NCT02730923进行中（未招募）1 期
A Multicentric, Randomized, Non Comparative, Open-label Phase I/II Evaluating AZD2014 (Dual Mammalian Target of Rapamycin Complex 1/2 (mTORC1/mTORC2) Inhibitor) in Combination With Anastrozole Versus Anastrozole Alone in the Treatment of Metastatic Hormone Receptor-positive Endometrial Adenocarcinoma
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 72
- 试验地点
- 12
- 主要终点
- Number of patients with severe toxicities occurring during the first 8 weeks of follow-up assessed using National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) V4
研究概览
简要总结
The investigators hypothesize that the dual inhibition of mTORC1/mTORC2 by AZD2014 combined with inhibition of aromatase enzyme by anastrozole will act synergistically and may be an interesting therapeutic option for endometrial cancer with a manageable toxicity profile.
The investigators proposal is to conduct a multicenter, 2-step, randomized, Phase I/II trial to evaluate the safety and efficacy of a combination treatment associating anastrozole to AZD2014 in advanced endometrial cancer patients.
The study is divided in 2 steps :
- A safety run-in phase aiming to evaluate the safety of the proposed combination AZD2014 + anastrozole (Arm A) versus anastrozole alone (Arm B). No dose escalation is scheduled (doses are based on maximum tolerated dose (MTD) defined for AZD2014 and the summary of product characteristics (SPC) of anastrozole). However, dose de-escalation for AZD2014 will be applied in case of toxicity.
- A two-stage randomized Phase II part aiming to evaluate the clinical benefit of the AZD2014 + anastrozole (Arm A) combination therapy versus anastrozole (Arm B).
详细描述
TREATMENT PLAN :
Following randomisation patients will receive Arm A : AZD2014 plus anastrozole or Arm B: anastrozole alone AZD2014 will be administered with an intermittent schedule i.e. 125 mg bis in die (BID) intermittent with 2 days on followed by 5 days off per week for a total weekly dose of 500 mg/week (250mg D1 and D2, 5 days off) Anastrozole will be administered at the standard dose defined in the SPC i.e. 1mg/d, per os, continuously.
Both treatment will be administered until progressive disease (PD), unacceptable toxicity or willingness to stop.
STATISTICS :
A total of 72 patients will be randomized in the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Postmenopausal female patient at the time of consent
- •Histologically-confirmed diagnosis of advanced or recurrent endometrial carcinoma, not amenable to curative treatments. Carcinosarcoma are not eligible.
- •Documented estrogen receptor and/or progesterone receptor positive endometrial cancer. Hormone receptor positivity is defined according to routine practice at each participating site.
- •Availability of a pre-treatment tumor sample (archival formalin-fixed paraffin-embedded (FFPE) block or fresh biopsy if feasible) and presence of at least one biopsiable tumor lesion for on-treatment biopsy
- •Documented disease progression after no more than one prior first-line chemotherapy regimen and/or more than 2 lines endocrine therapy in the metastatic setting
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 and minimum life expectancy of 8 weeks
- •At least one measurable lesion according to response evaluation criteria in solid tumor (RECIST 1.1)
- •Adequate bone marrow, renal and liver function as shown by:
- •Absolute neutrophil count > 1.5 x 109/L, Platelets > 100 x 109/L, Hemoglobin (Hb) >9 g/dL
- •Serum bilirubin ≤ 1.5 upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 2.5 ULN (≤ 5 ULN in patients with liver metastases)
- •Creatinine clearance > 50 mL/min (using Cockcroft formula, or MDRD formula for patients over 65 years Appendix 3 - Creatinine Clearance)
- •Fasting serum cholesterol ≤ 300 mg/dL (7.75 mmol/L) AND fasting triglycerides ≤ 2.5 ULN (lipid-lowering drugs allowed),
- •Fasting plasma glucose ≤7 mmol/L (126 mg/dL)
- •Recovered from prior significant treatment-related toxicity i.e. no persistent treatment-related toxicity > Grade 1 as per Common Terminology Criteria for Adverse Events (CTCAE) v4.3, except grade 2 alopecia, grade 2 anemia but with Hb >9 g/dL.
- •Minimal wash-out period before the start of the study drugs for the following treatments:
- •Any anti-cancer treatment approved or investigational medicinal product :> 21 days
- •Any chemotherapy, radiation therapy, androgens : > 21 days (not including palliative radiotherapy at focal sites).
- •Any monoclonal antibody therapy: > 4 weeks
- •Major surgery: > 4 weeks
- •Minor surgery (excluding tumour biopsies) >14 days.
- •Any haemopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating factor (G-CSF)], sargramostim [granulocyte-macrophage colony-stimulating factor (GM-CSF)]): > 14 days
- •Vaccinated with live, attenuated vaccines : > 4 weeks.
- •Sensitive or narrow therapeutic range substrates of drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K: see the appropriate wash-out period (a minimum of 5 x reported elimination half-life) in Appendix 5 - Restricted CYP and transporter related co-medications
- •Potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BCRP - Restricted CYP and transporter related co-medications
- •Patient willing to follow sunlight-protection measures. Patients should be advised of the need for sunlight protection measures during administration of AZD2014, and should be advised to adopt such measures for a period of 3 months after receiving their final dose of AZD
- •Patient able and willing to provide informed consent with ability to understand and willingness for follow-up visits.
