Neurofibromatosis 1, NF1, Plexiform Neurofibroma
Conditions
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.
Interventions
DRUGFCN-159
FCN-159 is administered orally in once daily schedule for 28 days a cycle.
Sponsors
Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
General inclusion criteria for Phase I and II: 1.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: 1. 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 - 2. Clinical and imaging confirmation: Meets at least 2 of the following 7 NF1 diagnostic criteria according to the clinical NIH consensus criteria: 1. ≥ 6 cafe-au-lait macules (\>0.5 cm in prepubertal participants and \> 1.5 cm in post-pubertal participants); 2. Axillary freckling or freckling in inguinal regions; 3. ≥2 neurofibromas of any type, or ≥ 1 plexiform neurofibroma; 4. An optic pathway glioma; 5. ≥2 Lisch nodules (iris hamartomas); 6. A distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex); 7. First-degree relative with NF1. 3. Participants should meet one of the following criteria <!-- --> 1. 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. 2. 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. 4\. 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. 5\. Adult participants: Karnofsky performance level of ≥70%; Pediatric participants: Lansky performance score ≥ 70%, see Appendix 18. Note: Participants who are wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be considered ambulatory when they are in the wheelchair. Similarly, participants with limited mobility secondary to the need for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be considered ambulatory for the purposes of this study. 6\. Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 ULN. 7\. Participants or their legal guardians (if the participant is \<18 years old) are able to understand and voluntarily sign a written informed consent form. 8\. For participants of childbearing potential: participants must agree to take effective contraception, and receive double barrier contraception, condom, oral or injectable contraceptives, intrauterine device and other contraceptive methods during treatment and for at least 90 days after the last dose. Male participants must agree to avoid sperm donation for at least 90 days after the last dose. 9\. Willing to avoid excessive sun exposure and use adequate amounts of sunscreen if sun exposure is anticipated.
Exclusion criteria
Participants who meet any of the following conditions shall not be included in this clinical study:
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Phase I Changes in NF1-related symptoms. | Through study completion, an average of 2 years] | Each participant will undergo standardized functional evaluations according to the relevant category or categories of PN-related complications. The incidence of patients with improved function or quality of life will be measured. Key measurements are chosen from each complication category to assess for change over time. |
| Phase II: Critical secondary endpoint: Objective response rate (ORR) by BIRC assessment | Through study completion, an average of 2 years | — |
| Phase II: Other efficacy endpoints: Clinical Benefit Rate (CBR) | Through study completion, an average of 2 years | Per investigator/BIRC assessment including CR (Complete Response), PR (Partial Response), and SD (Stable Disease) lasting more than 6 months; |
| Phase II: Other efficacy endpoints: Disease Control Rate (DCR) | Through study completion, an average of 2 years | Defined as the percentage of cases with best response (PR or CR or stable disease (SD) after treatment in evaluable cases. |
| Phase II: Other efficacy endpoints: Progression-Free Survival (PFS) | Through study completion, an average of 2 years | Defined as the time from participant enrollment to disease progression or death (whichever occurs first). Participants without an event (no progression or death) were censored at the date of last tumor evaluation. |
| 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 II: Other efficacy endpoints: Time To Response (TTR) | Through study completion, an average of 2 years | Defined as the time from participant enrollment to the first observation of tumor response among participants with an objective response |
| Phase II: Other efficacy endpoints: Duration Of Response (DOR) | Through study completion, an average of 2 years | Defined as the time from first observation of tumor response to tumor progression or death from any cause in participants with an objective response, (whichever occurs first). |
| Phase II Other safety endpoints: - 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 II Dose intensity | Through study completion, an average of 2 years | Dose intensity, planned dose intensity and relative dose intensity will be measured. Dose Intensity (mg/day) = Actual Cumulative Dose (mg)/ Total Duration of Exposure (Days). Plan Dose Intensity (mg/day) = Plan Cumulative Dose (mg) / Total Duration of Exposure (Days). Relative Dose Intensity (%) = Dose Intensity / Plan Dose Intensity. |
| Phase II Ctrough After 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 II Clinical outcome variables: Changes in pain intensity. | Through study completion, an average of 2 years | Each participant will undergo standardized assessments to evaluate changes in pain intensity, using validated pain scales and questionnaires. The incidence of patients experiencing a decrease in pain intensity, as well as the reduction in pain intensity scores, will be evaluated. |
| Phase II Other clinical outcome variables: Changes in COA variables other than pain intensity. | Through study completion, an average of 2 years | — |
| Phase II: Other efficacy endpoints: Time To Progression (TTP) | Through study completion, an average of 2 years | Defined as the time from participant enrollment to disease progression, and participants without events (without progression or death) were censored at the date of tumor evaluation. |
| 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 | — |
Countries
China, Spain, United States
Outcome results
None listed