Type I Neurofibromatosis
Conditions
Brief summary
This study is a Phase I clinical trial to evaluate the tolerability and pharmacokinetics of TQ-B3234 capsules in Chinese subjects associated with neurofibromatosis type I (neurofibroma and peripheral malignant neurilemmoma). Two study phases were designed, including (1) dose escalation and (2) cohort expansion. The purpose of this study was to evaluate the tolerance, pharmacokinetic characteristics, efficacy and safety of TQ-B3234 capsule, and to explore the therapeutic biomarkers related to this product.
Interventions
DRUGTQ-B3234 capsule
TQ-B3234 is an anti-tumor molecular targeted drug, which is a selective Mitogen-activated protein kinase kinase（MEK）1/2 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
1. Patients voluntarily join the study, Sign the informed consent form; 2. Aged: \[18\ 75\] years old (when signing informed consent); Eastern cooperative oncology group performance Status（ECOG PS )score: ≤2 points; patients with malignant peripheral nerve sheath tumors （MPNST）are expected to survive ≥12 weeks; 3. NF1 patients (including patients with malignant peripheral nerve sheath tumor (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 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 Institutes of Health(NIH) consensus criteria, at least two of the following seven 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 4\. 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; 5\. 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): 1. White blood cell count (WBC) ≥3.5×109/L 2. Hemoglobin (HGB) ≥90 g/L; 3. The absolute value of neutrophils (NEUT) ≥ 1.5×109/L; 4. 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 times the upper limit of normal (ULN), and patients with Gilbert syndrome are ≤ 2.5 times the upper limit of normal (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, T3 and T4 levels should be examined, and T3 and T4 levels are normal. 5\) Heart color Doppler ultrasound assessment: Left ventricular ejection fraction (LVEF) ≥50%. 6\. 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; 7\. Patients enrolled in the second stage need to be pathologically confirmed to be enrolled in cohort 1, cohort 2 or cohort 3.
Exclusion criteria
1\. Combined diseases and medical history: 1. Have other malignant tumors within 3 years before the first medication or is currently suffering from other malignancies The following two situations can be included in the group: other malignant tumors treated by a single operation, to achieve 5 consecutive years of disease-free survival (DFS); 2. Many 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. Have 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), 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 |
|---|---|---|
| Dose limiting toxicity (DLT) | Baseline up to 4 weeks | Some drug-related toxicities occurred within 28 days of treatment |
| Phase II clinical recommended dose （RP2D） | Baseline up to 48 weeks | Phase II clinical recommended dose |
| Maximum tolerated dose (MTD) | Baseline up to 48weeks | If DLT occurs in 2 or more subjects in a given dose group, the dose level in the previous dose group is considered MTD |
| objective response rate（ORR） | Baseline up to 96 weeks | Percentage of participants achieving complete response (CR) and partial response (PR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Steady state clearance half-life (t1/2, SS) | Pre-dose of day 1, day 8, day 15, day 28 on multiple dose and 10 , 20 , 30 , 45 minutes,1 , 2 , 4 , 6 , 10 , 24 hours post-dose on multiple dose of day 1 and day 28 | Steady state clearance half-life (t1/2, SS) |
| Plasma concentration at steady state (Cav, SS) | Pre-dose of day 1, day 8, day 15, day 28 on multiple dose and 10 , 20 , 30 , 45 minutes,1 , 2 , 4 , 6 , 10 , 24 hours post-dose on multiple dose of day 1 and day 28 | The plasma concentration at which the rate of administration and rate of elimination are in equilibrium |
| Area under plasma concentration-time curve at steady state (AUCss) | Pre-dose of day 1, day 8, day 15, day 28 on multiple dose and 10 , 20 , 30 , 45 minutes,1 , 2 , 4 , 6 , 10 , 24 hours post-dose on multiple dose of day 1 and day 28 | Area under plasma concentration-time curve at steady state |
| Coefficient of fluctuation (DF) | Pre-dose of day 1, day 8, day 15, day 28 on multiple dose and 10 , 20 , 30 , 45 minutes,1 , 2 , 4 , 6 , 10 , 24 hours post-dose on multiple dose of day 1 and day 28 | Coefficient of fluctuation |
| Adverse event rate | Baseline up to 96 weeks | The occurrence of all adverse events (AE), serious adverse events (SAE) and treatment-related adverse events (TEAEs) |
| 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. |
| Duration of Response (DOR) | up to 96 weeks | The time when the participants first achieved complete or partial remission to disease progression. |
| Area under plasma concentration-time Curve (AUC) | Before administration, 10 , 20 , 30, 45 minuets, 1 , 2 , 4 , 6 , 10 , 24 , 48 , 72 hours after administration | Area under plasma concentration-time Curve |
| 1 year PFS rate | up to 1 year | Rate of patients with PFS reaching 1 year among all patients |
| Overall survival time (OS, observed only in peripheral malignant schwannomas) | up to 5 year | The time between the start of treatment and death directly due to the disease. |
| Effects on pain score in subjects | up to 96 weeks | Questionnaire: pain score：The line segments below all have numbers from 0 to 10, where 0 means no pain and 10 is the worst pain you can imagine. |
| Effects on subjects' health-related quality of life | up to 96 weeks | Questionnaire: Quality of life related scale（The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 3rd edition）.For questions 1 to 28, choose a number from 1 to 4. 1 means none and 4 means very.For questions 29 and 30, choose a number from 1 to 7, with 1 being very poor and 7 being very good. |
| Effects on subjects' related symptoms | up to 96 weeks | Patients' overall impression of severity of cancer symptoms (self-reported) |
| Effects on pain interference index in subjects | up to 96 weeks | Questionnaire: pain interference index：Please answer each one by circling a number from 0 to 6, where 0 means none at all and 6 means completely |
| Disease Control Rate (DCR) | up to 96 weeks | The proportion of patients whose tumor shrank or remained stable for some time, including those with complete response (CR), partial response (PR), and stable (SD). |
| Peak concentration (Cmax) | Before administration, 10 , 20 , 30, 45 minuets, 1 , 2 , 4 , 6 , 10 , 24 , 48 , 72 hours after administration | Maximum plasma drug concentration |
| Peak time (Tmax) | Before administration, 10 , 20 , 30, 45 minuets, 1 , 2 , 4 , 6 , 10 , 24 , 48 , 72 hours after administration | Time to maximum plasma concentration |
| Clearance half-life (t1/2) | Before administration, 10 , 20 , 30, 45 minuets, 1 , 2 , 4 , 6 , 10 , 24 , 48 , 72 hours after administration | The time required for the concentration of a drug to fall by half in a living organism |
Countries
China
Contacts
Primary ContactQingfeng Li, Doctor
Outcome results
None listed