Sponsor R&D strategy adjustment

Melanoma is one of the most common cutaneous cancers worldwide. Activating mutations in RAS oncogenes are found in a third of all human cancers and NRAS mutations are found in 15%-20% of melanomas. Acquisition of a functional mutation in NRAS results in activation of the Ras / Raf / MEK / ERK signaling pathway leading to unconstrained cell growth and cell transformation. NRAS mutation status was identified as an independent poor prognostic factor in stage IV melanoma. No drug was approved to treat melanoma patients with NRAS mutation or amplification until now. FCN-159, an oral and potent MEK1/2 inhibitor, has more than 10 folds higher selectivity against activated MEK1 and MEK2 compared with trametinib, and has demonstrated significant antitumor growth inhibition in two patient-derived xenograft (PDX) models with NRAS mutation. Approximately 10%-15% of melanomas is reported to be NF1-mutant. NF1 gene is located in chromosome 17 q11.2 and encodes neurofibromin 1. Neurofibromin 1 is a RAS-specific GTP enzyme-activated protein that converts RAS from the active guanosine triphosphate (GTP) binding state to the inactivated guanosine diphosphate (GDP) binding state and acts as a negative regulatory factor for RAS and its downstream MAPK and PI3K-Akt pathways. Recent treatments of NF1 mutation focus on the downstream of the MAPK pathway, such as MEK kinase. Blocking the MEK kinase can reduce neurofibroma in mice with NF1 mutation and prolong the survival time of mice with malignant peripheral nerve sheath tumor (MPNST) xenograft. In the NF1 mutant monocytic leukemia mouse model, the use of MEK inhibitors can improve mouse survival rate. This is the first in human study to evaluate the safety and anti-tumor activity in patients.

This is a phase Ia/Ib, open label, dose-escalation and dose-expansion study that will evaluate the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of FCN-159 in up to 85 patients with NRAS-aberrant including both NRAS amplification and mutation (Ia) and NRAS-mutation (Ib) or NF-1 mutation (Ib) in local advanced or metastatic melanoma. In this study, the dose escalation phase utilizes accelerated titration design (switch to 3+3 mode once a grade≥2 AE is reported) with starting dose of 0.2 mg, QD, orally, and the dose will be escalated up to Maximum-Tolerated Dose (MTD) or until the Recommended Phase 2 dose (RP2D) is identified. The dose level will be considered to expand up to 6 patients if the objective response is observed, intends to collect more clinical data to support the RP2D determination. After the MTD or RP2D dose is identified, dose expansion stage (Phase Ib) is conducted to further evaluate the safety and efficacy of FCN-159 in patients with NRAS-mutant (Cohort 1) or NF1-mutant melanoma (Cohort 2).

Inclusion Criteria:

1. Male and female, 18-70 years old (Ia); 18 years old and above (Ia expansion part & phase Ib);
2. Histologically or cytologically diagnosed advanced melanoma who cannot be surgically resected, stage III or IV, and have failed or rejected standard treatment;
3. Written report of NRAS aberrant (Ia) or NRAS mutation (Ib) or NF1 mutation (Ib);
4. ECOG 0 or 1;
5. Expected survival of at least 12 weeks;
6. Adequate organ functions;
7. At least one measurable lesion per RECIST v1.1 criteria.
8. Able to understand and sign consent form.
9. For female patients or partners with fertility: maintain abstinence.

Exclusion Criteria:

1. Radiotherapy, major surgery, mono-clone antibody targeted therapy, immunotherapy or other treatment within 4 weeks prior to enrollment.
2. Chemotherapy and small molecule targeted therapy within 2 weeks of enrollment.
3. Participated in other clinical trials within 4 weeks prior to enrollment or 5 T1/2;
4. Previous usage of MEK inhibitor;
5. Uncontrolled central nervous system metastasis or injury.
6. Unrecovered >grade 2 AE caused by previous anti-tumor therapy;
7. Strong inhibitors/inducers of CYP3A4, CYP2C8 or CYP2C9 within 14 days prior to the start of dosing.
8. Taking drugs that prolong QTc interval;
9. Dysphagia, or active digestive system disease, or malabsorption syndrome, or other conditions affecting FCN-159 absorption.
10. Previous or current retinal vein stenosis, retinal detachment, central retinal vein occlusion, glaucoma.
11. Interstitial pneumonia, including clinically significant radiationpneumonitis.
12. Insufficient cardiac function or disease;
13. Pregnant or lactating woman.
14. Known to be allergic to any excipients of FCN-159.
15. Clinically active infections;
16. Significant active disease that in the investigator's opinion would adversely impact on his/her participation in the study.