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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05828069




Registration number
NCT05828069
Ethics application status
Date submitted
21/04/2023
Date registered
25/04/2023

Titles & IDs
Public title
A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis
Scientific title
Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis
Secondary ID [1] 0 0
NCI-2022-06282
Secondary ID [2] 0 0
NCI-2022-06282
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent Langerhans Cell Histiocytosis 0 0
Refractory Langerhans Cell Histiocytosis 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Surgery - Biospecimen Collection
Treatment: Surgery - Bone Marrow Aspiration
Treatment: Surgery - Bone Marrow Biopsy
Treatment: Surgery - Computed Tomography
Treatment: Surgery - Echocardiography Test
Treatment: Surgery - FDG-Positron Emission Tomography and Computed Tomography Scan
Treatment: Surgery - Lumbar Puncture
Treatment: Surgery - Multigated Acquisition Scan
Treatment: Drugs - Tovorafenib

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 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.


Treatment: Surgery: Biospecimen Collection
Undergo collection of blood samples

Treatment: Surgery: Bone Marrow Aspiration
Undergo bone marrow aspiration

Treatment: Surgery: Bone Marrow Biopsy
Undergo bone marrow biopsy

Treatment: Surgery: Computed Tomography
Undergo CT

Treatment: Surgery: Echocardiography Test
Undergo ECHO

Treatment: Surgery: FDG-Positron Emission Tomography and Computed Tomography Scan
Undergo FDG-PET imaging

Treatment: Surgery: Lumbar Puncture
Undergo lumbar puncture

Treatment: Surgery: Multigated Acquisition Scan
Undergo MUGA

Treatment: Drugs: Tovorafenib
Given PO
Intervention code [1] 0 0
Treatment: Surgery
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Frequency of dose limiting toxicity (DLT) (dose finding phase)
Timepoint [1] 0 0
Up to 28 days
Primary outcome [2] 0 0
Overall response rate (ORR) (phase II)
Timepoint [2] 0 0
After 2 cycles of therapy (each cycle is 28 days)
Secondary outcome [1] 0 0
Event free survival rate (EFS)
Timepoint [1] 0 0
At 1 and 2 years
Secondary outcome [2] 0 0
Progression free survival rate (PFS)
Timepoint [2] 0 0
Up to 2 years
Secondary outcome [3] 0 0
Duration of response rate
Timepoint [3] 0 0
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 outcome [4] 0 0
Overall survival rate (OS)
Timepoint [4] 0 0
Up to 2 years

Eligibility
Key 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 (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 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/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
Minimum age
180 Days
Maximum age
22 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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. 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 design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Suspended
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/03/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/09/2028
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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United States of America
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Arkansas
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United States of America
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California
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United States of America
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Colorado
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Connecticut
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United States of America
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Delaware
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United States of America
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District of Columbia
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Florida
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Georgia
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Illinois
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Indiana
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Iowa
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Kentucky
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Louisiana
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Maryland
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Michigan
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Minnesota
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Mississippi
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Missouri
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Nebraska
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Nevada
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New Jersey
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New York
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North Carolina
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Ohio
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Oklahoma
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Oregon
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Pennsylvania
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South Carolina
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Tennessee
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Texas
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Utah
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Virginia
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Washington
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West Virginia
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Canada
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Alberta
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Canada
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Nova Scotia
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Canada
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Ontario
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Canada
State/province [39] 0 0
Quebec

Funding & Sponsors
Primary sponsor type
Government body
Name
National Cancer Institute (NCI)
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Michelle L Hermiston
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05828069