Inclusion Criteria:
1. Age 2-16 (inclusive)
2. Patients with histologically confirmed Langerhans cell histiocytosis (LCH) diagnosed
by the central laboratory.
3. If sufficient tumor tissue samples and peripheral blood samples are available, central
laboratory biomarker testing is required as follows: including but not limited to
ERBB3, BRAF, ARAF, HRAS, KRAS, NRAS, MEK (MAP2K1 and MAP2K2), and other MEK upstream
genes.If inability to get tissue, the gene testing results from a local laboratory
also can be accepted.
4. Patients who have received at least prior first-line systemic treatment, defined as
treatment including vinblastine (VBL) and glucocorticoids for at least 2 weeks. VBL
can be substituted with vincristine (VCR) or vindesine (VDS). Alternatively, patients
may be unable to tolerate chemotherapy due to severe chemotherapy toxicity. Inability
to tolerate chemotherapy is defined as one of the following: Severe liver impairment
(liver enzyme elevation ≥ 5 × upper limit of normal (ULN) and bilirubin elevation ≥
1.5 × ULN), severe neurotoxicity related to vinca alkaloids, chemotherapy-related
intracranial hypertension, or grade 4 bone marrow depression with severe infection
(sepsis, severe pneumonia, etc.) after chemotherapy.
5. Refractory/relapsed LCH is defined as the presence of one of the following:
1. Failure of prior treatment, i.e., no regression in risk organs after at least 2
weeks of systemic treatment, or overall evaluation of AD-progression or AD-mix;
2. Initial response of the disease to first or second-line systemic treatment is NAD
or AD-better or AD-stable, followed by disease reactivation after maintenance
therapy for more than 3 months. Second-line treatment includes cytarabine and/or
cladribine.
3. Persistent mutated gene positive in plasma free DNA testing during prior
treatment (confirmed by 2 consecutive tests) or retest positive after treatment
discontinuation;
4. Lack of regression in the affected central nervous system (including the
pituitary gland) after treatment;
5. Presence of bone marrow involvement and/or hemophagocytic lymphohistiocytosis
(HLH);
6. Presence of evaluable lesions based on PET response criteria (PRC).
7. Patients who have to have recovered from all acute toxic effects of prior anti-tumor
therapy, and all relevant toxicities must be ≤ grade 1 (except for alopecia and
ototoxicity).
8. Expected survival at least ≥ 3 months;
9. Lansky (≤ 15 years old) and Karnofsky (≥ 16 years old) performance status scores
should be ≥ 50%, as shown in Appendix 4.
10. Patients or their legal guardians must be able to understand and willingly sign a
written informed consent form.
11. For women of childbearing potential, a serum human chorionic gonadotropin (HCG)
pregnancy test must be negative within 7 days before starting treatment.
12. For female patients of childbearing potential: Patients should agree to use effective
contraception methods during the treatment period and for at least 90 days after the
last dose of study treatment, using dual barrier contraception methods such as
condoms, oral or injectable contraceptives, intra-uterine contraceptive devices, etc.
Male patients should agree to refrain from donating sperm for at least 90 days after
the last dose of study treatment.
13. Adequate bone marrow function: Absolute neutrophil count ≥ 1.0×10^9/L, hemoglobin ≥
90g/L, and platelets ≥ 75×10^9/L without the use of blood transfusions, blood
products, or granulocyte colony-stimulating factors. Patients with hematocytopenia
below these thresholds due to the underlying disease may be considered for inclusion
based on the investigator's comprehensive judgment.
14. Adequate hepatic and renal function: Serum total bilirubin ≤ 1.5 × the upper limit of
normal (ULN), or ≤ 5× ULN for patients with Gilbert's syndrome or liver involvement;
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (AKP) ≤ 2.5 × ULN, or ≤ 10 × ULN for patients with liver involvement;
albumin ≥ 3g/dL; and creatinine clearance or isotopic glomerular filtration rate (GFR)
≥ 50ml/min/1.73㎡or serum creatinine based on age; hepatic and renal impairment caused
by the primary disease may be considered for inclusion based on the investigator's
comprehensive judgment.
