Dovitinib In 1st-Line Renal Cell Carcinoma, an Investigation Into Tumour GENe Status and Correlation With Efficacy - 1st Exploratory Study
试验速览
- 阶段
- 2 期
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Progression-free survival (PFS) as assessed by RECIST 1.1.
研究概览
简要总结
The main purpose of this study is to find out how useful dovitinib is when given as the initial treatment to participants with advanced kidney cancer, that has spread to other parts of the body. The usefulness of dovitinib will be assessed by: how long the disease is controlled while participants are receiving the drug, the proportion of participants who get a reduction in the size of their tumours and how long participants live (both while on dovitinib and on any subsequent therapy they may receive).
If participants have secondary disease in the bones, the study will evaluate how useful dovitinib is in controlling this site of disease. In addition, this study will look for changes in the genetic makeup of tumour cells and see if some of these changes are associated with a benefit from dovitinib. The study will also compare and contrast the genetic changes in the primary tumour cells with cells from secondary tumour specimens, and with cells from tumour specimens taken if a participant's disease has worsened. The purpose of the latter is to identify possible ways in which the tumour becomes resistant to the study drug.
详细描述
The purpose of this prospective, single centre, non-randomised, open-label, phase II study will evaluate the activity of dovitinib in the treatment naïve population of patients with advanced RCC.
Background: Prior to the middle of last decade, the only systemic therapy for patients with advanced RCC was immunotherapy (interleukin-2 and interferon-alpha) with limited effectiveness and a multitude of side-effects. Since 2006, there have been 6 targeted therapies that have been FDA-registered for the treatment of advanced RCC; the anti-VEGFR tyrosine kinase inhibitors (sunitinib, sorafenib and pazopanib), the anti-VEGF antibody bevacizumab (with interferon-alpha) and the mTOR inhibitors (everolimus and temsirolimus). These treatments have significantly advanced outcomes for patients with this disease but unfortunately they do not represent cures. The median overall survival for patients treated with a standard first-line therapy (sunitinib) is just over 2 years and the median PFS for subjects receiving this agent is only 11 months. This means that the typical time it takes for subjects to develop resistance to standard first-line tyrosine kinase inhibitor (TKI) treatment, as evidenced by significant tumour growth on imaging, is under 1 year.
Despite the recent rapid advancements in the treatment options for subjects with advanced RCC, there is still an unmet need for more effective therapeutic options for patients with this disease so as to improve survival and make steps towards the ultimate treatment aim for patients with metastatic disease - cure. Available data suggests that dovitinib is a very active agent in metastatic RCC. If it has efficacy in the heavily pre-treated RCC population, one would expect it to be considerably more active when it is moved forward into the first-line setting.
Dovitinib is a broad-targeted receptor Tyrosine Kinase Inhibitor (TKI) primarily active against three receptors that mediate tumour growth and survival: vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR). A distinguishing feature of dovitinib (compared to other anti-VEGFR TKI's) is its FGFR inhibition. Up-regulation of the fibroblast growth factor receptor 1 (FGFR1) pathway has been demonstrated in metastatic RCC and is a postulated mechanism of resistance to anti-VEGFR therapies. This is thought to be one of the reasons why dovitinib has activity in subjects treated with prior anti-VEGFR therapies. If we move the FGFR inhibition forward into the first-line setting (by using dovitinib) we hope to be able prevent or delay the development of resistance acquired through FGFR up-regulation. We hope this may allow subjects to remain on first-line therapy for much longer and in doing so improve survival and outcomes for this group of patients.
Dovitinib has been studied in heavily pre-treated subjects with metastatic RCC, and in these phase I/II studies it looks very active. If it has efficacy in the heavily pre-treated RCC population, it is possible it would be more active when it is moved forward in to the first-line setting.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Advanced renal cell (clear cell) carcinoma confirmed histologically, including either distant metastases or locally advanced disease that is not resectable or potentially resectable following response. Sarcomatoid change is allowed if clear cell predominant. Histological variants, papillary, chromophobe and collecting duct carcinoma are not allowed.
- •Availability of FFPE tissue for gene status analysis. If unavailable, an image-guided biopsy of a metastatic disease site is required.
