Study of AZD1775 in Combination With Paclitaxel, in Advanced Gastric Adenocarcinoma Patients Harboring TP53 Mutation as a Second-line Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Objective response rate (ORR)
研究概览
简要总结
This study is a single arm, single center phase II study of AZD1775 in combination with paclitaxel in patients with advanced gastric adenocarcinoma harboring TP53 mutation as a second-line chemotherapy.
Patients will receive AZD 1775 plus weekly paclitaxel combination regimen. The arm is composed of 25 patients.
AZD1775 225 mg BID q 12 hours (x 5 doses) administered days 1~3 + paclitaxel 80 mg/m2 given days 1, 8 and 15 of a 28 day cycle.
Tumour evaluation using Response Evaluation Criteria in Solid Tumors 1.1 will be conducted at screening every 16 weeks until objective disease progression .
详细描述
AZD1775 is an inhibitor of Wee1, a protein tyrosine kinase. Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 (CDK1) and 2 (CDK2), and is involved in regulation of the intra-S and G2 cell cycle checkpoints.
In in vitro and in vivo preclinical models, AZD1775 selectively enhanced chemotherapy induced death of cells deficient in p53 signaling. Tumor context-specific sensitization to the DNA damaging agents gemcitabine and platinums was observed in TOV21G (ovarian carcinoma) cell lines matched for wild type and knock down of p53.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 20 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of fully informed consent prior to any study specific procedures.
- •Patients must be ≥20 years of age.
- •Advanced gastric adenocarcinoma (including GEJ) that has progressed during or after first line therapy.
- •The 1st line regimen must have contained doublet 5-fluoropyrimidine or platinum based regimen.
- •Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy containing doublet 5-fluoropyrimidine and platinum-based regimen could be considered as 1st line therapy.
- •Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6 months prior to starting the 1st line therapy.
- •Provision of tumor sample (from either a resection or biopsy)
- •Patients with p53mutation
- •Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
- •Eastern Cooperative Oncology Group performance status 0-1
- •Patients must have a life expectancy ≥ 3 months from proposed first dose date.
- •Patients must have acceptable bone marrow, liver and renal function measured within 28 days prior to administration of study treatment as defined below:
- •Haemoglobin ≥9.0 g/dL (transfusion allowed)
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •White blood cells (WBC) > 3 x 109/L
- •Platelet count ≥100 x 109/L (transfusion allowed)
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- •aspartate aminotransferase (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5x ULN
- •Serum creatinine ≤1.5 x institutional ULN
- •At least one measurable lesion that can be accurately assessed by imaging or physical examination at baseline and following up visits.
- •Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1.
排除标准
- •More than one prior chemotherapy regimen (except for adjuvant/neoadjuvant chemotherapy with more than 6 month wash out period) for the treatment of gastric cancer in the advanced setting.
- •Any previous treatment with P53 inhibitors (small molecules)
- •Any previous treatment with paclitaxel
- •Patients with second primary cancer, except: adequately treated non-melanoma skin cancer,curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≤5 years.
- •HER2 positive patients (defined by HER2 3+ by immunohistochemistry or HER2 SISH +)
- •Patients unable to swallow orally administered medication.
- •Treatment with any investigational product during the last 14 days before the enrollment (or a longer period depending on the defined characteristics of the agents used).
- •Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 3 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates or denusomab for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment.
- •Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole,ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
- •With the exception of alopecia, any ongoing toxicities (>Common Toxicity Criteria for Adverse Effects grade 1) caused by previous cancer therapy.
- •Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks before the enrollment.
- •Resting ECG with measurable QTcB > 480 msec on 2 or more time points within a 24hour period or family history of long QT syndrome.
- •Patients with cardiac problem as follows: uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy) Left ventricular ejection fraction <55% measured by echocardiography, Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest , Symptomatic heart failure (NYHA grade II-IV), Prior or current cardiomyopathy, Severe valvular heart disease, Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy), Acute coronary syndrome within 6 months prior to starting treatment
- •Ophthalmological conditions as follows:Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure), Current or past history of central serous retinopathy or retinal vein occlusion
- •Female patients who are breast-feeding or child-bearing
- •Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
研究组 & 干预措施
AZD1775 in Combination With Paclitaxel
AZD1775 225 mg BID q 12 hours (x 5 doses, 2.5 days) administered days 1~3 Weekly paclitaxel 80 mg/m2 IV on 1, 8 and 15 of a four week l cycle is an widely used dose of paclitaxel given on this schedule in gastric adenocarcinoma patients as second-line therapy.
干预措施: AZD1775 (Drug)
AZD1775 in Combination With Paclitaxel
AZD1775 225 mg BID q 12 hours (x 5 doses, 2.5 days) administered days 1~3 Weekly paclitaxel 80 mg/m2 IV on 1, 8 and 15 of a four week l cycle is an widely used dose of paclitaxel given on this schedule in gastric adenocarcinoma patients as second-line therapy.
干预措施: paclitaxel (Drug)
结局指标
主要结局
Objective response rate (ORR)
时间窗: 8weeks
次要结局
- progression-free survival (PFS)(24weeks)
- safety and tolerability measured by Adverse Events,Vital signs,Collection of clinical chemistry/haematology parameters,ECGs(24weeks)
- Duration of response(24weeks)
- Disease control rate(8weeks)
- Overall survival(24weeks)
研究者
Jeeyun Lee
MD,PhD
Samsung Medical Center