MEK Inhibitor FCN-159 To Treat Advanced Melanoma With NRAS-aberrant (Ia) and NRAS-mutant (Ib)or NF1-mutant(1b)

A Single-arm Phase Ia/Ib Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Patients With Advanced Melanoma Harboring NRAS Aberration(Ia)and NRAS/NF1 Mutation(Ib)

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.

Study Overview

• Status: Suspended
• Conditions: Melanoma
• Intervention / Treatment: Other: FCN-159

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1a：0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg，8mg, 12mg, 15mg.1b(NRAS),1b(NF1); 1a dose-escalation phase: 9 dose groups during the dose-escalation phase, 0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg,8mg, 12mg and 15mg orally, continuous once a day for 28 days a cycle. 1b dose-extension phase: 12mg orally,continuous once a day for 28 days a cycle.	Other: FCN-159; Administered orally once a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	To assess safety and tolerability of FCN-159 with a maximum tolerated dose (MTD) in patients with advanced melonoma.	1 month.
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. in patients with unresectable stage III or IV melanoma with NRAS mutation or NF1 mutation.	through study completion, an average of 1 year.

Secondary 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.	through study completion, an average of 1 year.
PFS in months	To assess the efficacy of FCN-159 monotherapy in patients with unresectable stage III or IV melanoma with NRAS mutation or NF1 mutation.	through study completion, an average of 1 year.
OS in months	To assess the efficacy of FCN-159 monotherapy in patients with unresectable stage III or IV melanoma with NRAS mutation or NF1 mutation.	through study completion, an average of 1 year.
1-year OS rate(%)	To assess the efficacy of FCN-159 monotherapy in patients with unresectable stage III or IV melanoma with NRAS mutation or NF1 mutation.	through study completion, an average of 1 year.
DoR in months	To assess the efficacy of FCN-159 monotherapy in patients with unresectable stage III or IV melanoma with NRAS mutation or NF1 mutation.	through study completion, an average of 1 year.
CBR in months	To assess the efficacy of FCN-159 monotherapy in patients with unresectable stage III or IV melanoma with NRAS mutation or NF1 mutation.	through study completion, an average of 1 year.
AUC(0-last)	Pharmacokinetics of FCN-159	1 month.
AUC(0-∞)	Pharmacokinetics of FCN-159	1 month.
Cmax	Pharmacokinetics of FCN-159	1 month.
Tmax	Pharmacokinetics of FCN-159	1 month.
t1/2	Pharmacokinetics of FCN-159	1 month.
CL/F	Pharmacokinetics of FCN-159	1 month.
RAUC	Pharmacokinetics of FCN-159	1 month.
RCmax	Pharmacokinetics of FCN-159	1 month.

Collaborators and Investigators

• Sponsor: Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.

Publications and helpful links

General Publications

• Mao L, Guo J, Zhu L, Jiang Y, Yan W, Zhang J, Hui AM, Yang Y, Diao L, Tan Y, Zhao H, Jiang Y, Wu Z, Si L. A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma. Eur J Cancer. 2022 Nov;175:125-135. doi: 10.1016/j.ejca.2022.08.005. Epub 2022 Sep 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2019
• Primary Completion (Actual): April 30, 2023
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: April 25, 2019
• First Submitted That Met QC Criteria: April 28, 2019
• First Posted (Actual): April 30, 2019

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma
• Other Study ID Numbers: FCN-159-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No