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

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Description

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.

Study Overview

Start Date
April 1, 2024
Completion Date
May 29, 2025
Enrollment
29
Date Posted
April 25, 2023
Accepts Healthy Volunteers?
No
Gender
All

Locations

Full Address
Children's Hospital of Alabama
Birmingham, Alabama 35233, United States

Kaiser Permanente Downey Medical Center
Downey, California 90242, United States

Loma Linda University Medical Center
Loma Linda, California 92354, 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

UCSF Medical Center-Mission Bay
San Francisco, California 94158, 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

Alfred I duPont Hospital for Children
Wilmington, Delaware 19803, United States

Golisano Children's Hospital of Southwest Florida
Fort Myers, Florida 33908, United States

University of Florida Health Science Center - Gainesville
Gainesville, Florida 32610, United States

Nemours Children's Clinic-Jacksonville
Jacksonville, Florida 32207, United States

Nicklaus Children's Hospital
Miami, Florida 33155, United States

Saint Joseph's Hospital/Children's Hospital-Tampa
Tampa, Florida 33607, United States

Riley Hospital for Children
Indianapolis, Indiana 46202, 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

Michigan State University Clinical Center
East Lansing, Michigan 48824, United States

Helen DeVos Children's Hospital at Spectrum Health
Grand Rapids, Michigan 49503, United States

University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota 55455, United States

Washington University School of Medicine
Saint Louis, Missouri 63110, United States

Mercy Hospital Saint Louis
Saint Louis, Missouri 63141, 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

Saint Joseph's Regional Medical Center
Paterson, New Jersey 07503, United States

Albany Medical Center
Albany, New York 12208, United States

Montefiore Medical Center - Moses Campus
Bronx, New York 10467, United States

Maimonides Medical Center
Brooklyn, New York 11219, United States

New York Medical College
Valhalla, New York 10595, United States

East Carolina University
Greenville, North Carolina 27834, United States

Wake Forest University Health Sciences
Winston-Salem, North Carolina 27157, 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

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

Dell Children's Medical Center of Central Texas
Austin, Texas 78723, 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

University of Texas Health Science Center at San Antonio
San Antonio, Texas 78229, United States

Primary Children's Hospital
Salt Lake City, Utah 84113, United States

Children's Hospital of The King's Daughters
Norfolk, Virginia 23507, 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

Eligibility

Minimum Age (years)
0.493
Maximum Age (years)
22
Eligibility Criteria
Inclusion Criteria:

180 days- < 22 years (at time of study enrollment)

Patients with multifocal 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 (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary)

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, documented by radiographic imaging (LCH- specific response criteria (must be obtained within 28 days prior to enrollment and start of protocol therapy) (repeat if necessary).
Patients must have progressive or refractory disease or experience relapse after at least one previous systemic chemotherapy 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 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, 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 but must be discontinued fourteen (14) days prior to study enrollment. Patients with documented brain lesions receiving corticosteroids for management of cerebral edema must be on a stable dose for fourteen (14) days prior to study enrollment
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/gender 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)
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

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
Single bone lesion
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
Patient must not have received any prior MAPK pathway inhibitor therapy
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. Participants (male and female) who are sexually active must use two forms of an acceptable method of birth control (for men, one form must be a barrier method) from start of therapy through 180 days following last dose of tovorafenib (DAY101)

Study Contact Info

Study Contact Name
Site Public Contact; Matthew A. Kutny; Robert M. Cooper; Albert Kheradpour; Karen S. Fernandez; Jennifer G. Michlitsch; Aarati V. Rao; Elyssa M. Rubin; Michelle L. Hermiston; Jennifer J. Clark; Michael S. Isakoff; Ramamoorthy Nagasubramanian; Emad K. Salman; William B. Slayton; Maggie E. Fader; Don E. Eslin; Anthony Ross; David S. Dickens; James T. Badgett; Laura E. Agresta; Kathleen J. Yost; Lucie M. Turcotte; Bryan A. Sisk; Robin D. Hanson; Alan K. Ikeda; Katharine Offer; Alissa Kahn; Lauren R. Weintraub; Alice Lee; Mahmut Y. Celiker; Jessica C. Hochberg; Andrea R. Whitfield; Thomas W. McLean; Mark A. Ranalli; Mukund G. Dole; Rene Y. McNall-Knapp; Katrina Winsnes; Michael D. Hogarty; Gregory E. Halligan; Andrew Bukowinski; Stuart L. Cramer; Aniket Saha; Shannon M. Cohn; Olive S. Eckstein; Najat C. Daw; Timothy C. Griffin; Anne-Marie R. Langevin; Taumoha Ghosh; Eric J. Lowe; Sarah E. Leary; Judy L. Felgenhauer

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A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis 0 reviews

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Other Details

FDA Regulated Drug?
Yes
FDA Regulated Device?
No
Detailed Description
PRIMARY OBJECTIVE:

I. To determine overall response rate (ORR) for children and young adults with relapsed or refractory 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).

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 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 and then every 3, 6, 9, and 12 months.
NCTid (if applicable)
NCT05828069