- •Evaluable disease by RECIST 1.1 criteria
- •ECOG (WHO) performance status 0 or 1
- •Age ≥ 18 years
- •Absolute neutrophil count ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L; haemoglobin > 9 g/dL; serum total bilirubin ≤ 1.5 x ULN; ALT and AST ≤ 3.0 x ULN; serum creatinine ≤ 1.5 x ULN or creatinine clearance >35 ml/min by Cockcroft and Gault.
排除标准
- •Uncontrolled brain metastases. For know brain metastases, definitive treatment with either surgery, stereotactic radiotherapy or whole brain radiotherapy is required. Patients must be neurologically stable for > 4 weeks after CNS treatment ends, and either be off corticosteroids or receiving a low daily dose.
- •Another primary malignancy within 3 years prior to starting study treatment, except for adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix. If another primary tumour was noted within this period, a metastatic disease site biopsy is required to confirm renal origin.
- •Prior systemic anticancer treatment for renal carcinoma. Prior bisphosphonates are allowed.
- •Radiotherapy ≤ 4 weeks prior to starting the study drug or non-recovery from related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study drug is allowed.
- •Major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic) ≤ 4 weeks prior to starting study treatment or non-recovery from surgical side effects.
- •History of pulmonary embolism or untreated deep venous thrombosis within the past 6 months. If a history of PE or DVT within the past 6 months is present, patients must be clinically stable on appropriate doses of anticoagulation as per thrombosis specialist advice.
- •Impaired cardiac function or clinically significant cardiac diseases, including history of serious uncontrolled ventricular arrhythmias; clinically significant resting bradycardia; LVEF assessed by 2-D echocardiogram < 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan < 45% or lower limit of normal (whichever is higher). Within 6 months prior to starting study drug: myocardial infarction, severe/unstable angina, coronary artery bypass graft, congestive heart failure, cerebrovascular accident, transient ischemic attack; uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 90 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication is allowed before study entry.
- •Impaired gastrointestinal function or GI disease that may significantly alter dovitinib absorption, e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection.
- •Cirrhosis, chronic active hepatitis or chronic persistent hepatitis
- •Known diagnosis of human immunodeficiency virus infection (testing is not mandatory)
- •Current full dose anticoagulation treatment with therapeutic doses of warfarin, dabigatran or anti-platelet therapy. Treatment with ≤ 100mg acetylsalicyclic acid daily is allowed as are therapeutic or prophylactic doses of low molecular weight heparin, provided there is no recent evidence of bleeding.
- •Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. infection, diabetes) that could cause unacceptable safety risks or compromise protocol compliance.
- •Pregnant or breast-feeding women
- •Women of child-bearing potential or fertile males not using effective contraception.
研究组 & 干预措施
Dovitinib
Dovitinib 500 mg taken orally once daily 5 days on / 2 days off, until disease progression
干预措施: Dovitinib (Drug)
结局指标
主要结局
Progression-free survival (PFS) as assessed by RECIST 1.1.
时间窗: From baseline until documented disease progression, estimated to be up to 65 weeks
Description: Subjects will undergo baseline radiology assessment with a CT scan of the chest, abdomen, pelvis and head within 4 weeks of registration. Thereafter subjects will then undergo CT scans of the chest, abdomen and pelvis (where possible using the same technique) every 9 weeks until week 54. From week 54 onward, subjects will undergo CT scans of the chest, abdomen and pelvis every 12 weeks until disease progression. Tumour responses will be evaluated using RECIST 1.1. Confirmation of responses (PR/CR) with repeat CT is not required as the primary end-point is PFS. CT will be the only imaging modality required for subjects on study. The RECIST 1.1 assessments will be done in Auckland by one of the members of the Tumour Response EvAluation Team (TREAT) who have expertise in RECIST reporting.
次要结局
- Efficacy (PFS, RR, OS) by FGFR gene amplification status as measured by Spearman's rho correlation coefficient(Baseline until documented disease progression, estimated to be up to 65 weeks)
- Response rate (RR) using RECIST 1.1.(Change from baseline until disease progression, estimated to be up to 65 weeks)
- Proportion of subjects who are FGFR-1,-2,-3 amplified using gene analysis by Fluorescent in-situ hybridization(Disease progression, estimated to be up to 65 weeks.)
- Safety profile of dovitinib (specifically in this first-line patient population) using NCI CTCAE v4.0(From documented disease progression up to 2 years.)