Overview

A Clinical Trial to Evaluate the Tolerability and Pharmacokinetics of TQ-B3234 in Patients With Type I Neurofibromatosis

Status:
Not yet recruiting
Trial end date:
2024-12-01
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Criteria
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 exclusion criteria;

10. Interstitial pneumonia, including clinically significant radiation pneumonia;

11. Patients with any severe and/or uncontrollable disease, including:

1. Unsatisfactory blood pressure control (systolic blood pressure ≥150 mmHg or
diastolic blood pressure ≥100 mmHg);

2. Suffering from grade ≥2 myocardial ischemia or myocardial infarction, arrhythmia
(including male QTc ≥450 ms (male), QTc ≥470 ms (female)) and grade ≥2 congestive
heart failure (New York Heart Association ( NYHA) classification, appendix 2);

3. Active or uncontrolled serious infection (≥CTCAE v5.0 Grade 2 infection);

4. Active hepatitis: hepatitis B reference:hepatitis b surface antigen(HBsAg) is
positive, and the DNA of hepatitis B virus(HBV DNA) test value exceeds the upper
limit of normal; hepatitis C reference: HCV antibody is positive, and the HCV
virus titer test value exceeds the upper limit of normal; Note: Those who meet
the criteria for entry, hepatitis B surface antigen-positive or core
antibody-positive patients, and hepatitis C patients need to continue antiviral
therapy to prevent virus activation;

5. Renal failure requiring hemodialysis or peritoneal dialysis;

6. A history of immunodeficiency, including HIV positive or other acquired or
congenital immunodeficiency diseases, or a history of organ transplantation;

7. Poor diabetes control (fasting blood glucose (FBG)> 10 mmol/L);

8. Urine routines suggest that urine protein is ≥++, and the 24-hour urine protein
quantification is confirmed to be >1.0 g;

9. Those who suffer from epilepsy and need treatment;

2. Tumor-related symptoms and treatment:

1) Have received surgery, chemotherapy, radiotherapy or other anti-cancer therapies within
4 weeks before the first medication (the washout period will be calculated from the end of
the last treatment); 2) Have received NMPA approved Chinese patent medicines with
anti-tumor indications (including compound cantharidin capsules, Kangai injections,
Kanglaite capsules/injections, Aidi injections, Brucea javanica oil injections). /Capsules,
Xiaoaiping Tablets/Injections, Huachansu Capsules, etc.) treatment;

3. Research and treatment related:

1. Patients who have previously received one of the following treatments:

1. Patients who have received NF1 drug treatment within 3 months before enrollment,
and the related side effects have not yet recovered to below grade 1 (except for
hair loss). Note: Patients who are receiving NF1 drug treatment must recover from
the acute toxicity of the current NF1 treatment to less than or equal to Grade 1
(refer to CTCAE v5.0) before entering this study;

2. Patients Received tipifarnib, pirfenidone, peg-interferon, sorafenib or other
Vascular Endothelial Growth Factor Receptor(VEGFR) inhibitor or biological
treatments within 14 days before receiving study drug treatment ;

3. Receiving strong CYP3A4 inhibitors (amprenavir, atazanavir, boceprevir,
clarithromycin, cornivatan, delavirdine, diltiazem, erythromycin) within 14 days
before receiving study drug treatment , Fursanavir, Indinavir, Itraconazole,
Ketoconazole, Lopinavir, Mibefradil, Miconazole, Nefazodone, Nefinavir,
Posaconazole, Ritonavir, saquinavir, tilarrevir, telithromycin, verapamil,
voriconazole, etc.) or strong inducers (carbamazepine, felbamate, nevirapine,
phenobarbital, phenytoin, Patients with primidone, rifabutin, rifampicin,
rifapentine, etc.), except for external use on the skin;

2. Unable to perform Nuclear Magnetic Resonance Imaging(MRI) examination and/or there are
contraindications for MRI examination, such as prosthesis, orthotics or orthodontics,
which will interfere with the volume analysis of the target plexiform neurofibromas(
PN) on MRI;

3. Patients who need to take more than the recommended dose of vitamin E daily;

4. Participated within 4 weeks before the first medication and used other anti-tumor
clinical trial drugs or those who have not exceeded 5 drug half-lives;

5. According to the judgment of the investigator, there are situations that seriously
endanger the safety of the patients or affect the completion of the research by the
patients.