Chiauranib Plus Weekly Paclitaxel in Patients With Platinum-refractory or Platinum-resistant Recurrent Ovarian Cancer

Study Overview
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Brief Summary
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This randomized, double-blind, 2-arm study will evaluate the efficacy and safety of Chiauranib plus weekly paclitaxel versus placebo plus weekly paclitaxel in patients with Platinum-refractory or Platinum-resistant Recurrent ovarian cancer.

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. Patients will be randomized to receive treatment with either paclitaxel + Chiauranib or paclitaxel + placebo. Paclitaxel will be repeated every 21 days for a maximum of 6 cycles. Patients with objective response/stable disease after completing 6 courses of chemotherapy will continue Chiauranib or placebo until progression.

Official Title
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A Multi-center, Double-blind, Randomized Phase III Clinical Trial of Chiauranib Plus Weekly Paclitaxel in Patients With Platinum-refractory or Platinum-resistant Recurrent Ovarian Cancer

Conditions
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Ovarian Cancer, Relapsed or Refractory, Chiauranib, Paclitaxel

Intervention / Treatment
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* Drug: chiauranib
* Drug: Placebo
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willingness to sign a written informed consent document . Female, age ≥18 yrs and ≤70 yrs. Histological or cytological confirmation of epithelial ovarian cancer, carcinoma tube, or primary peritoneal carcinoma. Patients with platinum refractory or platinum resistant ovarian cancer: Platinum refractory: progression during the first platinum-based treatment or within 4 weeks after the first platinum-based primary therapy; Platinum resistant: progression during the platinum-based treatment except for platinum refractory, or within 6 months after the last receipt of platinum-based treatment (patients have received platinum containing chemotherapy at least 4 weeks); Radiological progression during the last treatment administered; no more than 1 prior treatment regimens for recurrent disease. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. At least 1 lesion can be accurately measured, as defined by RECIST1.1. Laboratory criteria are as follows: Complete blood count: hemoglobin (Hb) ≥90g/L ; absolute neutrophil count (ANC) ≥1.5×109/L ; platelets ≥90×109/L; Biochemistry test: serum creatinine(cr) <1.5×ULN; total bilirubin<1.5×ULN; alanine aminotransferase(ALT) ,aspartate aminotransferase(AST)≤2.5×ULN; (ALT,AST≦5×ULN if liver involved) ; Coagulation test: International Normalized Ratio (INR) < 1.5, activeated partial thromboplasting time (APTT) <1.5×ULN Life expectancy of at least 3 months. Exclusion Criteria: Patients received vascular endothelial growth factor(VEGF)/vascular endothelial growth factor receptor(VEGFR) inhibitor, like Apatinib, Anlotinib, Fruquintinib, Bevacizumab, etc., or Aurora kinase inhibitors. Patients received weekly paclitaxel therapy. Has known allegies to Chiauranib, paclitaxel or any of the excipients. Biological therapy, immunotherapy, hormonal therapy within 28 days prior to the first dose of study drug. prior major surgery or trauma within 14 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer. Treatment with an investigational agent/instrument within 28 days prior to first dose of study drug. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1. Patients with prior invasive malignancies in the past five years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis. clinically significant central/peripheral nervous system disease. Have uncontrolled or significant cardiovascular disease, including: Congestive heart failure, unstable angina pectoris, myocardial infarction within 6 months prior to study entry; arrhythmia, or Left Ventricular Ejection Fraction (LVEF) < 50% requiring treatment with agents 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) > 470 ms prior to study entry Symptomatic coronary heart disease requiring treatment with agents History of hypertension treated by≥2 agents, or the Blood pressure (Bp) ≥140/90 mmHg prior to study entry. Other condition investigator considered inappropriate Significant intravenous or arterial thrombosis, such as cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. History of active bleeding within the past 2 months, patients with bleeding potential during the screening period, or receiving anticoagulation therapy. 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, history of immune-associated pneumonia after treatment of PD1/PDL1 inhibitor. Have clinical significant gastrointestinal abnormality that would impair the ingestion, transportation or absorption of oral agents, history of gastrointestinal perforation or abdominal fistula, peptic ulcer disease within 6 months prior to first dose of study drug or GI obstruction within the past 3 months. Pleural fluid, ascites or pericardial effusion with significant symptoms or required treatment of puncture or drainage during the screening period, or history of drainage for therapy within 1 months prior to first dose of study drug. 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. Active infection requiring oral or intravenous systemic antimicrobial therapy during the screening period. Any mental or cognitive disorder, that would impair the ability to understand the informed consent document, or the compliance of study. History of organ transplantation or allo-HSCT. 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. Participants of reproductive potential not willing to use adequate contraceptive measures for the duration of the study.Pregnant or breastfeeding women. Any other condition which is inappropriate for the study in the opinion of the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chiauranib plus weekly paclitaxel<br>Patients receive the combined treatment of chiauranib plus paclitaxel, 21 days for a cycle, 6 cycles at most,Chiauranib is given orally, 50mg once daily. Paclitaxel is given in intravenous infusion on Day 1, 8 and 15. After 6 cycles combined treatment, patients enter the single agent therapy of chiauranib. | Drug: chiauranib<br>* 50mg orally once daily<br>* Other names: CS2164;Drug: Paclitaxel<br>* at the first cycle, 60mg/m2, i.v infusion on day 1, 8 and 15 ; at the begining of the second cycle, after a comprehensive assessment , investigators decide whether to increase the dosage to 80mg/m2, i.v infusion on day 1, 8 and 15 ;<br>* Other names: Anzatax;|
| Placebo Comparator: placebo plus weekly paclitaxel<br>Patients receive the combined treatment of placebo plus paclitaxel, 21 days for a cycle, 6 cycles at most,placebo is given orally, 50mg once daily. Paclitaxel is given in intravenous infusion on Day 1, 8 and 15. After 6 cycles combined treatment, patients enter the single agent therapy of placebo. | Drug: Placebo<br>* 50mg orally once daily<br>Drug: Paclitaxel<br>* at the first cycle, 60mg/m2, i.v infusion on day 1, 8 and 15 ; at the begining of the second cycle, after a comprehensive assessment , investigators decide whether to increase the dosage to 80mg/m2, i.v infusion on day 1, 8 and 15 ;<br>* Other names: Anzatax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival (PFS) | From the first time of treatment until the date of first documented progression or date of death from any cause, whichever comes first (Assessed by IRC) | assessed up to 1 years | 
| overall survival (OS) | OS is defined as the length of time from treatment to death from any cause | assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate (ORR) | ORR is defined as the proportion of participants who have a partial response (PR) or complete response (CR) to therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | assessed up to 2 years | 
| duration of response (DOR) | From the first date of response until the date of first documented progression | assessed up to 2 years | 
| Disease control rate (DCR) | DCR is defined as the Proportion of participants in partial, complete or stable desease according to RECIST 1.1. criteria | assessed up to 2 years | 
| Quality of life (QoL) | QoL assessed by EORTC QLQ-OV28 | assessed up to 2 years | 
| Toxicity according to NCI CTCAE v5.0 criteria | tolerance of the treatment based on AE occurrence according to NCI CTCAE v5.0 criteria | assessed up to 2 years |