Chiauranib in Combination With Chemotherapy in Patients With Ovarian Cancer

1. Female, aged ≥ 18 yrs and ≤70 yrs;
2. Histological or cytological confirmation of epithelial ovarian cancer, carcinoma tube, or primary peritoneal carcinoma.

3. Patients with platinum-resistant or platinum-refractory ovarian cancer,

   1. platinum-resistant disease (disease progression within 6 months of the last receipt of platinum-based chemotherapy);
   2. platinum-refractory disease (disease progression during the period of platinum-based chemotherapy);
   3. patients are platinum-sensitive for the first time, then disease progression within 6 months of the last receipt of platinum-based chemotherapy.
4. Patients have received at least 1 platinum containing chemotherapy (at least 4 cycles), the disease has progressed or relapsed no more than 2 different chemotherapy regimens.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
6. At least 1 lesion can be accurately measured, as defined by RECIST1.1.
7. The time for participants received anti-cancer therapy (including chemotherapy, radiotherapy, immunotherapy and surgical therapy, et al) should be more than 4 weeks before enrollment; The time for participants received mitomycin chemotherapy should be more than 6 weeks before enrollment.

8. Laboratory criteria are as follows:

   1. Complete blood count: hemoglobin (Hb) ≥90g/L ; absolute neutrophil count (ANC) ≥1.5×109/L ; platelets ≥90×109/L;
   2. 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) ;
   3. Coagulation test: International Normalized Ratio (INR) \< 1.5.
9. Life expectancy of at least 3 months.
10. Willingness to sign a written informed consent document.

Exclusion Criteria:

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;
2. Patients with allergic to Chiauranib, Etoposide and Paclitaxel;
3. Patients received vascular endothelial growth factor(VEGF)/vascular endothelial growth factor receptor(VEGFR) inhibitor, like Apatinib, Anlotinib, Fruquintinib, Bevacizumab, etc., or Aurora kinase inhibitors;
4. Patients received Etoposide therapy;
5. Patients received weekly Paclitaxel therapy ;
6. Clinical evidence of central nervous system involvement;

7. Have uncontrolled or significant cardiovascular disease, including:

   1. 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.
   2. primary cardiomyopathy(dilated cardiomyopathy, hypertrophic cardiomyocyte, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, et,al)
   3. History of significant QT interval prolongation, or Corrected QT Interval (QTc) > 470 ms prior to study entry
   4. Symptomatic coronary heart disease requiring treatment with agents
   5. Uncontrolled hypertension (≥ 140/90 mmHg) by single agent.
8. Have active bleeding current thrombotic disease, patients with bleeding potential ,or receiving anticoagulation therapy; within 2 months prior to screening;
9. Proteinuria positive (≥1g/24h).
10. History of deep vein thrombosis or pulmonary embolism;
11. Have unsolved toxicities (> grade 1) from prior anti-cancer therapy;
12. Have clinical significant gastrointestinal abnormality, e.g., unable to swallow, chronic diarrhea, ileus, that would impair the ingestion, transportation or absorption of oral agents, or patients undergone gastrectomy;
13. History of organ transplantation;
14. Major surgery within 6 weeks and minor surgery within 2 weeks prior to screening;
15. Serologically positive for HIV, hepatitis B or C, or other serious infectious diseases (positive infectious diseases refer to that needed systemic therapy; HIV, hepatitis B or C: qualitative detection priority, quantitative detection if needed).
16. History of interstitial lung disease (ILD).
17. Any mental or cognitive disorder, that would impair the ability to understand the informed consent document or the operation and compliance of study;
18. Candidate with drug and alcohol abuse (alcohol abuse: alcohol consumption is no more than 5040ml beer or 2100ml wine or 630ml strong wine with alcohol content tops out at 40 percent each week).
19. Patients participated in other clinical trials in 4 weeks before enrollment, or washout period less than 5 half-life after received other clinical trial drugs (whichever is the longest);
20. Participants of reproductive potential not willing to use adequate contraceptive measures for the duration of the study (both male and female participants).Pregnant or breastfeeding women. Female participants must have a negative urinary or serum pregnancy test when done or have evidence of post-menopausal status (Defined as absence of menstruation for greater than 12 months, bilateral oophorectomy or hysterectomy).
21. Any other condition which is inappropriate for the study in the opinion of the investigators.