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.
180 days- < 22 years (at time of study enrollment)
Patient must have a body surface area of ≥ 0.3 m²
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
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)
Sequential
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood and urine samples
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Computed Tomography
Procedure/SurgeryUndergo CT
Echocardiography Test
Procedure/SurgeryUndergo ECHO
FDG-Positron Emission Tomography and Computed Tomography Scan
Procedure/SurgeryUndergo FDG-PET imaging
Lumbar Puncture
Procedure/SurgeryUndergo lumbar puncture
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Tovorafenib
DrugGiven PO
Frequency of dose limiting toxicity (dose finding phase)
Will be analyzed descriptively.
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.
Event free survival rate
Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated two years after enrollment of the last patient on the trial and estimates at specific timepoints will be presented along with log-log transformed 95% confidence intervals. Events are defined as relapse/progression, second malignant neoplasm, or death.
Progression free survival rate
Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated by two years after enrollment of the last patient on the trial and estimates at specific timepoints will be presented along with log-log transformed 95% confidence intervals.
Duration of response rate
Response is based on modified Response Evaluation Criteria for Solid Tumors (RECIST)/Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) consistent with other recent pediatric Langerhans Cell Histiocytosis trials (NCT02670707 and NCT04079179) and adult histiocytosis trials with MAPK inhibitors. Comparison of response assessed via RECIST versus (vs.) PERCIST will be analyzed by displaying two-way tables of the responses with no formal statistical testing.
Overall survival rate
Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated two years after enrollment of the last patient on the trial and estimates at specific timepoints will be presented along with log-log transformed 95% confidence intervals.
Percent peripheral blood mononuclear cells with mutated allele
Will be analyzed descriptively using logistic regression with complete response/progressive response vs. stable disease/progressive disease as the response variable.
Click on the lead sponsor to view all of their trials.