Phase 3 Clinical Study of Chiauranib Capsule in Patients With Small-cell Lung Cancer

Study Overview
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Brief Summary
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Chiauranib , which simultaneously targets against VEGFR/Aurora B/CSF-1R, several key kinases involved in tumor angiogenesis, tumor cell mitosis, and chronic inflammatory microenvironment.

Detailed Description
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Chiauranib is a novel orally active multi-target inhibitor that simultaneously inhibits the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRa and c-Kit), mitosis-related kinase Aurora B and chronic inflammationrelated kinase CSF-1R in a high potency manner with the IC50 at a single-digit nanomolar range. In particular, Chiauranib showed very high selectivity in the kinase inhibition profile with little activity on off-target non-receptor kinases, proteins, GPCR and ion channels, indicative of a better drug safety profile in terms of clinical relevance. In July 2017, the sponsor initiated a phase Ib/II trial (CAR105). As of October 9, 2020, a total of 42 subjects entered the safety analysis and 41 subjects entered the efficacy analysis. The results of the phased trial analysis show the preliminary efficacy of this product in the treatment of SCLC at ≥3 lines. This clinical trial is studying the efficacy and safety of chiauranib works in treating patients with relapsed or refractory small cell lung cancer, in the meantime, exploreing the latent biomarkers accompany with chiauranib, as well as the relevancy of which and clinical benefit.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multicenter Phase 3 Clinical Study of Chiauranib Capsule in Patients With Progressed or Relapsed Small-cell Lung Cancer After 2 Lines Chemotherapy (CHIS)

Conditions
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Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Chiauranib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age ≥ 18 years and ≤75 years; Cytologically or histologically confirmed small cell lung cancer; Patients have received at least 2 different systemic chemotherapy regimens (contained platinum based regimen) , and progressed or relapsed At least one measurable lesion that can be accurately assessed ( RECIST1.1 criteria). If the only site of measurable disease is in a previously irradiated area, the patient must have documented progression of disease in this area. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Laboratory criteria are as follows: Complete blood count: absolute neutrophil count (ANC) ≥1.5×10^9/L ; platelets ≥75×10^9/L; hemoglobin (Hb) ≥80g/L ; Biochemistry test: total bilirubin≤1.5×ULN; alanine aminotransferase (ALT) , aspartate aminotransferase(AST)≤2.5×ULN(ALT,AST≦5×ULN if liver involved); serum creatinine(cr)≤1.5×ULN; Coagulation test: International Normalized Ratio (INR) < 1.5. Life expectancy of at least 3 months. All patients must have given signed, informed consent prior to registration on study. Exclusion Criteria: Patients who known to brain metastases with neurological symptoms; Screening period imaging shows that the tumor has invaded the periphery of important blood vessels or the investigator judges that the tumor is likely to invade important blood vessels and cause hemorrhage during the trial Pleural fluid, ascites, pericardial effusion with clinical symptoms or need to be drained during the screening period Patients with second primary cancer, except: adequately treated basal cell or squamous cell skin cancer, curatively treated in-situ cancer of the cervix, unless received curative treatment and with documented evidence of no recurrence during the past five years Patients who have been used aurora kinase inhibitors, or VEGF/VEGFR inhibitors Patients have used any anti-cancer therapy, including adiotherapy, chemotherapy, immunotherapy, target therapy, and other anti-tumor treatments within 28 days before the first dose Patients have used experimental drugs or devices within 28 days before the first dose Patients received major surgical operations within 28 days before the first dose, or patients with serious non-healing wounds, ulcer or fracture at the time of screening With the exception of alopecia, any ongoing toxicities (>CTCAE grade 1) caused by previous cancer therapy Patients with uncontrolled or significant cardiovascular disease, including: Grade II or higher Congestive heart failure, unstable angina pectoris, myocardial infarction (NYHA Classification) within 6 months prior to study entry; or arrhythmia requiring treatment, or Left Ventricular Ejection Fraction (LVEF) < 50% during screening stage. Primary cardiomyopathy (dilated cardiomyopathy, hypertrophic cardiomyocyte, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, et,al). History of significant QT interval prolongation, or Corrected QT Interval QTc≥450ms(male),QTc≥470ms（female）at screening. patient's treatment record of using at least 2 antihypertensive drugs at the same Within 14 days before the first dose, or uncontrolled hypertension (> 140/90 mmHg) during the screening period. Obstructive atelectasis that requires chest radiotherapy or surgery during the screening period or CT or MRI of the chest during the screening period shows interstitial lung disease or pulmonary fibrosis or lung inflammation that requires treatment, or within 6 months before the first dose history of pneumonia requiring oral or intravenous steroid treatment Patients with factors that could affect oral medication (such as dysphagia，chronic diarrhea, intestinal obstruction, After small bowel resection,etc), or undergone gastrectomy, or history of gastrointestinal perforation Proteinuria positive(≥1g/24h) Active bleeding within 2 months before the first dose, or anticoagulant drugs are being taken during the screening period, or the investigator judges that there is a high risk of bleeding during the screening period History of deep vein thrombosis or pulmonary embolism within 6 months before the first dose Active infections that require systemic treatment (oral, intravenous infusion) during the screening period Screening for HIV antibody positive Screening test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive with virus replication, hepatitis C antibody (HCV-Ab) positive with virus replication Any mental or cognitive disorder, that would impair the ability to understand the informed consent document, or the compliance of study Candidates with drug and alcohol abuse Women of childbearing potential not willing to use and utilize an adequate method of contraception (such as intrauterine device, contraceptive and condom) throughout treatment and for at least 12 weeks after the last dose; pregnant or breastfeeding women; the result of urine pregnancy test was positive at screening; Man participants not willing to use and utilize an adequate method of contraception throughout treatment. Any other condition which is inappropriate for the study according to investigators' judgment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chiauranib<br>Patients take Chiauranib capsules 50mg, orally once daily, 21 days as a cycle until objective disease progression. | Drug: Chiauranib<br>* Patients take Chiauranib capsules 50mg, orally once daily, 21 days as a cycle until objective disease progression.<br>* Other names: CS2164;|
| Placebo Comparator: Placebo<br>Participants received Chiauranib placebo capsule matching Chiauranib orally once daily until objective disease progression. | Drug: Placebo<br>* Participants received Chiauranib placebo capsule matching Chiauranib orally once daily until objective disease progression.<br>* Other names: Simulation tablet of Chiauranib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression-free survival | From date of the first dose of study drug until the date of first documented progression or relapse or date of death from any cause, whichever came first, assessed up to 24 months | 
| OS | Overall survival | From date of the first dose of study drug until the date of death from any cause, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Objective reponse rate | Up to a minimum 24 weeks after the last participant's first dose, or progression, or 75% subjects died | 
| DOR | Duration of response | from the date of first documented objective response until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months | 
| DCR | Disease-control rate | Up to a minimum 24 weeks after the last participant's first dose, or progression, or 75% subjects died | 
| percentage of AEs | Safety | 28 days after the last participant 's last medication or new anti-tumor therapy |