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

March 25, 2024 updated by: Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.

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

Status

Indicates the current recruitment status or the expanded access status.
Suspended

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
79

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD)
Time Frame: 1 month.
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)
Time Frame: through study completion, an average of 1 year.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of subjects with adverse events (AEs)
Time Frame: through study completion, an average of 1 year.
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
Time Frame: through study completion, an average of 1 year.
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
Time Frame: through study completion, an average of 1 year.
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(%)
Time Frame: through study completion, an average of 1 year.
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
Time Frame: through study completion, an average of 1 year.
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
Time Frame: through study completion, an average of 1 year.
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)
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.
AUC(0-∞)
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.
Cmax
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.
Tmax
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.
t1/2
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.
CL/F
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.
RAUC
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.
RCmax
Time Frame: 1 month.
Pharmacokinetics of FCN-159
1 month.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 21, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 30, 2023

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 30, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 25, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 28, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 30, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 27, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 25, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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