A Prospective, Multicentre Phase II Study of the Efficacy of Lenvatinib Combined With Denosumab in the Treatment of Patients With Predominant Bone Metastatic Radioiodine Refractory Differentiated Thyroid Carcinomas (LENVOS)
试验速览
- 阶段
- 2 期
- 入组人数
- 35
- 试验地点
- 14
- 主要终点
- Determination of the efficacy of lenvatinib associated with denosumab in the treatment of patients with predominant bone metastases from Radioiodine-Refractory Differentiated Thyroid Carcinoma
研究概览
简要总结
This study evaluates the combination of lenvatinib with denosumab in bone-predominant metastatic Radioiodine Refractory Differentiated Thyroid Carcinomas. All patients will receive this combination of treatments.
详细描述
Patients are usually considered for directed therapy (radiotherapy and/or surgery and/or thermo-ablation) in case of symptomatic lesions or at high risk of local complications. They also usually receive systemic bone-directed agents (bisphosphonate or denosumab), despite sparse available data in the context of differentiated thyroid carcinomas (DTC). As bone-directed agents have no antitumor activity, patients may require additional treatments. To date, only sorafenib and lenvatinib have been approved in the treatment of advanced Radioiodine Refractory Differentiated Thyroid Carcinomas (RR-DTC).
Lenvatinib demonstrated efficacy in RR-DTC compared to placebo. While other kinase inhibitors appeared to be less effective in controlling bone metastatic disease compared to other soft tissue sites, lenvatinib showed, in a small number of patients, significant decrease in bone tumors size.
Even if both study drugs are indicated in the treatment of patients suffering from RR-DTC with bone metastases, it is of essential importance to confirm that lenvatinib can provide clinical benefit and antitumor activity when combined with denosumab in this population.
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
- •Males or females of 18 years of age or older at the day of consenting to the study;
- •Patients with follicular cell-derived thyroid (papillary, vesicular or and poorly differentiated);
- •Radioiodine-Refractory disease as defined by at least one of the following :
- •Presence of malignant/metastatic tissue that does not concentrate radioiodine (RAI),
- •Loss by the tumor tissue of the ability to concentrate RAI after previous evidence of RAI-avid disease,
- •Concentration of RAI in some lesions but not in others,
- •Progression of metastatic disease despite significant concentration of RAI;
- •Predominant bone metastases (without threatening extra-bone metastasis)
- •Patient at risk of Skeletal-Related Event defined by the occurrence of at least one of the following event within 12 months prior to inclusion:
- •Skeletal-Related Event, including indication of loco regional procedure (i.e. radiation therapy, interventional radiology),
- •Progressive disease with measurable metastatic bone lesion(s) as per the RECIST1.1; Nota Bene: bone lesions with soft tissue involvement are considered as measurable.
- •Performance Status of the Eastern Cooperative Oncology Group (ECOG) ≤2;
- •Adequate organ function within 14 days prior to treatment start, defined as the following:
- •Neutrophils count ≥ 1.5 Gi/l
- •Hemoglobin ≥ 9.0 g/dl
- •Platelets count ≥ 100 Gi/l
- •Prothrombin Time (PT) ≤ 1.2 x ULN or International Normalized Ratio ≤ 1.5 Nota bene: Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the targeted anticoagulation.
- •Serum transaminases (ASAT and ALAT) ≤ 3.0 x upper limit of the normal (ULN) (5.0 x ULN in case of liver metastases)
- •Serum total bilirubin ≤ 2 x ULN
- •Creatinine clearance ≥ 30ml/min;
- •Absence of proteinuria Nota Bene: patients with proteinuria ≥1+ on dipstick urinalysis will have to undergo 24 hours urine collection. Subjects with urine protein ≥1g/24h will be ineligible;
- •Albumin-adjusted serum calcium ≥ 2.0 mmol/l (8.0mg/dl) and ≤ 2.9 mmol/l (11.5mg/dl)
- •Patient and his/her partner using 2 forms of effective contraception:
- •For women of child-bearing potential: at least 4 weeks prior to study entry, during the study participation and for at least 1 month post-lenvatinib and at least 5 months post-denosumab,
- •For men: at least 4 weeks prior to study entry and during the study participation;
- •Patient must be covered by a medical insurance;
- •Willingness and ability to comply with the study requirements;
- •Signed and dated informed consent indicating that the patient has been informed of all the aspects of the trial prior to enrolment.
