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

NCT03932253 | Suspended Phase 1 DMC

• 1 other identifier: FCN-159-001
• Study Type: interventional
• Target: 79
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (14)

• Number of subjects with adverse events (AEs)

  through study completion, an average of 1 year.

• PFS in months

  through study completion, an average of 1 year.

• OS in months

  through study completion, an average of 1 year.

• 1-year OS rate(%)

  through study completion, an average of 1 year.

• DoR in months

  through study completion, an average of 1 year.

Study Arms (1)

1a：0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg，8mg, 12mg, 15mg.1b(NRAS),1b(NF1)

EXPERIMENTAL

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

Interventions

FCN-159 OTHER

Administered orally once a day

1a：0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg，8mg, 12mg, 15mg.1b(NRAS),1b(NF1)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Radiotherapy, major surgery, mono-clone antibody targeted therapy, immunotherapy or other treatment within 4 weeks prior to enrollment.
• Chemotherapy and small molecule targeted therapy within 2 weeks of enrollment.
• Participated in other clinical trials within 4 weeks prior to enrollment or 5 T1/2;
• Previous usage of MEK inhibitor;
• Uncontrolled central nervous system metastasis or injury.
• Unrecovered \>grade 2 AE caused by previous anti-tumor therapy;
• Strong inhibitors/inducers of CYP3A4, CYP2C8 or CYP2C9 within 14 days prior to the start of dosing.
• Taking drugs that prolong 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 radiationpneumonitis.
• Insufficient cardiac function or disease;
• Pregnant or lactating woman.
• Known to be allergic to any excipients of FCN-159.
• Clinically active infections;

Sponsors & Collaborators

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

Study Sites (1)

Beijing Cancer Hospital

Beijing, Beijing Municipality, 100142, China

Location

Related Publications (1)

• 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.

  PMID: 36113242 DERIVED

MeSH Terms

Conditions

Melanoma

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2019
• First Posted: April 30, 2019
• Study Start: March 21, 2019
• Primary Completion: April 30, 2023
• Study Completion: April 30, 2024
• Last Updated: March 27, 2024

Record last verified: 2024-03

Locations

CN (1)