Congratulations to Wuxi Beta for Providing SH-1028 New Drug of Shenghe Pharmaceutical Co., Ltd. with Carbon 14 Isotope Labeling Service
Release time:
2019-08-01
Congratulations to Wuxi Beta for providing carbon14 Isotope Labeling Services of St. and PharmaceuticalsSH-1028 New Drug
EnterPhase IIClinical Trials
On July 12, 2019, Nanjing Shenghe Pharmaceutical Co., Ltd. issued "Recruiting Patients: Phase II Clinical Trial of SH-1028 Tablets in Patients with Non-small Cell Lung Cancer" on its WeChat public account, marking that the new SH-1028 drug developed by Shenghe Pharmaceutical is about to enter Phase II clinical trials to evaluate the effectiveness and determine the recommended dose for Phase II clinical trials.
In September 2018, Wuxi Beta Pharmaceutical Technology Co., Ltd. and Nanjing Shenghe Pharmaceutical Co., Ltd. signed a "Technology Development Contract" to provide carbon 14(C14) isotope labeling services for the innovative drug SH-1028 new drug compound developed by Shenghe Pharmaceutical. After the contract was signed, Wuxi Beta quickly organized a team of experimenters to work overtime and successfully completed the C14 marker synthesis task in less than 12 weeks ahead of schedule. The radiochemical purity, chemical purity, chiral purity, specific activity, mass spectrometry and NMR data all met the requirements of policies and regulations. The synthesis of [C14]SH-1028 is an important part of the study on absorption, distribution and pharmacokinetics of this innovative drug. Thereafter, Wuxi Beta transported the isotope-labeled samples to a domestic third-party pharmacokinetic research institution designated by Shenghe Pharmaceutical for follow-up studies.
C14 isotope labeling refers to the use of C14 isotope as a labeling tracer to make a labeled compound containing C14 instead of the original non-labeled compound. Using the nuclear physical properties of C14 radioisotope continuously releasing soft beta rays, the position, quantity and transformation of the compound in vivo or in vitro can be traced at any time. It is equivalent to installing a navigation and positioning system for target molecular compounds, which is convenient for positioning and tracking during animal experiments and human clinical experiments. The radioactive tracer method can measure the level of 10-14-10-18 grams, that is, one radioactive atom can be detected from 1015 non-radioactive atoms, which is 107-108 times more sensitive than the current sensitive gravimetric analysis balance, while the most accurate chemical analysis method is difficult to measure the level of 10-12 grams. The positioning accuracy of tissues and organs can reach the cellular level, subcellular level and even molecular level.
The former State Food and Drug Administration issued the "Technical Guidelines for Non-clinical Pharmacokinetics of Drugs" in May 2014:
"Application of radioisotope labeling techniques for non-clinical pharmacokinetic studies of drugs. In the process of new drug development, it is very important to understand the changes of candidate drugs in human body and animals for toxicology and efficacy research. Therefore, various in vivo and in vitro pharmacokinetic tests must be conducted at different stages of new drug development to elucidate the absorption, distribution, metabolism and excretion (ADME) properties of candidate drugs. Although LC-MS techniques have been widely used in these tests, radioisotope labeling techniques are still widely used."
"Low-energy radioisotopes (such as C14, H3) labeled compounds are used in pharmacokinetic studies. Because of their low biological background values, they are easy and sensitive to detect, and have a long half-life without the need to correct the test results according to the radioactive half-life. They can quantitatively analyze the metabolites produced by candidate drugs without knowing their structures, and the energy of non-ionized β-rays produced is very low without special protection, it has been proved to be a safe and effective special technology. The results are simple, clear and reliable. At present, there is no other replacement method in most cases."
"The low-energy radioisotopes commonly used in the study of small molecule chemical drugs ADME are carbon -14(C14) and tritium (H3). C14 tag is most commonly usedIts biological background is low, biology has almost no isotope effect and affects metabolism, rarely occurs isotope exchange, and its sensitivity is higher than H3 and easy to quantify. In vivo testing H3 labeling is used unless the C14 labeling is very difficult or impossible to label and very low doses require very high specific activity."
In recent years, Wuxi Beta Pharmaceutical Technology Co., Ltd. has conquered dozens of C14 labeled key intermediate compound preparation technologies, and is committed to using C14 and other isotope labeling technologies to provide technical support for the research and development of new drugs by Chinese pharmaceutical companies, providing high-quality services with lower cost, higher efficiency and more convenient communication than sending labels abroad, meeting and exceeding customer needs, helping Chinese pharmaceutical companies reduce the research and development costs of original new drugs and improve research and development efficiency, to contribute to the cause of human health.
