A Multicenter, Randomized, Double-Blind Phase 2 Trial of Lenvatinib (E7080) in Subjects With 131I-Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 mg Daily Will Provide Comparable Efficacy to a 24-mg Starting Dose, But Have a Better Safety Profile
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Eisai Inc.
- 入组人数
- 241
- 试验地点
- 10
- 主要终点
- Objective Response Rate (ORR) as of Week 24 (ORR24wk)
研究概览
简要总结
This is a multicenter, randomized, double-blind study being conducted as a postmarketing requirement to the US Food and Drug Administration (FDA) to evaluate whether there is a lower starting dosage of lenvatinib 24 mg once daily (QD) that provides comparable efficacy but has a better safety profile in participants with radioiodine-refractory differentiated thyroid cancer RR-DTC with radiographic evidence of disease progression within the prior 12 months.
详细描述
This study consists of 2 phases, the Prerandomization Phase and the Randomization Phase. The Prerandomization Phase will last no longer than 28 days and will include a Screening Period to establish protocol eligibility and a Baseline Period to confirm eligibility and establish disease characteristics prior to randomization and treatment.
The Randomization Phase will consist of a Treatment Period and a Follow-up Period. It will begin at the time of randomization of the first participant and will consist of 28-day blinded study treatment cycles. The data cutoff for the primary analysis will occur at the end of the Randomization Phase, which is defined as when the last participant enrolled completes the Week 24 tumor assessments or discontinues study treatment if before Week 24.
Participants on treatment at the time of data cutoff for the primary analysis will remain on blinded investigational product until the primary analysis has been completed, after which they will transition to commercial lenvatinib outside the study. The last participant's last assessment (Off-treatment visit) will be the End of Study.
Participants will be randomly assigned to treatment with 1 of 2 blinded starting dosages of lenvatinib in a 1:1 ratio to receive lenvatinib 18 mg or 24 mg orally once daily (QD). Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, and 8 mg QD, or 18, 14, 10, 8, and 4 mg QD, respectively). Once the dose has been reduced, it may not be increased at a later date.
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
- Double (Participant, Investigator)
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
- •Participants must have histologically or cytologically confirmed diagnosis of one of the following differentiated thyroid cancer (DTC) subtypes:
- •Papillary thyroid cancer (PTC)
- •Follicular variant
- •Variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated)
- •Follicular thyroid cancer (FTC)
- •Hurthle cell
- •Clear cell
- •Measurable disease meeting the following criteria and confirmed by central radiographic review:
- •At least 1 lesion of greater than or equal to (>=)1.0 centimeter (cm) in the longest diameter for a non-lymph node or >=1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) using computed tomography/magnetic resonance imaging (CT/MRI). If there is only 1 target lesion and it is a non-lymph node, it should have a longest diameter of >=1.5 cm.
- •Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.
- •Participants must show evidence of disease progression within 12 months (an additional month will be allowed to accommodate actual dates of performance of screening scans, that is, within less than or equal to <=13 months) prior to signing informed consent, according to RECIST 1.1 assessed and confirmed by central radiographic review of CT and/or MRI scans.
- •Participants must be Iodine-131 refractory/resistant as defined by at least one of the following:
- •One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan.
- •One or more measurable lesions that have progressed according to RECIST 1.1 within 12 months (an additional month will be allowed to accommodate actual dates of performance of screening scans, ie, within ≤13 months) after Iodine-131 therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or posttreatment scanning. These participants must not be eligible for possible curative surgery.
- •Cumulative activity of Iodine-131 of greater than (>) 600 millicurie (mCi) or 22 gigabecquerels (GBq), with the last dose administered at least 6 months prior to study entry.
- •Participants with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection, will be eligible if they have remained clinically stable, asymptomatic, and off steroids for one month.
- •Participants must be receiving thyroxine suppression therapy and thyroid stimulating hormone (TSH) should not be elevated (TSH should be <=5.50 micro-international units per liter [mcIU/ML]). When tolerated by the participant, thyroxine dose should be changed to achieve TSH suppression (TSH <0.50 mcIU/ML) and this dose may be changed concurrently upon starting study drug treatment.
