Phase I/II study of FCN-159 in adults and children with neurofibromatosis type 1
- Conditions
- 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.MedDRA version: 20.0Level: LLTClassification code 10029270Term: Neurofibromatosis, type 1 (von Recklinghausen's disease)System Organ Class: 100000004850Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2021-001572-42-IT
- Lead Sponsor
- Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- A
- Sex
- All
- Target Recruitment
- 160
Phase I/II
1. 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 FCN159.
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) = 1.5ULN.
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 which is defined as
combined hormonal contraception, progesterone-only hormonal
contraception associated with inhibition of ovulation, intrauterine
device, intrauterine system, bilateral tubal occlusion, vasectomised
partner or abstinence 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.
Phase I (in addition to the common ones):
Refer to the Protocol
Phase II (in addition to the common ones):
1.Participants had adequate organ and bone marrow function:
- Absolute neutrophil count = 1.0 × 109/L;
- Hemoglobin = 9 g/dL (without red blood cell transfusio
1.Participants who have previously received one of the following:
a)Chemotherapy for NF1within 3months of enrollment. Ongoing side effects of that treatment>Grade1 (except alopecia).
b) Drug or biologic therapy(including investigational agents) for NF1within3weeks or at least5 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 within7 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 phase2 part).
2.Participants with malignant tumors associated with NF1 requiring chemotherapy, radiotherapy, or surgery, such as intermediate- to highgrade 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 5years);
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 > 140/90mmHg 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 App 16).
6. Participants with dysphagia, active digestive diseases, malabsorption syndrome, or other conditions that might affect the absorption of the study drug.
7.Previous RVO, 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 (ECG) 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 (women) and >450 ms (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.
b) NYHA Class=3 congestive heart failure;
c)Clinically significant arrhythmia, including but not limited to complete left bundle branch block, second degree atrioventricular block;
Please refer to the Protocol for the other Exclusion criteria
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method