A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis
Start Date
3/28/2024
Completion Date
9/30/2028
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.
Detailed Description
PRIMARY OBJECTIVE: I. To determine overall response rate (ORR) for children and young adults with relapsed or refractory BRAFV600E positive (cohort 1) and BRAFV600E negative (cohort 2) 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) criteria. 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 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. After completion of study treatment, patients are followed up at 28 days, months 3, 6, 9, and 12, and then at 2 years post cycle 12.
Eligibility Criteria
Age Range: No minimum to 22 years
Interventions
Biospecimen Collection
Bone Marrow Aspiration
Bone Marrow Biopsy
Computed Tomography
Echocardiography Test
FDG-Positron Emission Tomography and Computed Tomography Scan
Lumbar Puncture
Multigated Acquisition Scan
Tovorafenib
Conditions
Locations
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
Miller Children's and Women's Hospital Long Beach
Long Beach, California 90806
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
Johns Hopkins All Children's Hospital
St. Petersburg, Florida 33701
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
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii 96826
United States
Lurie Children's Hospital-Chicago
Chicago, Illinois 60611
United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois 60637
United States
OSF Children's Hospital of Illinois
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
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland 21287
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
UT MD 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
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin 54301
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