- •All chemotherapy or radiation-related toxicities must have resolved to Grade <2 severity per Common Terminology Criteria for Adverse Events (CTCAE v4.03), except alopecia and infertility.
- •Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or
- •Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week prior to Cycle 1/Day
- •Adequate renal function defined as calculated creatinine clearance >=30 mL/min per the Cockcroft and Gault formula.
- •Adequate bone marrow function:
- •Absolute neutrophil count (ANC) >=1500/mm^3 (>=1.5*10^3/uL)
- •Platelets >=100,000/mm^3 (>=100*10^9/L)
- •Hemoglobin >=9.0 g/dL
- •Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) <=1.
- •Adequate liver function:
- •Bilirubin <=1.5*upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome.
- •Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3*ULN (<=5*ULN if participant has liver metastases). If alkaline phosphatase is >3*ULN (in absence of liver metastases) or >5*ULN (in presence of liver metastases) AND the participant also is known to have bone metastases, the liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of total alkaline phosphatase.
- •Males or females age >=18 years at the time of informed consent.
- •Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [B-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of B-hCG. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
- •All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing).
- •Females of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with lenvatinib and for at least 1 month after finishing treatment. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (example, total abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. Women using oral hormonal contraceptives should add a barrier method.
- •Participants must voluntarily agree to provide written informed consent.
- •Participants must be willing and able to comply with all aspects of the protocol.
排除标准
- •Anaplastic or medullary carcinoma of the thyroid.
- •Diagnosed with meningeal carcinomatosis.
- •Two or more prior vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR)-targeted therapies or any ongoing treatment for RR-DTC other than TSH-suppressive thyroid hormone therapy.
- •Prior treatment with lenvatinib.
- •Participants who have received any anticancer treatment within 21 days or any investigational agent within 30 days (or 5 half-lives) prior to the first dose of study drug and should have recovered from any toxicity related to previous anticancer treatment. This does not apply to the use of TSH suppressive thyroid hormone therapy.
- •Major surgery (example, laparotomy, thoracotomy or joint replacement) within 3 weeks prior to randomization or elective surgery scheduled to be performed during the study.
- •Participants having >1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 g/24 h will be ineligible.
- •Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of study drug.
- •Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebral vascular accident within 6 months of the first dose of study drug, or cardiac arrhythmia associated with hemodynamic instability.
- •Prolongation of corrected QT interval (QTc) to >480 ms as demonstrated by a repeated electrocardiogram (ECG) or a clinically significant ECG abnormality, including a marked prolonged QT/QTc interval (example, a repeated demonstration of a QTc interval >500 ms).
- •Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
- •Active infection (any infection requiring treatment).
- •Active malignancy (except for DTC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
- •Bleeding or thrombotic disorders.
- •Known intolerance to study drug (or any of the excipients).
- •Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study.
- •Females who are pregnant or breastfeeding.
研究组 & 干预措施
24 mg Lenvatinib
Participants will receive 24 mg once daily (QD) as the starting dose. Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, or 8 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.
干预措施: Lenvatinib (Drug)
24 mg Lenvatinib
Participants will receive 24 mg once daily (QD) as the starting dose. Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, or 8 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.
干预措施: Lenvatinib matching placebo (Drug)
18 mg Lenvatinib
Participants will receive 18mg QD as the starting dose. Dose reductions will occur in succession based on the previous dose level (18,14, 10, 8, or 4 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.
干预措施: Lenvatinib (Drug)
18 mg Lenvatinib
Participants will receive 18mg QD as the starting dose. Dose reductions will occur in succession based on the previous dose level (18,14, 10, 8, or 4 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.
干预措施: Lenvatinib matching placebo (Drug)
结局指标
主要结局
Objective Response Rate (ORR) as of Week 24 (ORR24wk)
时间窗: From the date of randomization up to Week 24
ORR as of Week 24 was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) as of the Week 24 time point or earlier, as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.
Percentage of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) in the First 24 Weeks
时间窗: Baseline up to Week 24
This outcome measure reports TEAEs in the first 24 weeks only. A TEAE was defined as any adverse event (AE) that had an onset date on or after the first dose of study drug up to 28 days following the last dose of study drug, or a worsening in severity from Baseline (pretreatment). In addition, if an AE reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, it was also counted as a TEAE. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.
