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

Recurrent Langerhans Cell Histiocytosis Clinical Trial

Official title:

Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05828069
• Other study ID #: NCI-2022-06282
• Secondary ID: NCI-2022-06282AN
• Status: Recruiting
• Phase: Phase 2
• Start date: March 28, 2024
• Est. completion date: May 29, 2025

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT05287295

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 29
• Est. completion date: May 29, 2025
• Est. primary completion date: May 29, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 180 Days to 22 Years

Eligibility

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)

Related Conditions & MeSH terms

• Histiocytosis
• Histiocytosis, Langerhans-Cell
• Recurrent Langerhans Cell Histiocytosis
• Refractory Langerhans Cell Histiocytosis

Intervention

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Bone Marrow Aspiration
Undergo bone marrow aspiration
• Bone Marrow Biopsy
Undergo bone marrow biopsy
• Computed Tomography
Undergo CT
• Echocardiography
Undergo ECHO
• FDG-Positron Emission Tomography and Computed Tomography Scan
Undergo FDG-PET imaging
• Lumbar Puncture
Undergo lumbar puncture
• Multigated Acquisition Scan
Undergo MUGA

Drug:
• Tovorafenib
Given PO

Locations

Country	Name	City	State
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Albany Medical Center	Albany	New York
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Maimonides Medical Center	Brooklyn	New York
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	El Paso Children's Hospital	El Paso	Texas
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Valley Children's Hospital	Madera	California
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Nemours Children's Hospital	Orlando	Florida
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	New York Medical College	Valhalla	New York
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent peripheral blood mononuclear cells (PBMC) with mutated allele	Will be analyzed descriptively using logistic regression with complete response (CR)/progressive response (PR) vs. stable disease (SD)/progressive disease (PD) as the response variable	Up to 2 years
Primary	Frequency of dose limiting toxicity (DLT) (dose finding phase)	Will be analyzed descriptively.	Up to 28 days
Primary	Overall response rate (ORR) (phase II)	The 95% confidence interval for the overall response rate will be adjusted for the two-stage design.	After 2 cycles of therapy (each cycle is 28 days)
Secondary	Event free survival rate (EFS)	Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated using the Log-rank test 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 (SMN), or death.	At 1 and 2 years
Secondary	Progression free survival rate (PFS)	Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated by using the Log-rank test 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.	Up to 2 years
Secondary	Duration of response rate	Response is based on modified RECIST/PERCIST consistent with other recent pediatric LCH trials (NCT02670707 and NCT04079179) and adult histiocytosis trials with MAPK inhibitors. Comparison of response assessed via RECIST vs PERCIST will be analyzed by displaying two-way tables of the responses with no formal statistical testing.	After 12 months of therapy. From the scan confirming the complete response or partial response (whichever is recorded first), until the first occurrence of recurrent or progressive disease or death (event) or last known status on trial
Secondary	Overall survival rate (OS)	Will be estimated by the Kaplan-Meier method beginning at study enrollment. Will be evaluated using the Log-rank test 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.	Up to 2 years