15. Coagulation: International normalized ratio (INR) and activated partial thromboplastin
time (APTT) ≤ 1.5 ULN.
Exclusion Criteria:
1. Patients who have received any of the following prior treatments:
1. Chemotherapy, targeted therapy, immunotherapy, biologic therapy, or herbal
anti-tumor therapy for LCH within 4 weeks or < 5 half-lives (whichever is
shorter)before the start of the study drug .
2. Strong CYP3A4, CYP2C8, and CYP2C9 inhibitors or inducers within 14 days before
the start of the study drug, except for topical skin application.
3. Gowth factors that promote platelet or white blood cell count or function within
7 days before the start of the study drug.
4. Radiotherapy or major surgical treatment (including craniotomy, thoracotomy,
laparotomy, open bone or joint surgery, etc.) within 4 weeks before the start of
the study drug.
5. Participated in other interventional clinical trials within 4 weeks before the
start of the study drug.
6. MEK 1/2 inhibitors (those who have received this treatment for a short period of
≤ 2 weeks may be included).
7. Anticoagulants within 7 days before the start of the study drug for patients with
brain tumors (intracranial masses).
8. Prednisone treatment < 0.5mg/kg/day (or equivalent dose of other corticosteroids)
is allowed within one month before enrollment, but must be discontinued 14 days
before the start of the study drug. Patients with brain lesions receiving
corticosteroid therapy for brain edema must maintain a stable dose for 14 days
before enrollment. Hormone replacement therapy is allowed for patients with
hypopituitarism due to primary disease involvement of the pituitary.
2. Patients with a history of other malignant tumors or concurrent other malignant tumors
(excluding cured non-melanoma skin basal cell carcinoma, ductal carcinoma in situ of
the breast, or cervical carcinoma in situ).
3. Uncontrolled hypertension (with medication treatment): Blood pressure (BP) greater
than or equal to the 95th percentile for age, height, and sex, as described in
Appendix 6.
4. Patients with dysphagia, active gastrointestinal disease, malabsorption syndrome, or
other conditions that may affect the absorption of the study drug.
5. Prior or current history of retinal vein obstruction (RVO), retinal pigment epithelial
detachment (RPED), glaucoma, and other clinically significant abnormal ophthalmologic
examination results.
6. Interstitial pneumonia, including clinically significant radiation pneumonitis. Except
for interstitial pneumonia caused by pulmonary involvement of the primary disease.
7. Patients will be excluded if their cardiac function or comorbidities meet any of the
following criteria:
1. During the screening period, 12-lead electrocardiogram (ECG) measurements will be
taken three times at the study center with a mean value calculated using the QTcF
formula provided by the instrument; patients with a mean value of QTcF > 470
milliseconds or with risk factors for QTcF prolongation, such as uncorrected
hypokalemia, congenital long QT syndrome, or receiving drugs known to prolong
QTcF interval (mainly class Ia, Ic, and III antiarrhythmic drugs) will be
excluded from the study. Drugs with the potential to prolong the QTcF interval
are listed in Appendix 7.
2. New York Heart Association (NYHA) Class 2 and above congestive heart failure as
shown in Appendix 5.
3. Clinically significant arrhythmias, including but not limited to complete left
bundle branch block, and second-degree atrioventricular block.
4. Known presence of clinically significant coronary heart disease, cardiomyopathy,
or severe valvular disease.
5. Echocardiography examination indicating left ventricular ejection fraction (LVEF)
< 50%.
8. Patients with active bacterial, fungal, or viral infections, including active
hepatitis B (defined as positive hepatitis B surface antigen and hepatitis B virus DNA
> 1000IU/ml or meeting the diagnostic criteria for active hepatitis B infection at the
study center) or hepatitis C (positive hepatitis C virus RNA), or human
immunodeficiency virus (HIV positive) infection.
9. Patients with known allergies to the study drug, other MEK1/2 inhibitors, or their
excipients.
10. Patients with known tumor tissue genetic testing that indicates the presence of MAP2K1
exon 3 deletions (del) or deletion-insertion type (delins/indels) mutations.
11. The investigator considers clinically significant cases that will impede participation
in the study or prevent compliance with safety requirements.
