A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Eisai Inc.
- 入组人数
- 64
- 试验地点
- 50
- 主要终点
- Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
研究概览
简要总结
Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric participants with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design, will be conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric participants with selected recurrent/refractory solid tumors including Ewing sarcoma, rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase 1: Phase 1; Recurrent or refractory solid tumors
During Phase 1 (Treatment Phase: 1 cycle; 28 days of treatment), utilizing a rolling 6 design, participants with recurrent or refractory solid tumors will receive escalating doses of lenvatinib in combination with everolimus for determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Participants who complete 1 cycle of treatment will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Lenvatinib (Drug)
Phase 1: Phase 1; Recurrent or refractory solid tumors
During Phase 1 (Treatment Phase: 1 cycle; 28 days of treatment), utilizing a rolling 6 design, participants with recurrent or refractory solid tumors will receive escalating doses of lenvatinib in combination with everolimus for determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Participants who complete 1 cycle of treatment will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Everolimus (Drug)
Phase 2: Cohort 1, Ewing sarcoma
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory Ewing sarcoma (Cohort 1) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1. Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Lenvatinib (Drug)
Phase 2: Cohort 1, Ewing sarcoma
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory Ewing sarcoma (Cohort 1) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1. Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Everolimus (Drug)
Phase 2: Cohort 2, Rhabdomyosarcoma
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory rhabdomyosarcoma (Cohort 2) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks of treatment). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Lenvatinib (Drug)
Phase 2: Cohort 2, Rhabdomyosarcoma
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory rhabdomyosarcoma (Cohort 2) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks of treatment). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Everolimus (Drug)
Phase 2: Cohort 3, High Grade Glioma (HGG)
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory HGG (Cohort 3) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Lenvatinib (Drug)
Phase 2: Cohort 3, High Grade Glioma (HGG)
During Phase 2 (four 28-day cycles [up to 16 weeks of treatment]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory HGG (Cohort 3) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
干预措施: Everolimus (Drug)
结局指标
主要结局
Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
时间窗: From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
A TEAE was defined as an adverse event that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event is continuous. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
Phase 1: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE)
时间窗: From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months)
A TESAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An adverse event was defined as any untoward medical occurrence in a participant administered an investigational product.
Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib in Combination With Everolimus
时间窗: Cycle 1 (Each cycle was of 28 days)
MTD was defined as the highest dose level at which no more than 1/6 participants experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. DLT was graded according to common terminology criteria for adverse events (CTCAE) version 4.03.
Phase 1: Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Everolimus
时间窗: Cycle 1 (Each cycle was of 28 days)
The RP2D of lenvatinib in combination with everolimus was determined by Dose Escalation Committee (DEC) based on safety (including DLTs), pharmacokinetic and clinical data. DLT was graded according to CTCAE v4.03.
Phase 2: Objective Response Rate (ORR) at Week 16
时间窗: Week 16
ORR at Week 16 was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at Week 16 based on investigator assessment according to response evaluation criteria in solid tumors (RECIST) version 1.1 for non-HGG cohorts and response assessment in neuro-oncology (RANO) for HGG cohort. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis less than (\<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters.
次要结局
- Phase 2: Disease Control Rate (DCR)(From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months))
- Phase 2: Objective Response Rate (ORR)(From the date of the first dose of study drug to the date of first documentation of disease progression or death, which ever occurred first (up to 6.5 months))
- Phase 1: Objective Response Rate (ORR)(From the date of the first dose of study drug to the date of first documentation of disease progression or death, whichever occurred first (up to 16.5 months))
- Phase 1: Clinical Benefit Rate (CBR)(From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months))
- Phase 2: Duration of Response (DOR)(From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 6.5 months))
- Phase 1: Disease Control Rate (DCR)(From first dose of study drug until PD or death, whichever occurred first (up to 16.5 months))
- Phase 1: Maximum Plasma Concentration of Lenvatinib (Cmax)(Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days))
- Phase 1: Time to Reach Maximum Plasma Concentration (Cmax) of Lenvatinib (Tmax)(Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days))
- Phase 1: Trough Concentrations (Ctrough) of Everolimus When Administered in Combination With Lenvatinib(Cycle 1 Days 1, 2, 15 and 22: Pre-dose (Cycle length=28 days))
- Phase 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)(From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months))
- Phase 2: Clinical Benefit Rate (CBR)(From first dose of study drug until PD or death, whichever occurred first (up to 6.5 months))
- Phase 1: Duration of Response (DOR)(From date of the first observation of CR or PR until the date of first observation of progression or date of death (up to 16.5 months))
- Phase 1: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Lenvatinib (AUC[0-t Hours])(Cycle 1 Days 1 and 15: 0-8 hours post-dose (Cycle length=28 days))
- Phase 2: Number of Participants With Any Treatment-emergent Serious Adverse Event (TESAE)(From date of first dose up to 28 days after the last dose of study treatment (up to 7.5 months))