MEK Inhibitor FCN-159 To Treat Advanced Melanoma With NRAS-aberrant (Ia) and NRAS-mutant (Ib)

Study Overview
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Brief Summary
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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.This is the first in human study to evaluate the safety and anti-tumor activity in patients.

Detailed Description
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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 37 patients with NRAS-aberrant including both NRAS amplification and mutation (Ia) and NRAS-mutation only (Ib) in local advanced or metastatic melanoma. In this study, the dose escalation phase utilizes 3+3, accelerated titration design 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. Once the MTD or RP2D dose is identified, an expansion cohort will be followed to further evaluate the safety and efficacy of FCN-159 in patients with NRAS-mutation melanoma.

Official Title
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A Phase Ia/Ib Clinical Study to Evaluate the Safety, Pharmacokinetics (PK) and Preliminary Anti-tumor Activity of FCN-159 in Patients With Advanced Melanoma Harboring NRAS-aberrant (Ia) and NRAS-mutant (Ib)

Conditions
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Melanoma

Intervention / Treatment
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* Drug: FCN-159


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female, 18-70 years old (phase Ia); 18 years old and above (phase 1a expansion part & phase Ib). According to the American Joint Committee on Cancer (AJCC) criteria (version 2010), the patients with histologically or cytologically diagnosed advanced melanoma who cannot be surgically resected, stage III or IV, and have failed or rejected standard treatment. Patients in the dose-escalation stage (Ia) must provide NRAS aberrant written report prior to enrollment and agree to provide sufficient paraffin sections or fresh tissue specimens to be sent to the central laboratory for confirmation prior to registration. Patients in the dose- expansion phase (Ib) must provide a report of the NRAS mutation prior to enrollment and agree to provide sufficient paraffin sections or fresh tissue specimens to be confirmed by the central laboratory. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. Expected survival of at least 12 weeks. Patients must have adequate organ functions as indicated by the following screening laboratory values: Serum total bilirubin ≤ 1.5 × upper limit normal (ULN) (Serum total bilirubin can be ≤ 3.0 × ULN if patients have hemolysis or congenital hemolytic diseases); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN or 5 X ULN for patient with liver metastases; Albumin ≥ 3g/dL; Creatinine < 1.5 × ULN; Absolute neutrophil count (ANC) ≥ 1.5×10^9/L; Platelets ≥ 100×10^9/L; Hemoglobin ≥ 90 g/L (Note: Criteria must be met without a transfusion within 2 weeks of obtaining the sample). Patients with diagnosed melanoma must have at least one lesion that is measurable per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Able to understand and sign consent form. For female patients or partners with fertility: agree to maintain abstinence (no heterosexual intercourse), or use a contraceptive method with a failure rate of <1% per year during treatment and at least 30 days after the last dose of study treatment, and agree to avoid sperm donation. Exclusion Criteria: Participation in another therapeutic clinical trial within 4 weeks of enrollment. Having received chemotherapy, radiotherapy, major surgery, targeted therapy, immunotherapy or other treatment within 4 weeks of enrollment. Uncontrolled central nervous system metastasis or injury. The toxicity of previous anti-tumor therapy has not been restored (> grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, except for alopecia; the neurotoxicity of patients who have received chemotherapy before needs to be restored to NCI-CTCAE 5.0 grade 2 or below; Grade 3 bleeding specified in NCI-CTCAE 5.0 occurred within 4 weeks prior to first dose. On medications that are strong cytochrome P450(CYP3A) inhibitors within 14 days prior to the start of dosing. Taking drugs that prolong the value of QTc interval. Dysphagia, or active digestive system disease, or malabsorption syndrome, or other conditions affecting FCN-159 absorption. Previous or current retinal vein stenosis, retinal detachment, central retinal vein occlusion, glaucoma. Interstitial pneumonia, including clinically significant radiation pneumonitis. Cardiac function and disease meet one of the following conditions: During the screening period, electrocardiogram (ECG) measurements are performed at the research center, and the average values are calculated according to the QTc formula of the instrument, QTc > 470 milliseconds; New York Heart Association (NYHA) graded ≥ 3 congestive heart failure; Clinically significant arrhythmias, including but not limited to complete left bundle branch conduction abnormalities, 2 degree atrioventricular block. Pregnant or lactating woman. It is known to be allergic to any excipients of FCN-159. Clinically active bacterial, fungal or viral infections, including hepatitis B (hepatitis B virus surface antigen positive and hepatitis B virus DNA over 1000 IU/ml) or hepatitis C (hepatitis C virus RNA positive), human immunodeficiency virus infection (HIV positive). Significant active disease that in the investigator's opinion would adversely impact on his/her participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FCN-159<br>Preset 6 dose groups during the dose-escalation phase, 0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, and 6 mg, orally, continuous once a day for 21 days, followed by a 7-day break, 28 days is a cycle. | Drug: FCN-159<br>* Administered orally once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events (AEs) | All subjects , assessment according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. | During the first two years. | 
| Maximum Tolerated Dose (MTD) | To assess safety and tolerability of FCN-159 with a maximum tolerated dose (MTD) in patients with advanced melonoma. | During the first year. | 
| Objective response rate（ORR) | The proportion of confirmed complete response (CR) or partial response (PR) patients evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. | During the first year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The measurement of maximum plasma concentration (Cmax) |  | The first 35 days | 
| The measurement of the area under the plasma concentration-time versus time curve(AUC) |  | The first 35 days | 
| The measurement of elimination half life (T1/2) |  | The first 35 days | 
| The measurement of clearance (Cl) |  | The first 35 days |