Evaluating FCN-159 for treating pediatric patients with recurrent LCH

A Multi-center, Open-label, Single Arm Phase 2 Study to Evaluate the Efficacy, Safety, and Pharmacokinetic Characteristics of FCN-159 in Pediatric Patients With Refractory/Recurrent Langerhans Cell Histiocytosis

This study is testing a new medication called FCN-159 to see if it can help children aged 2 to 16 with recurring Langerhans cell histiocytosis feel better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 56 (estimated)
• Ages: 2 Years to 16 Years
• Sex: All
• Sponsor: Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. (Industry-sponsored)
• Drugs / interventions: chemotherapy, immunotherapy, radiation, Prednisone
• Locations: 11 sites (Beijing, Beijing Municipality and 10 other locations)
• Trial ID: NCT05997602 on ClinicalTrials.gov

What this trial studies

This clinical trial is a Phase 2, single-arm, open-label study aimed at assessing the efficacy, safety, and pharmacokinetics of FCN-159 in pediatric patients aged 2 to 16 with refractory or recurrent Langerhans cell histiocytosis (LCH). Approximately 56 participants will receive FCN-159 orally once daily for 28 days per treatment cycle, with evaluations conducted until disease progression or other specified reasons for discontinuation. The study will include tumor assessments based on established criteria and will involve both investigator and independent review committee evaluations.

Who should consider this trial

Good fit: Ideal candidates are pediatric patients aged 2 to 16 with histologically confirmed LCH who have previously received first-line systemic treatment.

Not a fit: Patients who have not been diagnosed with LCH or those who have not received prior systemic treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for children suffering from refractory or recurrent LCH.

How similar studies have performed: While this approach is focused on a rare disease, similar studies targeting LCH have shown promise, indicating potential for success.

Eligibility criteria

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.

Where this trial is running

Beijing, Beijing Municipality and 10 other locations

• Beijing Children's Hospital, Capital Medical University — Beijing, Beijing Municipality, China (Recruiting)
• Children's Hospital Affiliated to the Capital Institute of Pediatrics — Beijing, Beijing Municipality, China (Not_yet_recruiting)
• Children's Hospital of Chongqing Medical University — Chongqing, Chongqing Municipality, China (Recruiting)
• Sun Yat-Sen Memorial Hpsipital,Sun Yat-Sen Unniversity — Guangzhou, Guangdong, China (Not_yet_recruiting)
• The First Affiliated Hospital,Sun Yat-sen University — Guangzhou, Guangdong, China (Not_yet_recruiting)
• Shenzhen Children's Hospital — Shenzhen, Guangdong, China (Not_yet_recruiting)
• Henan Children's Hospital Zhengzhou Children's Hospital — Zhengzhou, Henan, China (Not_yet_recruiting)
• Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology — Wuhan, Hubei, China (Not_yet_recruiting)
• West China Second University Hospital,Sihuan University/West China women's and Children's Hospital — Chengdu, Sichuan, China (Not_yet_recruiting)
• Children's Hospital, Zhejiang University School of Medicine — Hangzhou, Zhejiang, China (Not_yet_recruiting)
• Children's Hospital of Soochow University — Suzhou, China (Not_yet_recruiting)

Study contacts

• Principal investigator: Rui Zhang, MD — Beijing Children's Hospital,Captial Medical University
• Study coordinator: Rui Zhang, MD

Conditions Langerhans Cell Histiocytosis; LCH