A Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer (DTC)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 153
- 试验地点
- 44
- 主要终点
- Progression Free Survival (PFS)
研究概览
简要总结
The purpose of this study is to assess the efficacy and safety of dabrafenib in combination with trametinib for treating adult patients with locally advanced or metastatic Differentiated Thyroid Cancer (DTC) harboring the BRAFV600E mutation, who are refractory to radioactive iodine (RAI) therapy and have experienced disease progression following one or two prior VEGFR-targeted treatments.
详细描述
This is a global, multicenter, randomized, double-blind, placebo-controlled Phase III study designed to evaluate the efficacy and safety of dabrafenib plus trametinib in adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that is positive for the BRAF V600E mutation, refractory to radioactive iodine (RAI), and has progressed following prior vascular endothelial growth factor receptor (VEGFR) targeted therapy.
After eligibility assessment, patients will be randomized in a 2:1 ratio to receive either dabrafenib plus trametinib or placebo. Patients will be stratified by the number of prior VEGFR targeted therapies (one versus two) and prior lenvatinib treatment (yes versus no).
The scientific objective guiding the primary estimand is based on progression-free survival (PFS) as per blinded independent review committee (BIRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
This study will enroll approximately 150 patients.
Patients randomized to the placebo arm who experience disease progression as per RECIST 1.1 confirmed by BIRC and meet eligibility criteria will have the option to cross over to the open-label combination of dabrafenib plus trametinib.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent
- •Male or female ≥ 18 years of age at time of informed consent
- •Histologically or cytologically confirmed diagnosis of advanced/metastatic differentiated thyroid carcinoma
- •Radioactive-iodine refractory disease
- •BRAF V600E mutation-positive tumor sample as per central laboratory result
- •Has progressed on at least 1 but not more than 2 prior VEGFR targeted therapies
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- •At least one measurable lesion as defined by RECIST v1.
排除标准
- •Anaplastic or medullary carcinoma of the thyroid
- •Previous treatment with a BRAF inhibitor and/or a MEK inhibitor
- •Concomitant RET Fusion-Positive Thyroid Cancer
- •Treatment with any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization
- •Treatment with any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before randomization
- •Treatment with radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before randomization
- •A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy
- •Other inclusion/exclusion criteria may apply.
研究组 & 干预措施
Dabrafenib Placebo plus Trametinib Placebo
Eligible participants will receive matching placebo for Dabrafenib 150 mg twice a day (BID) and matching placebo for Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.
干预措施: Trametinib Placebo (Drug)
Dabrafenib Placebo plus Trametinib Placebo
Eligible participants will receive matching placebo for Dabrafenib 150 mg twice a day (BID) and matching placebo for Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.
干预措施: Dabrafenib placebo (Drug)
Dabrafenib plus Trametinib
Eligible participants will receive Dabrafenib 150 mg twice a day (BID) and Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.
干预措施: Dabrafenib (Drug)
Dabrafenib plus Trametinib
Eligible participants will receive Dabrafenib 150 mg twice a day (BID) and Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.
干预措施: Trametinib (Drug)
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 2 years
Progression Free Survival (PFS) was defined as the time from the date of randomization to the date of the first documented progression according to RECIST 1.1 based on Blinded Independent Review Committee (BIRC) assessment, or death due to any cause.
次要结局
- Overall Survival (OS)(From randomization to death assessed up to approximately 5 years)
- Overall Response Rate (ORR)(From randomization up to approximately 2 years)
- Overall Survival (OS)(From randomization to death assessed up to approximately 5 years)
- Duration of Response (DOR)(From the start date of the first documented response of complete response or partial response and the date defined as the date of the first documented progression or death due to any cause up to 2 years)
- Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)(Throughout study completion, an average 5 years)
- Number of participants with trametinib associated serous retinopathy ocular events(screening, week 4, week 8, week 12, week 20 and every 12 weeks after week 20, up to approximately 2 years)