A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis
Purpose
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.
Conditions
- Recurrent Langerhans Cell Histiocytosis
- Refractory Langerhans Cell Histiocytosis
Eligibility
- Eligible Ages
- Between 180 Days and 22 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
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
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- N/A
- Intervention Model
- Sequential Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Treatment (tovorafenib) |
Patients 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. |
|
Recruiting Locations
Children's Hospital of Alabama
Birmingham 4049979, Alabama 4829764 35233
Birmingham 4049979, Alabama 4829764 35233
Arkansas Children's Hospital
Little Rock 4119403, Arkansas 4099753 72202-3591
Little Rock 4119403, Arkansas 4099753 72202-3591
Contact:
Site Public Contact
501-364-7373
Site Public Contact
501-364-7373
Kaiser Permanente Downey Medical Center
Downey 5343858, California 5332921 90242
Downey 5343858, California 5332921 90242
Contact:
Site Public Contact
626-564-3455
Site Public Contact
626-564-3455
Loma Linda University Medical Center
Loma Linda 5367696, California 5332921 92354
Loma Linda 5367696, California 5332921 92354
Contact:
Site Public Contact
909-558-4050
Site Public Contact
909-558-4050
Children's Hospital Los Angeles
Los Angeles 5368361, California 5332921 90027
Los Angeles 5368361, California 5332921 90027
Contact:
Site Public Contact
323-361-4110
Site Public Contact
323-361-4110
UCSF Benioff Children's Hospital Oakland
Oakland 5378538, California 5332921 94609
Oakland 5378538, California 5332921 94609
Kaiser Permanente-Oakland
Oakland 5378538, California 5332921 94611
Oakland 5378538, California 5332921 94611
Children's Hospital of Orange County
Orange 5379513, California 5332921 92868
Orange 5379513, California 5332921 92868
Lucile Packard Children's Hospital Stanford University
Palo Alto 5380748, California 5332921 94304
Palo Alto 5380748, California 5332921 94304
UCSF Medical Center-Mission Bay
San Francisco 5391959, California 5332921 94158
San Francisco 5391959, California 5332921 94158
Children's Hospital Colorado
Aurora 5412347, Colorado 5417618 80045
Aurora 5412347, Colorado 5417618 80045
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver 5419384, Colorado 5417618 80218
Denver 5419384, Colorado 5417618 80218
Connecticut Children's Medical Center
Hartford 4835797, Connecticut 4831725 06106
Hartford 4835797, Connecticut 4831725 06106
Contact:
Site Public Contact
860-545-9981
Site Public Contact
860-545-9981
Yale University
New Haven 4839366, Connecticut 4831725 06520
New Haven 4839366, Connecticut 4831725 06520
Alfred I duPont Hospital for Children
Wilmington 4145381, Delaware 4142224 19803
Wilmington 4145381, Delaware 4142224 19803
Children's National Medical Center
Washington D.C. 4140963, District of Columbia 4138106 20010
Washington D.C. 4140963, District of Columbia 4138106 20010
Golisano Children's Hospital of Southwest Florida
Fort Myers 4155995, Florida 4155751 33908
Fort Myers 4155995, Florida 4155751 33908
UF Health Cancer Institute - Gainesville
Gainesville 4156404, Florida 4155751 32610
Gainesville 4156404, Florida 4155751 32610
Nemours Children's Clinic-Jacksonville
Jacksonville 4160021, Florida 4155751 32207
Jacksonville 4160021, Florida 4155751 32207
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami 4164138, Florida 4155751 33136
Miami 4164138, Florida 4155751 33136
Contact:
Site Public Contact
305-243-2647
Site Public Contact
305-243-2647
Nicklaus Children's Hospital
Miami 4164138, Florida 4155751 33155
Miami 4164138, Florida 4155751 33155
Contact:
Site Public Contact
888-624-2778
Site Public Contact
888-624-2778
Arnold Palmer Hospital for Children
Orlando 4167147, Florida 4155751 32806