Attached:
【Recruiting patients】 SH-1028 tablets for patients with locally advanced or metastatic non-small cell lung cancer
A multicenter, open phase II clinical study of the safety and efficacy
(From Shenghe Pharmaceutical WeChat Public Number)
1. Brief introduction of experimental drug
SH-1028 tablets are the third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) drugs. The indication for this trial is locally advanced or metastatic non-small cell lung cancer with EGFR-T790M mutations.
2. Purpose of the test
Ø..In the dose exploration phase, evaluate the effectiveness of different doses of SH-1028 tablets in the treatment of patients with locally advanced or metastatic non-small cell lung cancer with positive EGFR-T790M mutation, and determine the recommended dose of phase II clinical trial (RP2D);
Ø..In the expanded sample size evaluation phase, the effectiveness of SH-1028 tablets in subjects with locally advanced or metastatic non-small cell lung cancer positive for EGFR-T790M mutation was evaluated based on the objective response rate (ORR).
3. Test design
Test Stage: Phase II
Design type: single arm test
Randomized: non-randomized
Blinded: Open
Test range: domestic multi-center
Number of people tested: 300 cases
4. Inclusion Criteria
1) Age above 18 years old (including boundary value), gender is not limited;
2) Patients with locally advanced and recurrent non-small cell lung cancer confirmed by histology or cytology or who cannot undergo radical surgery;
3) For patients with non-small cell lung cancer who are newly diagnosed (diagnosed without any systemic treatment or recurrence after previous surgical treatment, for patients who have received local treatment, if the lesions within the scope of local treatment are non-target lesions, patients can participate in the study), EGFR mutation (such as E19del, L858R, L861Q, G719X or double mutation) related to EGFR-TKI sensitivity must be confirmed by tissue/cytology sample test (this article is only applicable to newly diagnosed patients of Part B);
4) For patients who have EGFR-TKI sensitive mutations and have disease progression after continuous treatment with first-and second-generation EGFR-TKI (such as gefitinib, erlotinib, icotinib or afatinib, etc.), or have clinically benefited from first-and second-generation EGFR-TKI treatment (PR/CR, or SD for ≥ 6 months) according to Jackman criteria, there must be EGFR-T790M mutation (confirmed by tissue/cytological sample testing), and the number of previous treatment lines can exceed 1 line (patients with primary T790M mutation positive are required to have not received EGFR targeted therapy before testing and sampling) (this article is applicable to EGFR-T790M positive patients in Part A and Part B);
5) ECOG score of 0-2, life expectancy of at least 3 months;
6) According to RECIST 1.1 evaluation criteria for solid tumor efficacy, the patient has at least one measurable lesion, which meets the following requirements: it has not been irradiated in the past and can be accurately measured, the longest diameter at baseline period is ≥ 10mm (if it is lymph node, the short diameter is ≥ 15mm), and the selected measurement method should be able to accurately repeat the measurement, which can be computed tomography (CT) or magnetic resonance scanning (MRI);
7) If bone marrow reserve or organ function is normal, the following laboratory test values must be reached: absolute neutrophil count ≥ 1.5 × 109/L; Platelet count ≥ 100 × 109/L; Hemoglobin ≥ 90g/L; If there is no liver metastasis, alanine aminotransferase (ALT)≤ 2.5 times the upper limit of normal value (ULN), if there is liver metastasis, ALT ≤ 5 times ULN; If there is no liver metastasis, aspartate aminotransferase (AST)≤ 2.5 times ULN, AST ≤ 5 times ULN if there is liver metastasis; If there is no liver metastasis, total bilirubin ≤ 1.5 times ULN; if there is definite Gilbert syndrome (non-binding hyperbilirubinemia) or liver metastasis, total bilirubin ≤ 3 times ULN; Creatinine ≤ 1.5 times ULN. When creatinine> 1.5 times ULN, creatinine clearance rate shall be checked for confirmation, creatinine clearance rate should be ≥ 50 ml/min (measured value, or calculated value Cockcroft-Gault formula);
8) Female subjects who are likely to have children should be willing to use effective contraceptive measures within 6 months after the end of the trial period and the last medication, and the pregnancy test is negative before the start of treatment;
9) Male subjects are willing to take effective contraceptive measures during the trial period and within 6 months after the end of the last medication;
10) Have not participated in other drug clinical trials within 1 month;
11) Informed the test before the start of the test, and voluntarily signed the name signature and date on the informed consent form.
