| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Participants diagnosed with Neurofibromatosis 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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| NF-1 is a genetic disorder, which causes tumors to grow along the nervous system anywhere on the body. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029270 |
| E.1.2 | Term | Neurofibromatosis, type 1 (von Recklinghausen's disease) |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I:
-To evaluate the safety and tolerability of FCN-159 administered PO daily.
-To determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D).
Phase II:
-To assess the efficacy of FCN-159 per REiNS criteria. |
|
| E.2.2 | Secondary objectives of the trial |
Phase I:
-To assess the preliminary efficacy of FCN-159 per REiNS criteria.
-To determine the pharmacokinetic (PK) characteristics and pharmacodynamics (PD) of FCN-159 treatment.
-To evaluate clinical response to FCN-159 in terms of pain, quality of life, disfigurement, and function as compared to baseline in participants with NF1-related PN.
Phase II:
-To evaluate the safety and tolerability of FCN-159 administered PO daily in continuous 28-day cycles.
-To evaluate clinical response to FCN-159 in terms of pain, quality of life, disfigurement, and function as compared to baseline in participants with NF1-related PN.
-To evaluate the population PK characteristics of FCN-159.
-To evaluate dose intensity of FCN-159 administered to in participants with NF1-related PN. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General Inclusion Criteria for Phase I and II:
1.Cohort 1: >18 years of age and ≤ 70 years of age.
Cohort 2: 2-18 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. - OR -
2)Clinical and imaging confirmation: Meets at least 2 of the following 7 NF1 diagnostic criteria according to the clinical NIH consensus criteria:
a.≥ 6 cafe-au-lait macules (>0.5 cm in prepubertal participants and > 1.5 cm in post-pubertal participants);
b.Axillary freckling or freckling in inguinal regions;
c.≥2 neurofibromas of any type, or ≥ 1 plexiform neurofibroma;
d.An optic pathway glioma;
e.≥2 Lisch nodules (iris hamartomas);
f.A distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex);
g.First-degree relative with NF1.
3. Participants should meet one of the following criteria
a.Must be judged by the investigator to be inoperable for complete resection without causing substantial damage, or unsuitable for surgery with high surgical risks or participant refuses surgery,
b.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. Participants (>16 years of age) : Karnofsky performance level of ≥70%; Participants (≤16years of age): Lansky performance score ≥ 70%, see Appendix 15.
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: during treatment and for at least 90 days after the last dose, participants must agree to use a highly effective method of contraception(ie, combined hormonal contraception, progesterone-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine system, bilateral tubal occlusion, vasectomised partner or abstinence). Male participants must agree to avoid sperm donation for at least 90 days after the last treatment.
9. Willing to avoid excessive sun exposure and use adequate amounts of sunscreen if sun exposure is anticipated.
Specific inclusion criteria for Phase I (in addition to those required for common inclusion
criteria):
1. Participants have adequate organ and bone marrow function:
- Absolute neutrophil count ≥ 1.5 × 109/L;
- Hemoglobin ≥ 9 g/dL (within 14 days without red blood cell transfusion);
- Platelets ≥ 100 × 109/L (within 14 days without platelet transfusion);
- Serum total bilirubin ≤ 1.5 × upper limit normal (ULN) for age, ≤ 3.0 × ULN in
participants with Gilbert's syndrome;
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN;
- Albumin ≥ 3g/dL;
- Creatinine < 1.5 × ULN (serum creatinine based on age) or a creatinine clearance or radioisotope GFR ≥ 60ml/min/1.73 m2
Specific inclusion criteria for Phase II:(in addition to those required for common inclusion
criteria)
1.Participants had adequate organ and bone marrow function:
- Absolute neutrophil count ≥ 1.0 × 109/L;
- Hemoglobin ≥ 9 g/dL (without red blood cell transfusion within 14 days);
- Platelets ≥ 75 × 109/L (without platelet transfusion within 14 days);
- Serum total bilirubin ≤ 1.5 × upper limit normal (ULN) for age, ≤ 3.0 × ULN in participants with Gilbert's syndrome;
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN;
- Albumin ≥ 3 g/dL;
- Creatinine < 1.5 × ULN (serum creatinine based on age ) or a creatinine clearance or radioisotope GFR ≥ 50ml/min/1.73 m2 |
|
| E.4 | Principal exclusion criteria |
1.Participants who have previously received one of the following:
a)Chemotherapy for NF1 within 3 months of enrollment. Ongoing side effects of that treatment > Grade 1 (except alopecia).
b) Drug or biologic therapy( including investigational agents) for NF1 within 3 weeks or at least 5 half-lives of starting FCN-159,whichever is shorter (such as:tipifarnib, pirfenidone, Peg-Interferon, sorafenib or other VEGFR inhibitors).
c)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.
d)Use of growth factors to increase the number or function of platelets or white blood cells within 7 days before administration of FCN-159.
e)Radiotherapy, surgery or immunotherapy within 4 weeks before administration of FCN-159.
f)Participation in other interventional clinical trials within 4 weeks before administration of FCN-159.
g)Prior treatment with selumetinib or any other MEK 1/2 inhibitors (specific for phase 2 part).
2.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.
3.Participants 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)
4. 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).
5.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 greater than or equal to the 95th percentile for age, height, and gender (measured as described in Appendix 16).
6. Participants with dysphagia, active digestive diseases, malabsorption syndrome, or other conditions that might affect the absorption of the study drug.
7.Previous or current retinal vein occlusion (RVO), retinal pigment epithelial detachments (RPED), glaucoma or other significant abnormality in ophthalmic examination.
