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NCT05828069PHASE2Recruiting

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

National Cancer Institute (NCI)

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

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

Interventions

PROCEDURE

Biospecimen Collection

PROCEDURE

Bone Marrow Aspiration

PROCEDURE

Bone Marrow Biopsy

PROCEDURE

Computed Tomography

PROCEDURE

Echocardiography Test

PROCEDURE

FDG-Positron Emission Tomography and Computed Tomography Scan

PROCEDURE

Lumbar Puncture

PROCEDURE

Multigated Acquisition Scan

DRUG

Tovorafenib

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Conditions

Recurrent Langerhans Cell HistiocytosisRefractory Langerhans Cell Histiocytosis

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