Neurofibromatosis and Malignant Peripheral Nerve Sheath Tumors
Conditions
Brief summary
AL2846 is a multi-target receptor tyrosine kinase inhibitor. The purpose of this study is to evaluate the safety and efficacy of AL2846 capsules in Chinese patients with type I neurofibromatosis (NF1) (neurofibromas and malignant peripheral nerve sheath tumors).
Interventions
DRUGAL2846 capsules
AL2846 is a multi-target receptor tyrosine kinase inhibitor.
Sponsors
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients who voluntarily join the study and sign the informed consent form; * Aged 18 to 75 years (when signing informed consent); Eastern cooperative oncology group（ ECOG） score: ≤2 ; patients with malignant peripheral nerve sheath tumors （MPNST）who are expected to survive ≥12 weeks; * NF1 patients (including patients with MPNST) who are judged by the investigator as incomplete surgical resection, require systemic treatment, and have measurable lesions; Note: NF1 diagnostic criteria meets at least one of the following: 1. Genetic examination confirmation: test positive for NF1 germline mutation in a Clinical Laboratory Improvement Amendments （CLIA）-certified laboratory (positive NF1 germline mutation must be confirmed by the central laboratory of this project, or an NF1 mutation test report issued by a CLIA-certified laboratory; 2. Clinical and imaging examination confirmation: According to the clinical National Institute of Health (NIH) consensus criteria, at least two of the following NF1 diagnostic criteria are met: 1. Six or more café-au-lait macules (≥0.5cm in prepubertal patients or ≥1.5 cm in post pubertal patients) 2. Freckling in axilla or groin 3. ≥2 neurofibromas of any type, or ≥1 plexiform neurofibromas 4. Optic glioma 5. Two or more Lisch nodules 6. A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex) 7. A first-degree relative with NF1 \- Patients who are confirmed by direct measurement or according to the Response Evaluation Criteria in Solid Tumors（RECIST） 1.1 standard that there is at least one evaluable lesion, and the diameter of the lesion is greater than 3 cm, and the lesion can be seen in three consecutive sections; * The main organs function well and meet the following standards: <!-- --> 1. Blood routine examination standard (no blood transfusion and no hematopoietic stimulating factor drugs used for correction within 7 days before the examination): a. White blood cell count (WBC) ≥3.5×109/L b. Hemoglobin (HGB) ≥90 g/L; c. The absolute value of neutrophils (NEUT) ≥ 1.5×109/L; d. Platelet count (PLT) ≥ 100×109/L. 2. The biochemical inspection shall meet the following standards: a. Albumin (ALB) ≥35g/L; b. Total bilirubin (TBIL) ≤ 1.5× the upper limit of normal (ULN), and patients with Gilbert syndrome are ≤ 2.5× ULN; c. Alanine-based transferase (ALT) and aspartate-based transferase (AST) ≤2.5×ULN; d. Serum creatinine (CR) ≤1.5×ULN or creatinine clearance (CCR) ≥50ml/min (application of standard Cockcroft-Gault formula); 3. The coagulation function test shall meet the following standards: International normalized ratio (INR)≤1.5×ULN (have not received anticoagulant therapy); 4. Thyroid function examination must meet the following standards: Thyroid-stimulating hormone (TSH)≤ULN; if abnormal, Triiodothyronine （T3） and thyroxine（T4）levels should be examined, and T3 and T4 levels are normal. 5\. Heart color Doppler ultrasound assessment: Left ventricular ejection fraction (LVEF) ≥50%. \- Female patients of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; serum pregnancy test within 7 days before study entry Negative, and must be a non-lactating subject; male patients should agree to adopt avoidance measures during the study period and within 6 months after the end of the study period; \- Patients enrolled in the second stage need to be pathologically confirmed to be enrolled in cohort 1, cohort 2 or cohort 3.
Exclusion criteria
* Combined diseases and medical history: 1\. Patients who have other malignant tumors within 3 years before the first medication or are currently suffering from other malignancies. The following two situations can be enrolled: other malignant tumors treated by a single operation; achieving 5 consecutive years of disease-free survival (DFS); 2\. With factors that affect oral medications (such as dysphagia, chronic diarrhea and intestinal obstruction, etc.) 3\. Unreliable toxic reactions higher than Common Terminology Criteria for Adverse Events(CTCAE) v5.0 level 1 caused by any previous treatment, excluding hair loss; 4\. Received major surgical treatment or obvious traumatic injury within 28 days before the first medication; 5\. Long-term unhealed wounds or fractures caused by surgery or trauma; 6\. Arterial/venous thrombosis occurred within 6 months before the first medication, such as cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism; 7\. With a history of psychotropic drug abuse and cannot be quit or have mental disorders; 8\. There are risk factors for prolonging the corrected QT interval（QTc）interval, such as uncorrectable hypokalemia, hereditary long QT syndrome, or taking drugs that prolong the QTc interval (mainly class Ia, Ic, and III antiarrhythmic drugs) ； 9\. Past or current retinal vein stenosis, retinal detachment, central retinal vein occlusion, glaucoma, grade 1 cataract, related symptoms caused by the disease are not considered as
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse event rate | :Baseline up to 96 weeks | The occurrence of all adverse events (AEs), serious adverse events (SAEs) and treatment-related adverse events (TEAEs) |
| objective response rate (ORR) | Baseline up to 96weeks | Percentage of participants achieving complete response (CR) and partial response (PR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II clinical recommended dose （RP2D） | Baseline up to 96 weeks | recommended dose of Phase II clinical trial |
| PFS rate of one year | up to 96 weeks | Rate of patients with PFS reaching one year among all patients |
| Overall Survival（OS） | assessed up to100 months | From date of first administration of test drug until the date of death from any cause |
| Progression-free survival (PFS) | up to 96 weeks | PFS defined as the time from randomization until the first documented progressive disease (PD) or death from any cause. |
| Quality of life related scale（European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire version 3.0, EORTC QLQ-C30(V3)） | up to 96 weeks | Questionnaires about the quality of life (including mental state, appetite state, sleep, etc.) |
| The patient's overall impression of the severity of symptoms (self-report) | up to 96 weeks | Self-report on the severity of tumor pain, overall pain status, and tumor-related problems other than pain (vision, hearing, mobility, hearing, appearance, etc.) |
| Pain Scale (self-report form) | up to 96 weeks | Self-report of pain in target tumor and other parts of body |
| Duration of Response (DOR) | up to 96 weeks | The time when the participants first achieved complete or partial remission to disease progression. |
Countries
China
Outcome results
None listed