次要结局
- PFS After Next Line of Treatment (PFS2)(Time from randomization to PD on next-line treatment or death from any cause, whichever occurs first up to approximately 2 years 6 months)
- Number of Participants With Weight Decrease Stratified by AUC Quartile (Q) Group(Up to 3 years 3 months)
- Number of Participants With Hypertension Stratified by AUC Quartile (Q) Group(Up to 3 years 3 months)
- Progression-free Survival (PFS)(Time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurs first up to approximately 2 years 6 months)
- Number of Participants With TEAE and Serious Adverse Events (SAEs)(From date of first administration of study drug up to 28 days after last dose of study drug up to approximately 3 years 3 months)
- Time to First Dose Reduction(From date of first administration of study drug up to approximately 2 years 6 months)
- Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib(Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days))
- Time to Treatment Discontinuation Due to an Adverse Event (AE)(From date of first administration of study drug up to approximately 2 years 6 months)
- Number of Dose Reductions(From date of first administration of study drug up to approximately 2 years 6 months)
- Scale Factor Estimate for Final Parametric Time to Event PK/PD Model for PFS(Time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 3 years 3 months)
- Shape Factor Estimate for Final Parametric Time to Event PK/PD Model for PFS(Time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 3 years 3 months)
- Lenvatinib AUC Exposure Effect Estimate for Final Parametric Time to Event PK/PD Model for PFS(Time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 3 years 3 months)
- Predicted Percent Change in Tumor Size Estimate for Final Parametric Time to Event PK/PD Model for PFS(Time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 3 years 3 months)
- Model Predicted Apparent Total Clearance (CL/F) Following Oral Dosing of Lenvatinib(Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days))
- Parameter Estimates From the Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Thyroglobulin Levels(Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days))
- Parameter Estimates From the Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Thyroid-Stimulating Hormone (TSH) Levels(Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days))
- Baseline Level Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Vascular Endothelial Growth Factor (VEGF), Soluble Tie-2, Angiopoietin-2 (Ang-2) and Fibroblast Growth Factor-23 (FGF23) Levels(Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days))
- Mean Residence Time (MRT) Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and VEGF, Soluble Tie-2, Ang-2 and FGF23 Levels(Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days))
- Hill Coefficient Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and VEGF, Soluble Tie-2, Ang-2 and FGF23 Levels(Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days))
- Parameter Estimates From the PK/PD Model for Tumor Growth Inhibition and Serum Biomarkers Tie-2 and Ang-2(Baseline up to week 120)
- Lenvatinib Mean AUC Resulting in 50% of the Emax (EC50) Estimate From the PK/PD Model for Tumor Growth Inhibition and Serum Biomarkers Tie-2 and Ang-2(Baseline up to week 120)
- Baseline Tumor Size Estimate for Final Parametric Time to Event PK/PD Model for PFS(Time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 3 years 3 months)
- Input Rate Indirect Effect Model Estimate From Base/Final PK/PD Blood Pressure Model(From date of first administration of study drug up to 6 months)
- Drug Effect on Systolic and Diastolic Input Rate Estimates From Base/Final PK/PD Blood Pressure Model(From date of first administration of study drug up to 6 months)
- Number of Participants With Proteinuria Stratified by AUC Quartile (Q) Group(Up to 3 years 3 months)
- Number of Participants With Fatigue Stratified by AUC Quartile (Q) Group(Up to 3 years 3 months)
- Number of Participants With Diarrhea Stratified by AUC Quartile (Q) Group(Up to 3 years 3 months)
- Number of Participants With Nausea Stratified by AUC Quartile (Q) Group(Up to 3 years 3 months)
- Number of Participants With Vomiting Stratified by AUC Quartile (Q) Group(Up to 3 years 3 months)
- Change From Baseline in the Health-Related Quality of Life (HRQoL) Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS)(Baseline, Week 8, 16, and 24)
- Change From Baseline in the HRQoL Assessed by Functional Assessment of Cancer Therapy-General (FACT-G) Total Score(Baseline, Week 8, 16 and 24)