Orlando 4167147, Florida 4155751 32806
Nemours Children's Hospital
Orlando 4167147, Florida 4155751 32827
Orlando 4167147, Florida 4155751 32827
Nemours Children's Clinic - Pensacola
Pensacola 4168228, Florida 4155751 32504
Pensacola 4168228, Florida 4155751 32504
Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa 4174757, Florida 4155751 33607
Tampa 4174757, Florida 4155751 33607
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta 4180439, Georgia 4197000 30329
Atlanta 4180439, Georgia 4197000 30329
Memorial Health University Medical Center
Savannah 4221552, Georgia 4197000 31404
Savannah 4221552, Georgia 4197000 31404
Lurie Children's Hospital-Chicago
Chicago 4887398, Illinois 4896861 60611
Chicago 4887398, Illinois 4896861 60611
Contact:
Site Public Contact
773-880-4562
Site Public Contact
773-880-4562
University of Chicago Comprehensive Cancer Center
Chicago 4887398, Illinois 4896861 60637
Chicago 4887398, Illinois 4896861 60637
Saint Jude Midwest Affiliate
Peoria 4905687, Illinois 4896861 61637
Peoria 4905687, Illinois 4896861 61637
Contact:
Site Public Contact
888-226-4343
Site Public Contact
888-226-4343
Riley Hospital for Children
Indianapolis 4259418, Indiana 4921868 46202
Indianapolis 4259418, Indiana 4921868 46202
Contact:
Site Public Contact
800-248-1199
Site Public Contact
800-248-1199
Blank Children's Hospital
Des Moines 4853828, Iowa 4862182 50309
Des Moines 4853828, Iowa 4862182 50309
University of Iowa/Holden Comprehensive Cancer Center
Iowa City 4862034, Iowa 4862182 52242
Iowa City 4862034, Iowa 4862182 52242
Contact:
Site Public Contact
800-237-1225
Site Public Contact
800-237-1225
University of Kentucky/Markey Cancer Center
Lexington 4297983, Kentucky 6254925 40536
Lexington 4297983, Kentucky 6254925 40536
Contact:
Site Public Contact
859-257-3379
Site Public Contact
859-257-3379
Children's Hospital New Orleans
New Orleans 4335045, Louisiana 4331987 70118
New Orleans 4335045, Louisiana 4331987 70118
Contact:
Site Public Contact
504-894-5377
Site Public Contact
504-894-5377
Ochsner Medical Center Jefferson
New Orleans 4335045, Louisiana 4331987 70121
New Orleans 4335045, Louisiana 4331987 70121
Sinai Hospital of Baltimore
Baltimore 4347778, Maryland 4361885 21215
Baltimore 4347778, Maryland 4361885 21215
Contact:
Site Public Contact
410-601-9083
Site Public Contact
410-601-9083
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
Grand Rapids 4994358, Michigan 5001836 49503
Grand Rapids 4994358, Michigan 5001836 49503
Bronson Methodist Hospital
Kalamazoo 4997787, Michigan 5001836 49007
Kalamazoo 4997787, Michigan 5001836 49007
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis 5037649, Minnesota 5037779 55404
Minneapolis 5037649, Minnesota 5037779 55404
University of Mississippi Medical Center
Jackson 4431410, Mississippi 4436296 39216
Jackson 4431410, Mississippi 4436296 39216
Contact:
Site Public Contact
601-815-6700
Site Public Contact
601-815-6700
Cardinal Glennon Children's Medical Center
St Louis 4407066, Missouri 4398678 63104
St Louis 4407066, Missouri 4398678 63104
Contact:
Site Public Contact
314-268-4000
Site Public Contact
314-268-4000
Washington University School of Medicine
St Louis 4407066, Missouri 4398678 63110
St Louis 4407066, Missouri 4398678 63110
Mercy Hospital Saint Louis
St Louis 4407066, Missouri 4398678 63141
St Louis 4407066, Missouri 4398678 63141
Contact:
Site Public Contact
314-251-7066
Site Public Contact
314-251-7066
Children's Hospital and Medical Center of Omaha
Omaha 5074472, Nebraska 5073708 68114
Omaha 5074472, Nebraska 5073708 68114
Contact:
Site Public Contact
402-955-3949
Site Public Contact
402-955-3949
University of Nebraska Medical Center
Omaha 5074472, Nebraska 5073708 68198
Omaha 5074472, Nebraska 5073708 68198
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
Las Vegas 5506956, Nevada 5509151 89135