- •Covered by a medical insurance
排除标准
- •Patient pre-treated by a non-steroidal aromatase inhibitor
- •Active uncontrolled or symptomatic central nervous system metastases or spinal cord compression
- •Clinically relevant abnormal levels of potassium or sodium.
- •Use of any forbidden concomitant treatment during the treatment period:
- •Any anti-cancer treatment (approved or investigational) not mentioned in the protocol
- •Chronic treatment with corticosteroids or other immunosuppressive agents. Stable low dose of corticosteroids are allowed (unless contra-indicated) provided that they were initiated before the last disease progression or were started at least 4 weeks prior to study treatment. Topical or inhaled corticosteroids are allowed.
- •Potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BCRP (see Appendix 5 - Restricted CYP and transporter related co-medications)
- •Sensitive or narrow therapeutic range substrates of the drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K outside the wash out period and restrictions presented in Appendix 5 - Restricted CYP and transporter related co-medications)
- •Patient with known hypersensitivity to anastrozole or to any of the excipients (Lactose monohydrate, Povidone, Sodium starch glycollate, Magnesium stearate, Hypromellose, Macrogol 300, Titanium dioxide)
- •History of hypersensitivity to active or inactive excipients of AZD2014 or drugs with a similar chemical structure or class to AZD2014
- •History of other malignancies except for basal cell or squamous cell skin cancer, in situ cervical cancer, unless they have been disease-free for at least five years
- •Patient who has any severe and/or uncontrolled medical conditions such as:
- •Recent history of specific cardiovascular events, or laboratory parameters that may affect cardiac parameters including : unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to start of study drug, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease; Symptomatic congestive heart failure of New York heart Association Class III or IV
- •Haemorrhagic or thrombotic stroke, including transient ischemic attack (TIA) or any other CNS bleeding.
- •Mean resting corrected QT interval (QTc), calculated using Fridericia's formula, > 470 msec obtained from 3 electrocardiograms (ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12 months of the patient entering in the study
- •Abnormal cardiac function at baseline :left ventricular ejection fraction (LVEF) <50%
- •Any evidence of interstitial lung disease and uncompensated respiratory conditions.
- •Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active or chronic hepatitis (i.e. quantifiable hepatitis B virus (HBV-DNA) and/or positive HbsAg, quantifiable hepatitis C virus (HCV-RNA)),
- •Active, bleeding diathesis
- •Current refractory nausea and vomiting, chronic gastro-intestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD
- •Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
- •Type 1 and uncontrolled Type 2 diabetes
- •Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis.
研究组 & 干预措施
Arm A: AZD2014 plus anastrozole
Experimental
干预措施: AZD2014 (Drug)
Arm A: AZD2014 plus anastrozole
Experimental
干预措施: Anastrozole (Drug)
Arm B: anastrozole alone
Active Comparator
干预措施: Anastrozole (Drug)
结局指标
主要结局
Number of patients with severe toxicities occurring during the first 8 weeks of follow-up assessed using National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) V4
时间窗: during the first 8 weeks of follow up
Severe toxicities defined as * Any grade ≥ 4 treatment related toxicity * Any grade≥ 3 treatment related toxicity lasting more than 7 days
The 8-week non progression rate using RECIST v1.1 to assess tumor response to treatment
时间窗: 8 weeks after start of treatment
次要结局
- Duration of objective response as per RECIST v1.1(Up to 3 years)
- The accumulation of the 47S precursor ribosomal ribonucleic acid (rRNA), which reflects RNA polymerase I activity analysed by fluorescence in situ hybridization (FISH)(Baseline and 8 weeks after treatment)
- The expression of components of rRNA methylation complex analysed by real time quantitative PCR (RTqPCR)(Baseline and 8 weeks after treatment)
- Number of patients with AE graded using CTCAE V4(For each participant, up to 30 days after the last dose of treatment (up to 3 years))
- Levels of expression of nucleolin assessed by IHC(Baseline and 8 weeks after treatment)
- Levels of expression of phosphorylated UBF assessed by IHC(Baseline and 8 weeks after treatment)
- Overall survival (OS) defined as the duration of time from start of treatment to time of death.(3 years)
- Area under the curve (AUC) of AZD2014(Week 1 Day 1: pre-dose, 2h and 6-8 hours later and Week 2 Day 1: pre-dose, 2h and 6-8 hours later.)
- Levels of expression of fibrillarin assessed by immunohistochemistry (IHC)(Baseline and 8 weeks after treatment)
- Levels of expression of upstream binding factor (UBF) assessed by IHC(Baseline and 8 weeks after treatment)
- Progression-free survival (PFS) defined as the duration of time from start of treatment to time of progression or death, whichever occurs first(up to 3 years)
- The levels of circulating anti-fibrillarin (anti-FBL) autoantibody on serum samples by Elisa assays(Baseline and 8 weeks after treatment)
- Levels of expression of protein B23 assessed by IHC(Baseline and 8 weeks after treatment)
- Best response rate defined as (percentage of patients with complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) according to RECIST V1.1)(Up to 3 years)
- Apparent clearance of AZD2014(Week 1 Day 1: pre-dose, 2h and 6-8 hours later and Week 2 Day 1: pre-dose, 2h and 6-8 hours later)
研究者
研究点 (12)
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