8.Interstitial pneumonia, including existing clinically significant radiation pneumonitis.
9.Cardiac dysfunction or concomitant diseases meeting any one of the following conditions will be excluded:
a)Three 12-lead electrocardiogram measurements performed at the study site during the screening period for which the mean value of three measurements was calculated according to the QTcF formula using the instrument, with QTcF > 470 ms (for women) and > 450 ms (for men); Participants with risk factors for QTcF prolongation, such as uncorrectable hypokalemia, hereditary long QT syndrome; or receiving drugs that prolong QTcF interval (mainly class Ia, Ic, III antiarrhythmic drugs). Drugs with potential to prolong QTcF interval, see Appendix 17.
)New York Heart Association (NYHA) Class ≥ 3 congestive heart failure
c)Clinically significant arrhythmia, including but not limited to complete left bundle branch block, second degree atrioventricular block
d)Known concurrent clinically significant coronary artery disease, cardiomyopathy, severe valvular disease.
e)Ultrasound Cardiogram performed during the screening showing. Left ventricular ejection fraction LVEF < 50%.
f)Bradycardia (< 50 beats per minute).
10.Family history of sudden cardiac death before age 50.
11.History of any acute neurological event(e.g., intracranial or subarachnoid haemorrhage, stroke, intracranial trauma) within 6 months prior to enrolment.
12.Participants with active bacterial, fungal or viral infections, including active hepatitis B (hepatitis B virus surface antigen positive and hepatitis B virus DNA > 1000 IU/ml or meeting the study site's diagnostic criteria for active hepatitis B infection), hepatitis C (hepatitis C virus RNA positive), or human immunodeficiency virus infection (HIV positive).
13.Concurrent use of full-dose,therapeutic anti-coagulation(e.g., vitamin K antagonist, dabigatran, hirudin, direct factor Xa inhibitors) or high dose anti-platelet therapy.Aspirin ≤81mg/day,prophylactic subcutaneous (SC) heparin or SC low-molecular weight heparin for thrombosis prophylaxis or heparin flush to maintain intravenous catheter patency is allowed
14.Pregnant or lactating women.
15.Known hypersensitivity to the study drug, other MEK 1/2 inhibitor or its excipients.
16.Clinically significant condition that, in the opinion of the investigator would preclude study participation or compliance with safety requirements.
17.Inability to attend in-person appointments per current clinical site COVID 19 guidelines and restrictions.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I
-Safety dose-limiting toxicity (DLT) incidence rate.
-MTD and RP2D.
Phase II
-Objective response rate (ORR) by BIRC assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I
DLT assessment is conducted throughout the continuous administration period on C1D1, C1D2, C1D8, C1D15 and C1D28
MTD is defined as the highest dose level with a DLT incidence rate of less than, or equal to, 33% (0/3 or 1/6). Dose escalation will continue until MTD is reached. Once MTD has been reached, the RP2D will be defined after review of the data from the Phase I stage
Phase II
BIRC assessment will be conducted 12 months after the first dose of the last enrolled participant, and at the end of the study
|
|
| E.5.2 | Secondary end point(s) |
Phase I secondary Endpoints:
Other safety:
The type and frequency of adverse events (AE) occurring during treatment will be evaluated for toxicity grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0;
- Treatment-Emergent Serious Adverse Events (SAE), and toxic reactions leading to permanent discontinuation;
- The frequency and causes of death events within 30 days after last administration;
- Laboratory safety test results
- Changes in vital signs
Changes in NF1-related symptoms.
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;
Clinical outcome variables: patient- and observer-reported outcomes and functional measures;
PK parameters.
PD marker: ERK phosphorylation inhibition in peripheral blood mononuclear cells(PBMCs), obtained pre-treatment, C1D1, C1D8, and at steady state
on treatment with FCN-159.
Phase II Secondary Endpoints:
Other efficacy endpoints: objective response rate (ORR); Clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), time to response (TTR), duration of response (DOR), 1- and 2-year PFS rate per investigator +/- BIRC assessment; overall survival (OS);
Safety endpoints:
- The type and frequency of adverse events (AE) occurring during treatment will be evaluated for toxicity grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0;
- Treatment-Emergent Serious Adverse Events (SAE), and toxic reactions leading to permanent discontinuation;
- The frequency and causes of death events within 30 days after last administration;
-Laboratory safety test results graded according to NCI-CTCAE version 5.0;
- Changes in vital signs;
Dose intensity
Changes in NF1-related symptoms.
Population PK parameters.
Clinical outcome variables |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I & II
SAEs: monitored continuously 30 days from signing ICF until end of study treatment
Clinical outcome variables (PhI & II) & changes in NF1-related symptoms (PhII): screening period; every 4 cycles for 1st 2 years & every 6 cycles thereafter; at end of treatment
Phase I
Changes in vital signs & lab safety tests: screening period; C1D1, C1D8, C1D15, C1D28 & CXD1; at end of treatment; at safety follow-up
BIRC assessment: 12 months after first dose of last enrolled participant & at end of study
PK/PD: C1D1, C1D2 (PK only), C1D8, C1D28 & C2D1 (PK only)
Phase II
Efficacy endpoints: Assessed 12 months after 1st dose of last enrolled participant & at end of study
Changes in vital signs & lab safety tests: screening period; CXD1; end of treatment; safety follow up
PK: CXD1 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I/II study in adult and paediatric patients with NF1. Dose escalation and dose expansion |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose escalation and dose expansion |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| China |
| United States |
| France |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study is defined as 2 years after the first dose of FCN-159 administered to the last participant enrolled on the trial or the last dose of FCN-159 for the last participant, whichever occurs first.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
Print