Las Vegas 5506956, Nevada 5509151 89135
Summerlin Hospital Medical Center
Las Vegas 5506956, Nevada 5509151 89144
Las Vegas 5506956, Nevada 5509151 89144
Hackensack University Medical Center
Hackensack 5098706, New Jersey 5101760 07601
Hackensack 5098706, New Jersey 5101760 07601
Contact:
Site Public Contact
551-996-2897
Site Public Contact
551-996-2897
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
New Brunswick 5101717, New Jersey 5101760 08903
New Brunswick 5101717, New Jersey 5101760 08903
Contact:
Site Public Contact
732-235-8675
Site Public Contact
732-235-8675
Saint Joseph's Regional Medical Center
Paterson 5102466, New Jersey 5101760 07503
Paterson 5102466, New Jersey 5101760 07503
Albany Medical Center
Albany 5106834, New York 5128638 12208
Albany 5106834, New York 5128638 12208
Contact:
Site Public Contact
518-262-5513
Site Public Contact
518-262-5513
Maimonides Medical Center
Brooklyn 5110302, New York 5128638 11219
Brooklyn 5110302, New York 5128638 11219
Contact:
Site Public Contact
718-765-2500
Site Public Contact
718-765-2500
The Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park 5128514, New York 5128638 11040
New Hyde Park 5128514, New York 5128638 11040
Contact:
Site Public Contact
718-470-3460
Site Public Contact
718-470-3460
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York 5128581, New York 5128638 10016
New York 5128581, New York 5128638 10016
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York 5128581, New York 5128638 10032
New York 5128581, New York 5128638 10032
Memorial Sloan Kettering Cancer Center
New York 5128581, New York 5128638 10065
New York 5128581, New York 5128638 10065
Contact:
Site Public Contact
212-639-7592
Site Public Contact
212-639-7592
NYP/Weill Cornell Medical Center
New York 5128581, New York 5128638 10065
New York 5128581, New York 5128638 10065
Contact:
Site Public Contact
212-746-1848
Site Public Contact
212-746-1848
State University of New York Upstate Medical University
Syracuse 5140405, New York 5128638 13210
Syracuse 5140405, New York 5128638 13210
Contact:
Site Public Contact
315-464-5476
Site Public Contact
315-464-5476
Montefiore Medical Center - Moses Campus
The Bronx 5110266, New York 5128638 10467
The Bronx 5110266, New York 5128638 10467
New York Medical College
Valhalla 5142090, New York 5128638 10595
Valhalla 5142090, New York 5128638 10595
Contact:
Site Public Contact
914-594-3794
Site Public Contact
914-594-3794
Mission Hospital
Asheville 4453066, North Carolina 4482348 28801
Asheville 4453066, North Carolina 4482348 28801
Duke University Medical Center
Durham 4464368, North Carolina 4482348 27710
Durham 4464368, North Carolina 4482348 27710
Contact:
Site Public Contact
888-275-3853
Site Public Contact
888-275-3853
East Carolina University
Greenville 4469160, North Carolina 4482348 27834
Greenville 4469160, North Carolina 4482348 27834
Wake Forest University Health Sciences
Winston-Salem 4499612, North Carolina 4482348 27157
Winston-Salem 4499612, North Carolina 4482348 27157
Contact:
Site Public Contact
336-713-6771
Site Public Contact
336-713-6771
Rainbow Babies and Childrens Hospital
Cleveland 5150529, Ohio 5165418 44106
Cleveland 5150529, Ohio 5165418 44106
Contact:
Site Public Contact
216-844-5437
Site Public Contact
216-844-5437
Nationwide Children's Hospital
Columbus 4509177, Ohio 5165418 43205
Columbus 4509177, Ohio 5165418 43205
Dayton Children's Hospital
Dayton 4509884, Ohio 5165418 45404
Dayton 4509884, Ohio 5165418 45404
Contact:
Site Public Contact
800-228-4055
Site Public Contact
800-228-4055
University of Oklahoma Health Sciences Center
Oklahoma City 4544349, Oklahoma 4544379 73104
Oklahoma City 4544349, Oklahoma 4544379 73104
Oregon Health and Science University
Portland 5746545, Oregon 5744337 97239
Portland 5746545, Oregon 5744337 97239
Geisinger Medical Center
