Antonio, Texas, 78207, United States
Methodist Children's Hospital of South Texas
San Antonio, Texas, 78229, United States
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229, United States
Scott and White Memorial Hospital
Temple, Texas, 76508, United States
Primary Children's Hospital
Salt Lake City, Utah, 84113, United States
University of Virginia Cancer Center
Charlottesville, Virginia, 22908, United States
Children's Hospital of The King's Daughters
Norfolk, Virginia, 23507, United States
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298, United States
Seattle Children's Hospital
Seattle, Washington, 98105, United States
Providence Sacred Heart Medical Center and Children's Hospital
Spokane, Washington, 99204, United States
West Virginia University Charleston Division
Charleston, West Virginia, 25304, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, 53226, United States
Sydney Children's Hospital
Randwick, New South Wales, 2031, Australia
Queensland Children's Hospital
South Brisbane, Queensland, 4101, Australia
Royal Children's Hospital
Parkville, Victoria, 3052, Australia
Perth Children's Hospital
Perth, Western Australia, 6009, Australia
University of Alberta Hospital
Edmonton, Alberta, T6G 2B7, Canada
British Columbia Children's Hospital
Vancouver, British Columbia, V6H 3V4, Canada
IWK Health Centre
Halifax, Nova Scotia, B3K 6R8, Canada
McMaster Children's Hospital at Hamilton Health Sciences
Hamilton, Ontario, L8N 3Z5, Canada
Children's Hospital
London, Ontario, N6A 5W9, Canada
Hospital for Sick Children
Toronto, Ontario, M5G 1X8, Canada
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, H3T 1C5, Canada
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
Sherbrooke, Quebec, J1H 5N4, Canada
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
Québec, G1V 4G2, Canada
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Carl E Allen
Children's Oncology Group
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 21, 2023
First Posted
April 25, 2023
Study Start
March 28, 2024
Primary Completion (Estimated)
September 30, 2028
Study Completion (Estimated)
September 30, 2028
Last Updated
April 16, 2026
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.