MelanomaPhase 1NCT03932253
MEK Inhibitor FCN-159 To Treat Advanced Melanoma With NRAS-aberrant (Ia) and NRAS-mutant (Ib)or NF1-mutant(1b)
A Phase 1 study testing FCN-159 in people with Melanoma, run by Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. at 1 site in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Melanoma
- What is being tested?
- FCN-159
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 79 participants
- Where
- 1 siteChina
- Study dates
- 21 Mar 2019to 30 Apr 2024
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
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- 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.
Who cannot join
- 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;
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- 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;
- Significant active disease that in the investigator's opinion would adversely impact on his/her participation in the study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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).
- Conditions
- Melanoma
- Being tested
- FCN-159
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FCN-159Other
Administered orally once a day
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Other: FCN-159 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD)
To assess safety and tolerability of FCN-159 with a maximum tolerated dose (MTD) in patients with advanced melonoma.
Measured: 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.
Measured: through study completion, an average of 1 year.
Secondary outcomes (14)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: through study completion, an average of 1 year.
AUC(0-last)
Pharmacokinetics of FCN-159
Measured: 1 month.
AUC(0-∞)
Pharmacokinetics of FCN-159
Measured: 1 month.
Cmax
Pharmacokinetics of FCN-159
Measured: 1 month.
Tmax
Pharmacokinetics of FCN-159
Measured: 1 month.
t1/2
Pharmacokinetics of FCN-159
Measured: 1 month.
CL/F
Pharmacokinetics of FCN-159
Measured: 1 month.
RAUC
Pharmacokinetics of FCN-159
Measured: 1 month.
RCmax
Pharmacokinetics of FCN-159
Measured: 1 month.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Apr 2019
- Study start21 Mar 2019
- Primary completion30 Apr 2023
- Study completion30 Apr 2024 (estimated)
Why it stopped: Sponsor R\&D strategy adjustment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 79 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03932253
- Sponsor's protocol ID
- FCN-159-001
- Status last verified
- Mar 2024
- First submitted
- 25 Apr 2019
- Last updated
- 27 Mar 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 36113242
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT03932253
- Acronym / sponsor ID
- FCN-159-001
- Conditions
- Melanoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: Sponsor R\&D strategy adjustment
- Enrolment
- 79 participants (actual)
- Lead sponsor
- Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.Industry (pharma, biotech, devices)
- Study start
- 21 Mar 2019 (actual)
- Primary completion
- 30 Apr 2023 (actual)
- Study completion
- 30 Apr 2024 (estimated)
- First posted
- 30 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1a：0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg，8mg, 12mg, 15mg.1b(NRAS),1b(NF1) | Experimental | Other: FCN-1591a 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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;
Key exclusion criteria (16 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FCN-159Administered orally once a day | Other | 1a：0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg，8mg, 12mg, 15mg.1b(NRAS),1b(NF1) |
Primary outcome
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.
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.
14 secondary outcomes
Number of subjects with adverse events (AEs)
Time frame: through study completion, an average of 1 year.
PFS in months
Time frame: through study completion, an average of 1 year.
OS in months
Time frame: through study completion, an average of 1 year.
1-year OS rate(%)
Time frame: through study completion, an average of 1 year.
DoR in months
Time frame: through study completion, an average of 1 year.
CBR in months
Time frame: through study completion, an average of 1 year.
AUC(0-last)
Time frame: 1 month.
AUC(0-∞)
Time frame: 1 month.
Cmax
Time frame: 1 month.
Tmax
Time frame: 1 month.
t1/2
Time frame: 1 month.
CL/F
Time frame: 1 month.
RAUC
Time frame: 1 month.
RCmax
Time frame: 1 month.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2024.
- Derived from this study: PubMed 36113242Mao 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing FCN-159 in people with Melanoma, run by Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 27 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) (time frame: 1 month.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03932253, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2024.