Danville 5186327, Pennsylvania 6254927 17822
Danville 5186327, Pennsylvania 6254927 17822
Children's Hospital of Philadelphia
Philadelphia 4560349, Pennsylvania 6254927 19104
Philadelphia 4560349, Pennsylvania 6254927 19104
Saint Christopher's Hospital for Children
Philadelphia 4560349, Pennsylvania 6254927 19134
Philadelphia 4560349, Pennsylvania 6254927 19134
Contact:
Site Public Contact
215-427-8991
Site Public Contact
215-427-8991
Children's Hospital of Pittsburgh of UPMC
Pittsburgh 5206379, Pennsylvania 6254927 15224
Pittsburgh 5206379, Pennsylvania 6254927 15224
Prisma Health Richland Hospital
Columbia 4575352, South Carolina 4597040 29203
Columbia 4575352, South Carolina 4597040 29203
BI-LO Charities Children's Cancer Center
Greenville 4580543, South Carolina 4597040 29605
Greenville 4580543, South Carolina 4597040 29605
East Tennessee Childrens Hospital
Knoxville 4634946, Tennessee 4662168 37916
Knoxville 4634946, Tennessee 4662168 37916
Contact:
Site Public Contact
865-541-8266
Site Public Contact
865-541-8266
The Children's Hospital at TriStar Centennial
Nashville 4644585, Tennessee 4662168 37203
Nashville 4644585, Tennessee 4662168 37203
Contact:
Site Public Contact
615-342-1919
Site Public Contact
615-342-1919
Vanderbilt University/Ingram Cancer Center
Nashville 4644585, Tennessee 4662168 37232
Nashville 4644585, Tennessee 4662168 37232
Contact:
Site Public Contact
800-811-8480
Site Public Contact
800-811-8480
Dell Children's Medical Center of Central Texas
Austin 4671654, Texas 4736286 78723
Austin 4671654, Texas 4736286 78723
UT Southwestern/Simmons Cancer Center-Dallas
Dallas 4684888, Texas 4736286 75390
Dallas 4684888, Texas 4736286 75390
El Paso Children's Hospital
El Paso 5520993, Texas 4736286 79905
El Paso 5520993, Texas 4736286 79905
M D Anderson Cancer Center
Houston 4699066, Texas 4736286 77030
Houston 4699066, Texas 4736286 77030
Children's Hospital of San Antonio
San Antonio 4726206, Texas 4736286 78207
San Antonio 4726206, Texas 4736286 78207
Methodist Children's Hospital of South Texas
San Antonio 4726206, Texas 4736286 78229
San Antonio 4726206, Texas 4736286 78229
University of Texas Health Science Center at San Antonio
San Antonio 4726206, Texas 4736286 78229
San Antonio 4726206, Texas 4736286 78229
Scott and White Memorial Hospital
Temple 4735966, Texas 4736286 76508
Temple 4735966, Texas 4736286 76508
Contact:
Site Public Contact
254-724-5407
Site Public Contact
254-724-5407
Primary Children's Hospital
Salt Lake City 5780993, Utah 5549030 84113
Salt Lake City 5780993, Utah 5549030 84113
Contact:
Site Public Contact
801-585-5270
Site Public Contact
801-585-5270
University of Virginia Cancer Center
Charlottesville 4752031, Virginia 6254928 22908
Charlottesville 4752031, Virginia 6254928 22908
Children's Hospital of The King's Daughters
Norfolk 4776222, Virginia 6254928 23507
Norfolk 4776222, Virginia 6254928 23507
VCU Massey Comprehensive Cancer Center
Richmond 4781708, Virginia 6254928 23298
Richmond 4781708, Virginia 6254928 23298
Seattle Children's Hospital
Seattle 5809844, Washington 5815135 98105
Seattle 5809844, Washington 5815135 98105
Contact:
Site Public Contact
866-987-2000
Site Public Contact
866-987-2000
Providence Sacred Heart Medical Center and Children's Hospital
Spokane 5811696, Washington 5815135 99204
Spokane 5811696, Washington 5815135 99204
West Virginia University Charleston Division
Charleston 4801859, West Virginia 4826850 25304
Charleston 4801859, West Virginia 4826850 25304
Contact:
Site Public Contact
304-388-9944
Site Public Contact
304-388-9944
Children's Hospital of Wisconsin
Milwaukee 5263045, Wisconsin 5279468 53226
Milwaukee 5263045, Wisconsin 5279468 53226
More Details
- NCT ID
- NCT05828069
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
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.