HL-085 in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas

Study Overview
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Brief Summary
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This is a Multi-center, Open-label, Single-arm Phase II Study to Evaluate the Efficacy and Safety of HL-085 in the treatment of Adult Participants with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas(PN)

Detailed Description
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The study includes 2 parts, phase IIa and IIb. Phase IIa is to evaluate the preliminary safety, pharmacokinetic characteristics and efficacy of HL-085, and to determine the recommended dose. To observe the 9mg dose level, approximately 15 patients will receive HL-085 at a dose of 9mg BID on a continuous dosing schedule(1 cycle=21 days). The investigator and sponsor will evaluate the safety and efficacy data to determine whether HL-085 9mg BID is appropriate. HL-085 12mg BID, 6mg BID, or other HL-085 dosing regimen will be observed as needed. A total of 15-35 patients will be enrolled in phase IIa. Phase IIb is to further evaluate the safety and efficacy of HL-085 in patients with NF1 and inoperable PN and is expected to enroll 35 patients.

Official Title
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A Multi-center, Open-label, Single-arm Phase II Study to Evaluate the Efficacy and Safety of HL-085 in the Treatment of Adult Participants With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas

Conditions
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Neurofibromatosis 1, Plexiform Neurofibromas

Intervention / Treatment
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* Drug: HL-085


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: patients must be ≥18 years of age at the time of study entry. Diagnosis: Patients must have inoperable and symptomatic plexiform neurofibromas(PN), and patients must have NF1 mutation or meet at least 1 of the following NF1 diagnostic criteria: ① ≥6 cafe-au-lait macules ; ② Axillary freckling or freckling in inguinal regions; ③ ≥2 Lisch nodules (iris hamartomas); ④ A distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex); ⑤ An optic pathway glioma; ⑥ First-degree relative with NF1. Patients must have a measurable lesion, defined as at least 3 cm in length, amenable to MRI for efficacy assessment. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients are able to understand and voluntarily sign a written informed consent form. Patients must be willing and able to complete study procedures and follow-up examinations. Exclusion Criteria: Patients who are unable to undergo MRI scans (prosthesis, prosthesis, braces, etc.) or patients with lesions that cannot be evaluated by MRI. Patients do not have adequate organ function. Patients who are unable to take drugs orally, have difficulty swallowing or anything that may lead to inadequate drug absorption. Prior treatment with MEK 1/2 inhibitors. Patients known to be allergic to the ingredients or analogues of the study drug. Patients with previous or current retinal diseases such as retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), central serous retinopathy (CSR), etc. (except retinopathy caused by research diseases). With infections or other uncontrolled disease. Strong CYP2C9 inhibitors or inducers within 7 days before treatment of the study drug. Patients who received surgery within 4 weeks or radiotherapy within 6 weeks before enrollment. Patients who participated in any other clinical study treatment within 4 weeks before enrollment. Patients treated with anti-NF1 treatment with unresolved chronic toxicity. Clinical judgment by the investigator that the patient should not participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HL-085<br>HL-085 9mg BID | Drug: HL-085<br>* IIa: HL-085 capsule 9mg administered orally twice daily in a continuous 21-day treatment cycle. If required, dosing schedule can be adjusted to 12mg BID, 6mg BID, or other dosage regimens. IIb: HL-085 at the recommended dose or dosage regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | To assess the efficacy of HL-085 on the tumor volume (plexiform neurofibromas) using volumetric MRI per REiNS criteria. ORR is defined as the percentage of patients who have achieved a confirmed Partial Responses (PR) or Complete Responses (CR). | At the end of cycle 4,8,12,16,20,24,28,32.Then after every 8 cycles(each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate（DCR） | Defined as the percentage of patients who have achieved a confirmed response of CR or PR or SD | At the end of cycle 4,8,12,16,20,24,28,32.Then after every 8 cycles(each cycle is 21 days) | 
| Duration of Overall Response（DOR） | Defined as the time from first achieved CR or PR to disease progression | At the end of cycle 4,8,12,16,20,24,28,32.Then after every 8 cycles(each cycle is 21 days) | 
| Progression Free survival (PFS) | Defined as the time from first dosing (C1D1) to date of first observed progression or death from any cause (whichever comes first) | From date of dosing until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | 
| Pharmacokinetic characteristics | AUC | During the intervention |