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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат chiauranib
  50mg orally once daily
• Препарат Placebo
  50mg orally once daily
• Препарат Paclitaxel
  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 ;

Первичные конечные точки

• progression-free survival (PFS) [Срок оценки: assessed up to 1 years]
• overall survival (OS) [Срок оценки: assessed up to 2 years]

Вторичные конечные точки (6)

• overall response rate (ORR) [Срок оценки: assessed up to 2 years]
• duration of response (DOR) [Срок оценки: assessed up to 2 years]
• Disease control rate (DCR) [Срок оценки: assessed up to 2 years]
• Quality of life (QoL) [Срок оценки: assessed up to 2 years]
• Toxicity according to NCI CTCAE v5.0 criteria [Срок оценки: assessed up to 2 years]
• PK parameters of paclitaxel, chiauranib and M345 [Срок оценки: assessed up to 2 years]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

Китай · 1 центр

• Fudan University Shanghai Cancer Center — Шанхай

Идентификаторы

NCT: NCT04921527 · CAR301

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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