Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1

NCT04954001 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: FCN-159-002
• Study Type: interventional
• Target: 160
• Locations: 3 countries
• Sites: 14

Brief Summary

FCN-159 is a highly active MEK1/2 inhibitor that was designed, synthesized and screened on the basis of the structure of trametinib. FCN-159 is an orally available and highly potent selective inhibitor of MEK1/2, which is expected to be a targeted therapy for the treatment of advanced solid tumors and neurofibromatosis type 1.

Conditions

Neurofibromatosis 1; Plexiform Neurofibroma; NF1

Outcome Measures

Primary Outcomes (3)

• Phase I: Safety: Dose-limiting toxicity (DLT) incidence rate.

  28 days after the dose of FCN-159 for DLT

• Phase I: Safety: MTD and RP2D.

  Approximately 6-9 months for MTD and RP2D (phase I duration)

• Phase II: Objective response rate (ORR) by investigator assessment

  Through study completion, an average of 2 years

Secondary Outcomes (18)

• Phase I Other safety: - The type and frequency of adverse events (AE) - Treatment-Emergent Serious Adverse Events (SAE) - The frequency and causes of death events - Laboratory safety test results - Changes in vital signs

  Through study completion, an average of 2 years

• Phase I Efficacy: objective response rate (ORR) by investigator /BIRC assessment, clinical benefit rate (CBR) per investigator/BIRC assessment including CR, PR, and SD lasting more than 6 months;

  Through study completion, an average of 2 years

• Phase I: Maximum Observed Plasma Concentration (Cmax) After Single Dose and Multiple Dose of FCN-159

  Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 10, 24 hours post-dose on Cycle 1 Day 1 (1 cycle = 28 days) for single dose, Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 10, 24 hours post-dose on Cycle 1 Day 28 for multiple dose

• Phase I: AUC From Time Zero to Last Measurable Concentration (AUClast) After Single Dose and Multiple Dose of FCN-159

  Pre-dose (0 hour), 0.5~1, 1.5~3, 4~6, 24 hours on Day 1 of Cycles 2, Pre-dose (0 hour) on Cycle 5 and every 4 cycles thereafter (assessed up to 104 weeks) (1 cycle = 28 days)

• Phase I PD marker: ERK phosphorylation inhibition in peripheral blood mononuclear cells (PBMCs)

  During Cycle 1 (cycle is 28 days): Day 1, Day 8 and Day 28

Study Arms (1)

Single Arm

EXPERIMENTAL

Drug: FCN-159

Interventions

FCN-159 DRUG

FCN-159 is administered orally in once daily schedule for 28 days a cycle.

Single Arm

Eligibility Criteria

• Age: 2 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Cohort 1: 16-70 years of age (inclusive) with a body weight of ≥ 94 lbs or 42.5 kg.
• Cohort 2: 2-15 years of age (inclusive) and able to swallow whole tablet. 2.Participants must be diagnosed with NF1-related plexiform neurofibromas (PN) and symptomatic with requirement of systematic therapy per investigator's judgment. A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve. Diagnosis of neurofibromatosis type 1 (NF1) is based on meeting at least 1 of the following 2 diagnostic criteria:
• Genetic testing confirmation: i.e., positive for NF1 germline mutation per CLIA-certified laboratory (or equivalent) testing. Note: NF1 germline mutation positive must either be confirmed by the FCN-159-002 central laboratory or have documentation of NF1 mutation issued by a CLIA-certified laboratory (or equivalent) - OR -
• Clinical and imaging confirmation: Meets at least 2 of the following 7 NF1 diagnostic criteria according to the clinical NIH consensus criteria:
• ≥ 6 cafe-au-lait macules (\>0.5 cm in prepubertal participants and \> 1.5 cm in post-pubertal participants);
• Axillary freckling or freckling in inguinal regions;
• ≥2 neurofibromas of any type, or ≥ 1 plexiform neurofibroma;
• An optic pathway glioma;
• ≥2 Lisch nodules (iris hamartomas);
• A distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex);
• First-degree relative with NF1. 3. Participants should meet one of the following criteria
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• Must be judged by the investigator to be inoperable for complete resection without causing substantial damage, or unsuitable for surgery with high surgical risks , e.g. due to encasement of or close proximity to vital structures, invasiveness, or high vascularity、Extensive lesion scope surgery is not feasible. NF1 has to cause or has the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, paraspinal lesions that can cause myelopathy, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions.
• The participants who have previously received surgical treatment, if the PN resection is incomplete, the postoperative residual exceeds 15% of the primary lesion, or relapse after surgery, and the lesions of at least 3 cm are measured in one dimension, are eligible for enrollment. At least a 28-day interval is required between surgery and the first dose of FCN-159.
• \. Participants must have a measurable lesion, defined as at least 3 cm in length in at least one dimension, amenable to MRI for efficacy assessment.

