| 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 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 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 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 DAY101 and planned to be administered 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) =< 5 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 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 on NON-enzyme inducing
anticonvulsants and 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
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 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 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 DAY101
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