5. Exclusion criteria
1) From EGFR-TKI treatment to the first dose of study treatment, the time does not exceed 8 days or 5 half-lives (whichever is longer);
2) Has received any chemotherapy drugs or immunotherapy within 21 days before the first administration, or has used anti-tumor therapy such as targeted therapy and endocrine therapy other than EGFR-TKI within 14 days before the first administration;
3) Have used osimertinib or other third-generation EGFR-TKI drugs (such as CO-1686, avetinib, HS-10296, etc.) or their raw materials or generic drugs;
4) Major surgery within 4 weeks prior to the first dose of study treatment;
5) Palliative radiotherapy with limited irradiation range was carried out within 1 week before the first administration of the study treatment; More than 30% of bone marrow was treated with radiotherapy within 4 weeks before the first administration of the study treatment, or large-area field radiotherapy was carried out;
6) The patient is currently using (or cannot be discontinued at least 1 week before the first dose of the investigational drug) a drug or herbal supplement known to be a potent inhibitor or inducer of CYP3A4;
7) Use of high-dose glucocorticoids (prednisone> 10mg/day or equivalent) or other immunosuppressants for 4 weeks;
8) At the start of study treatment, the unrecovered toxicity of previous treatment exceeds CTCAE grade 1 (except for alopecia, the neuropathy related to previous platinum treatment can be relaxed to grade 2);
9) Spinal cord compression, meningeal metastases, or brain metastases (unless asymptomatic or in stable condition or without steroid, anticonvulsant, or mannitol medications for 4 weeks prior to the start of study therapy);
10) Any clinical evidence suggesting severe or uncontrolled systemic diseases, such as uncontrolled hypertension, active bleeding constitution, uncontrolled pleural and peritoneal effusion, and other serious mental, neurological, cardiovascular, respiratory and other system diseases that the researchers believe will affect the patient's compliance with the study protocol;
11) Active infections, such as hepatitis B, hepatitis C, human immunodeficiency virus (HIV) infection and syphilis infection (HCV-Ab positive but HCV-RNA ≤ the upper limit of the normal value of the detection unit, HBsAg positive but HBV-DNA ≤ the upper limit of the normal value of the detection unit can be included);
12) Meet any of the following cardiac criteria: Mean corrected QT interval (QTc)>470msec from 3 electrocardiogram (ECG) examinations at rest. Various clinically significant cardiac rhythm, conduction, resting ECG morphological abnormalities, such as complete left bundle branch block, III degree conduction block, II degree conduction block, PR interval> 250msec; Various factors that may increase the risk of QTc prolongation or arrhythmia events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of first-degree relatives with long QT syndrome or sudden unexplained death under 40 years of age, concomitant medications that may prolong the QT interval;
13) History of interstitial lung disease, history of drug-induced interstitial lung disease, history of radiation pneumonitis requiring steroid therapy, or any evidence of clinically active interstitial lung disease;
Have any other malignancy within five years (except for clinically cured cervical carcinoma in situ, basal cell or squamous cell skin cancer);
15) Any clinically serious gastrointestinal dysfunction that may affect the intake, transit or absorption of the study drug, such as inability to take oral drugs, uncontrollable nausea and vomiting, history of extensive gastrointestinal resection, untreated recurrent diarrhea, atrophic gastritis (onset age less than 60 years), untreated severe gastric disease, Crohn's disease, ulcerative colitis;
16) Those who are known to be allergic to compounds with similar structure of SH-1028 or any components in the formulation of SH-1028 tablets (such as lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talc, magnesium stearate, opal);
17) women who are breastfeeding;
18) The investigator determines that the subject has any clinical or laboratory abnormalities or other reasons and is not suitable to participate in the study.
6. Investigator Information
|
Name of institution |
Principal Investigator |
Provinces and cities |
Contact/Telephone |
|
Shanghai Pulmonary Hospital |
Zhou Caicun |
Shanghai |
Zhu Di 17821984436 |
|
Drum Tower Hospital Affiliated to Medical College of Nanjing University |
Miao Liyun |
Jiangsu Nanjing |
Xia Qian 15251826757 |
|
Henan Cancer Hospital (Respiratory) |
Ma Zhiyong, Wang Huijuan |
Henan Zhengzhou |
Yu Dandan 15137335292 |
|
Henan Cancer Hospital (Department of Integrated Traditional Chinese and Western Medicine) |
Liu Huaimin |
Henan Zhengzhou |
Shang Wanzhen 15837350981 |
|
Wannan Medical College Yijishan Hospital |
Lu Zhiwei, Shen Jie |
Anhui Wuhu |
Pantene 15665477091 |
|
Bengbu Medical College The First Affiliated Hospital |
Bi Minghong, Li Wei |
Anhui Bengbu |
Shao Zhong Change/Liu Bingjie
19942525292/ |
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