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

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 perCLIA-certified laboratory (or equivalent) testing. Note: NF1 germline mutationpositive must either be confirmed by the FCN-159-002 central laboratory or havedocumentation 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 NF1diagnostic criteria according to the clinical NIH consensus criteria:

3. ≥ 6 cafe-au-lait macules (>0.5 cm in prepubertal participants and > 1.5 cm inpost-pubertal participants);

4. Axillary freckling or freckling in inguinal regions;

5. ≥2 neurofibromas of any type, or ≥ 1 plexiform neurofibroma;

6. An optic pathway glioma;

7. ≥2 Lisch nodules (iris hamartomas);

8. A distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasiaor thinning of long bone cortex);

9. First-degree relative with NF1. 3. Participants should meet one of thefollowing criteria

10. Must be judged by the investigator to be inoperable for complete resectionwithout causing substantial damage, or unsuitable for surgery with highsurgical risks , e.g. due to encasement of or close proximity to vitalstructures, invasiveness, or high vascularity、Extensive lesion scope surgery isnot feasible. NF1 has to cause or has the potential to cause significantmorbidity, such as (but not limited to) head and neck lesions that couldcompromise the airway or great vessels, paraspinal lesions that can causemyelopathy, brachial or lumbar plexus lesions that could cause nervecompression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of theextremity that cause limb hypertrophy or loss of function, and painful lesions.

11. The participants who have previously received surgical treatment, if the PNresection is incomplete, the postoperative residual exceeds 15% of the primarylesion, or relapse after surgery, and the lesions of at least 3 cm are measuredin one dimension, are eligible for enrollment. At least a 28-day interval isrequired between surgery and the first dose of FCN-159.

12. Participants must have a measurable lesion, defined as at least 3 cm inlength in at least one dimension, amenable to MRI for efficacy assessment.

13. Adult participants: Karnofsky performance level of ≥70%; Pediatricparticipants: Lansky performance score ≥ 70%, see Appendix 18.Note: Participants who are wheelchair bound because of paralysis secondary to aplexiform neurofibroma should be considered ambulatory when they are in thewheelchair. Similarly, participants with limited mobility secondary to the needfor mechanical support (such as an airway PN requiring tracheostomy or CPAP)will also be considered ambulatory for the purposes of this study.

14. Coagulation function: International normalized ratio (INR) and activatedpartial thromboplastin time (APTT) ≤ 1.5 ULN.

15. Participants or their legal guardians (if the participant is <18 yearsold) are able to understand and voluntarily sign a written informedconsent form.

16. For participants of childbearing potential: participants must agree totake effective contraception, and receive double barrier contraception,condom, oral or injectable contraceptives, intrauterine device and othercontraceptive methods during treatment and for at least 90 days after thelast dose. Male participants must agree to avoid sperm donation for atleast 90 days after the last dose.

17. Willing to avoid excessive sun exposure and use adequate amounts ofsunscreen if sun exposure is anticipated.

Exclusion Criteria:Participants who meet any of the following conditions shall not be included inthis clinical study:Exclusion criteria for Phase I and II:

1. Participants who have previously received one of the following:
2. Chemotherapy for NF1 within 3 months of enrollment. Ongoing sideeffects of that treatment > Grade 1 (except alopecia).
3. Treatment with any drug or biologic therapy within 14 days ofstarting FCN-159, such as: tipifarnib, pirfenidone, Peg-Interferon,sorafenib or other VEGFR inhibitors
4. Strong CYP3A4, CYP2C8 and CYP2C9 inhibitors or inducers (moderateinducers for CYP2C8 and CYP2C9) within 14 days before treatment ofthe study drug, except for topical skin use.
5. Use of growth factors to increase the number or function of plateletsor white blood cells within 7 days before administration of FCN-159.
6. Radiotherapy, surgery or immunotherapy within 4 weeks beforeadministration of FCN-159.
7. Participation in other interventional clinical trials within 4 weeksbefore administration of FCN-159.
8. Prior treatment with selumetinib or any other MEK 1/2 inhibitors (specific for phase 2 part).
9. Participants with malignant tumors associated with NF1 requiringchemotherapy, radiotherapy, or surgery, such as intermediate- tohigh-grade optic gliomas or malignant peripheral nerve sheath tumors.
10. Patients have other malignant tumor history or with other malignant tumorssimultaneously (excluding cured non-melanoma skin basal cell carcinoma,breast carcinoma in situ or cervix cancer in situ, and other malignanttumors without disease evidence for the past 5 years);
11. Participants who are unable to undergo MRI examination and/or for whom MRIexamination is contraindicated (e.g., due to prostheses, orthotics ordental appliances or due to interference with volumetric analysis oftarget PN on MRI).
12. Uncontrolled hypertension (despite medical therapy)

• Adult participants: defined as systolic or diastolic blood pressures > 140/90 mmHg on repeat examination with existing anti-hypertensiontherapy.
• Pediatric participants: Blood pressure (BP) greater than or equal tothe 95th percentile for age, height, and gender measured as describedin (Appendix 19).

6. Participants with dysphagia, active digestive diseases, malabsorptionsyndrome, or other conditions that might affect the absorption of thestudy drug.
7. Previous or current retinal vein occlusion (RVO), retinal pigmentepithelial detachments (RPED), glaucoma and other significant abnormalityin ophthalmic examination.
8. Interstitial pneumonia, including existing clinically significantradiation pneumonitis.
9. Cardiac dysfunction or concomitant diseases meeting any one of thefollowing conditions will be excluded:
10. Three 12-lead electrocardiogram (ECG) measurements performed at thestudy site during the screening period for which the mean value ofthree measurements was calculated according to the QTcF formula usingthe instrument, with QTcF > 470 milliseconds; Participants with riskfactors for QTcF prolongation, such as uncorrectable hypokalemia,hereditary long QT syndrome; or receiving drugs that prolong QTcFinterval (mainly class Ia, Ic, III antiarrhythmic drugs). Drugs withpotential to prolong QTcF interval, See Appendix 20.
11. New York Heart Association (NYHA) Class ≥ 3 congestive heart failure;
12. Clinically significant arrhythmia, including but not limited tocomplete left bundle branch block, second degree atrioventricularblock;
13. Known concurrent clinically significant coronary artery disease,cardiomyopathy, severe valvular disease.
14. Ultrasound Cardiogram performed during the screening showing. Leftventricular ejection fraction LVEF < 50%.
15. Participants with active bacterial, fungal or viral infections, includingactive hepatitis B (hepatitis B virus surface antigen positive andhepatitis B virus DNA > 1000 IU/ml or meeting the study site's diagnosticcriteria for active hepatitis B infection), hepatitis C (hepatitis C virusRNA positive), or human immunodeficiency virus infection (HIV positive).
16. Pregnant or lactating women.
17. Known hypersensitivity to the study drug, other MEK 1/2 inhibitor or itsexcipients.
18. Clinically significant condition that, in the opinion of the investigator,would preclude study participation or compliance with safety requirements.
19. Inability to attend in-person appointments per current clinical site COVID 19 guidelines and restrictions.