You may not qualify if:

• Participants who meet any of the following conditions shall not be included in this clinical study:
• Participants who have previously received one of the following:
• Chemotherapy for NF1 within 3 months of enrollment. Ongoing side effects of that treatment \> Grade 1 (except alopecia).
• Treatment with any drug or biologic therapy within 14 days of starting FCN-159, such as: tipifarnib, pirfenidone, Peg-Interferon, sorafenib or other VEGFR inhibitors
• Strong CYP3A4, CYP2C8 and CYP2C9 inhibitors or inducers (moderate inducers for CYP2C8 and CYP2C9) within 14 days before treatment of the study drug, except for topical skin use.
• Use of growth factors to increase the number or function of platelets or white blood cells within 7 days before administration of FCN-159.
• Radiotherapy, surgery or immunotherapy within 4 weeks before administration of FCN-159.
• Participation in other interventional clinical trials within 4 weeks before administration of FCN-159.
• Prior treatment with selumetinib or any other MEK 1/2 inhibitors (specific for phase 2 part).
• Participants with malignant tumors associated with NF1 requiring chemotherapy, radiotherapy, or surgery, such as intermediate- to high-grade optic gliomas or malignant peripheral nerve sheath tumors.
• Patients have other malignant tumor history or with other malignant tumors simultaneously (excluding cured non-melanoma skin basal cell carcinoma, breast carcinoma in situ or cervix cancer in situ, and other malignant tumors without disease evidence for the past 5 years);
• Participants who are unable to undergo MRI examination and/or for whom MRI examination is contraindicated (e.g., due to prostheses, orthotics or dental appliances or due to interference with volumetric analysis of target PN on MRI).
• Uncontrolled hypertension (despite medical therapy)
• Adult participants: defined as systolic or diastolic blood pressures \> 140/90 mmHg on repeat examination with existing anti-hypertension therapy.
• Pediatric participants: Blood pressure (BP) greater than or equal to the 95th percentile for age, height, and gender measured as described in (Appendix 19).

Sponsors & Collaborators

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

Study Sites (14)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Principal Investigator Hans

Gainesville, Florida, 32608, United States

Location

John Hopkins All Children Hospital

St. Petersburg, Florida, 33701, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Medical University of South Carolina - Hollings Cancer Center - PPDS

Charleston, South Carolina, 29425, United States

Location

Research Site

Beijing, China

Location

Research Site

Guangzhou, China

Location

Research Site

Hangzhou, China

Location

Research Site

Shanghai, China

Location

Research Site

Shijiazhuang, China

Location

Research Site

Wuhan, China

Location

Hospital Universitario Vall d'Hebron

Barcelona, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

Related Publications (2)

• Hu X, Wu Z, Wang J, Li W, Zeng K, Li Y, Tao J, Guan Z, Kang Z, Xu Z, Ma Y, Yang L, Wang X, Han P, Lin H, Diao L, Tan Y, Zhong W, Hui AM, Li C, Lin X. Phase 1 Study of Luvometinib Use in Pediatric Patients with Neurofibromatosis Type 1-Related Unresectable Plexiform Neurofibromas. Target Oncol. 2025 Nov;20(6):991-1001. doi: 10.1007/s11523-025-01176-y. Epub 2025 Oct 26.

  PMID: 41139346 DERIVED

• Hu X, Li W, Zeng K, Xu Z, Li C, Kang Z, Li S, Huang X, Han P, Lin H, Hui AM, Tan Y, Diao L, Li B, Wang X, Wu Z, Lin X. Phase 1 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1-related unresectable plexiform neurofibromas. BMC Med. 2023 Jul 3;21(1):230. doi: 10.1186/s12916-023-02927-2.

  PMID: 37400844 DERIVED

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms

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: June 17, 2021
• First Posted: July 8, 2021
• Study Start: March 26, 2021
• Primary Completion: February 28, 2025
• Study Completion: March 30, 2025
• Last Updated: November 12, 2024

Record last verified: 2024-10

Locations

ES (3); CN (6); US (5)