- •Non-inclusion Criteria:
- •Histological diagnosis of the following DTC subtypes: medullar, anaplastic, lymphoma or sarcoma;
- •Prior history of malignancies other than study disease within the last 3 years, except locally curable disease with no sign of relapse;
- •Prior or current treatment with denosumab or any other bone-directed agent (including bisphosphonates), regardless of the indication;
- •Prior or current treatment with any tyrosine kinase inhibitor, including but not limited to lenvatinib and denosumab ;
- •Patient with imminent or confirmed Skeletal-Related Event as defined in the protocol;
- •Uncontrolled arterial hypertension (150mmHg/90mmHg) despite an optimal antihypertensive intervention; patients with high blood pressure can be enrolled provided that the hypertension is well controlled at a stable dose of antihypertensive therapy for at least 1 week prior to lenvatinib start;
- •Any condition leading to an increased risk of bleeding or hemorrhage;
- •Any other contraindication to lenvatinib and/or denosumab
- •Major surgery within 3 weeks prior to the first study drug administration or major surgery planned during the course of the study;
- •Unhealed lesion from dental or oral surgery;
- •Any dental or jaw condition that may lead or already led to osteonecrosis of the jaw or to oral surgery; Nota Bene: a consultation with a specialist must confirm that dental and oral cavity assessment allows starting a treatment with denosumab.
- •Any active infection, including known infection with HIV, Hepatitis B or Hepatitis C;
- •Patient participating to a clinical trial that can interfere with the primary outcome assessment or treatment with any investigational drug within 4 weeks prior to the start date of study drugs or planned during the study participation;
- •Any organic or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results;
- •Pregnant or breast feeding women. Women of childbearing potential* are required to have a negative serum pregnancy test within 72 hours prior to study treatment start. A positive urine test must be confirmed by a serum pregnancy test
- •*: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential:
- •≥50 years old and naturally amenorrheic for ≥ 1 year
- •Permanent premature ovarian failure confirmed by a specialist gynecologist
- •Previous bilateral salpingo-oophrectomy
- •XY genotype, Turner's syndrome, or uterine agenesis Female patients who do not meet at least one of the above criteria are defined as women of childbearing potential.
- •Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of lenvatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection);
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排除标准
- 未提供
研究组 & 干预措施
Trial arm
Lenvatinib and Denosumab will be used in the indication of their respective SmPCs.
Study treatments will be divided in fictitious cycles of 28 days. Lenvatinib and Denosumab will be administered as per investigator's decision, based on the data from their SmPC, at starting doses of 24mg once daily and 120mg once every 4 weeks, respectively. Dose modification guidelines of their respective SmPCs will apply.
Lenvatinib should be started the day after the inclusion. It will be taken every day at the same time, preferentially in the morning.
As in routine practice, all patients will be supplemented with daily doses of at least 500mg Calcium and 400IU Vitamin D, unless hypercalcemia is present.
Patients will be encouraged to maintain good oral hygiene during treatment with Denosumab.
Study drugs will be continued until a treatment discontinuation criterion is met.
干预措施: Lenvatinib + Denosumab (Drug)
结局指标
主要结局
Determination of the efficacy of lenvatinib associated with denosumab in the treatment of patients with predominant bone metastases from Radioiodine-Refractory Differentiated Thyroid Carcinoma
时间窗: 24 months
The 24-month Skeletal-Related Event-Free (24M-SREF) rate will be defined as the proportion of patients without bone-related orthopedic surgical intervention at 24 months
次要结局
- Determination of the progression free survival(24 months)
- Determination of the objective response rate(24 months)
- Determination of the time to treatment failure(24 months)
- Determination of the analgesic consumption(24 months)
- Determination of the tolerance profile(24 months)
- Determination of the time to the first local procedure(24 months)
- Determination of the Quality of life using European Organisation for Research and Treatment of Cancer (EORTC) questionnaire(24 months)