Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults With Osteosarcoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 117
- 试验地点
- 19
- 主要终点
- Cohort 1: Recommended Dose (RD) of Lenvatinib
研究概览
简要总结
This is a phase 1/2 study evaluating safety, tolerability, and efficacy of lenvatinib as single-agent, and in combination with chemotherapy (ifosfamide and etoposide) in children and adolescents with refractory or relapsed solid malignancies including differentiated thyroid carcinoma (single agent lenvatinib) and osteosarcoma (single agent and combination lenvatinib).
详细描述
The study consists of 5 cohorts:
Cohort 1 (Single-Agent Dose-Finding) dose-escalation to find the recommended dose (RD) of lenvatinib using time-to-event continual reassessment method (TiTE-CRM) in children and adolescents with relapsed or refractory solid malignant tumors. When the RD is identified, Cohorts 2A, 2B, and 3A will enroll in parallel.
Cohort 2 (Single-Agent Expansion) will evaluate the efficacy of lenvatinib at the RD in children, adolescents, and young adults with
- 131 iodine-refractory differentiated thyroid cancer (DTC) [Cohort 2A] or
- Relapsed or refractory osteosarcoma [Cohort 2B]
Cohort 3A (Combination Dose-Finding) will determine the RD of lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma.
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 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed diagnosis of solid malignant tumor.
- •Cohort 1: Any solid malignant tumor.
- •Cohort 2A: Differentiated Thyroid Cancer (DTC) with one of the following histological subtypes:
- •i) Papillary thyroid cancer (PTC). i.a) Follicular variant. i.b) Other variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis-like stroma, Hurthle cell variant of papillary carcinoma, or poorly differentiated carcinomas).
- •ii) Follicular thyroid cancer (FTC). ii.a) Hurthle cell. ii.b) Clear cell. ii.c) Insular.
- •c) Cohort 2B, 3A, and 3B: Relapsed or refractory osteosarcoma.
- •Relapsed or refractory solid tumor malignancy that has progressed on standard anticancer therapy with no available curative options. (Note: Osteosarcoma participants must be in first or subsequent relapse [greater than or equal to first relapse]). Only the osteosarcoma participants enrolled to Cohorts 3A and 3B must be deemed candidates for ifosfamide and etoposide chemotherapy).
- •Evaluable or measurable disease that meets the following criteria:
- •Participants must have evaluable or measurable disease based on RECIST 1.1 using computed tomography (CT)/magnetic resonance imaging (MRI).
- •Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must have subsequently grown unequivocally to be deemed a target lesion.
- •DTC participants must be 131 iodine-refractory/ relapsed as defined by at least one of the following:
- •One or more evaluable or measurable lesions that do not demonstrate iodine uptake on any radioiodine scan; or
- •One or more evaluable or measurable lesions that have progressed based on RECIST 1.1, within 12 months of 131 iodine therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or post-treatment scanning. These participants must not be eligible for possible curative surgery; or
- •Cumulative activity of 131 iodine greater than 400 millicuries (mCi) or 14.8 gigabecquerels (GBq), with the last dose administered at least 6 months prior to study entry.
- •Participants with DTC must be receiving thyroxine suppression therapy and levels of thyroid stimulating hormone (TSH) should not be elevated (TSH should be less than or equal to 5.50 milliunits per liter (mU/L)). When tolerated by the participant, thyroxine dose should be changed to achieve TSH suppression (TSH less than 0.50 mU/L).
- •Participants with known central nervous system (CNS) primary tumors or metastases who have completed brain therapy (such as radiotherapy, stereotactic radiosurgery, or surgical resection) and have remained clinically stable, asymptomatic, and off of steroids for 2 weeks prior to Cycle 1 Day 1 will be eligible.
- •Male or female participants age 2 years to less than18 years and less than or equal to 25 years for osteosarcoma subjects at the time of informed consent.
- •Lansky play score greater than or equal to 50% or Karnofsky Performance Status score greater than or equal to 50%. Use Karnofsky for participants greater than or equal to 16 years of age and Lansky for participants less than 16 years of age.
- •Life expectancy greater than or equal to 3 months.
- •Adequate bone marrow function as evidenced by:
- •absolute neutrophil count (ANC) greater than or equal to 1.0 x 10^9/L (for Cohorts 3A and 3B leucocyte count greater than or equal to 2 x 10^9/L; participants with bone marrow involvement should have ANC greater than or equal to 0.8 x 10^9/L and leucocyte count greater than or equal to 1 x 10^9/L).
- •hemoglobin greater than or equal to 8.0 grams/deciliter (g/dL) (a hemoglobin less than 8.0 g/dL is acceptable if it is corrected by growth factor or transfusion before starting lenvatinib).
- •platelet count greater than or equal to 75 x 10^9/L.
- •Adequate liver function as evidenced by:
- •bilirubin less than or equal 1.5 times the upper limit of normal (ULN).
- •alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN.
- •Adequate renal function as evidenced by:
- •a) Serum creatinine based on age/gender as below. If serum creatinine is greater than maximum serum creatinine for age/gender as shown in the table below, then creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be greater than 70 milliliter/minute/1.73 square meter (mL/min/1.73 m2).
- •Maximum Serum Creatinine in milligrams/deciliter (mg/dL) for male:
- •i. Age 2 to less than 6 years = 0.8
- •ii. Age 6 to less than 10 years = 1.0
- •iii. Age 10 to less than 13 years = 1.2
- •iv. Age 13 to less than 16 years = 1.5
- •v. Age greater than or equal to 16 years = 1.7
- •Maximum Serum Creatinine (mg/dL) for Female:
- •vi. Age 2 to less than 6 years = 0.8
- •vii. Age 6 to less than 10 years = 1.0
- •viii. Age 10 to less than 13 years = 1.2
- •ix. Age 13 to less than 16 years = 1.4
- •x. Age greater than or equal to 16 years = 1.4
- •The threshold creatinine values in this Table were derived from the Schwartz formula for estimating glomerular filtration rate using child length and stature data published by the CDC.
- •b) Urine dipstick less than 2+ for proteinuria. Participants who have greater than or equal to 2+ proteinuria on dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio that should be Grade less than
- •c) No clinical evidence of nephrotic syndrome.
- •Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) greater than or equal to 50%) at baseline as determined by echocardiography.
- •Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:
- •BP less than 95th percentile for sex, age, and height/length at screening (as per National Heart Lung and Blood Institute guidelines) and no change in antihypertensive medications within 1-week prior to Cycle 1/Day
- •Osteosarcoma subjects 18 to 25 years should have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1/Day
- •Washout of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, and 2 weeks for palliative radiotherapy; 3 months from high-dose chemotherapy and stem cell rescue; 3 weeks from major surgery. Participants must have recovered from the acute toxic effects of all prior anticancer therapy before enrollment into the study.
- •Written and signed informed consent from the parent(s) or legal representative (guardian) and assent from the minor participant. Written informed consent from subjects ≥18 years.
- •Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity as judged by the Investigator.
- 另有 19 项未显示
排除标准
- 未提供
研究组 & 干预措施
Cohort 1: Single-Agent Dose-Finding
Children and adolescents with relapsed or refractory solid malignant tumors.
干预措施: Lenvatinib (Drug)
Cohort 2A: Single-agent Expansion (DTC)
Children and adolescents with 131 iodine-refractory DTC.
干预措施: Lenvatinib (Drug)
Cohort 2B: Single-agent Expansion (Osteosarcoma)
Participants with relapsed or refractory osteosarcoma.
干预措施: Lenvatinib (Drug)
Cohort 3A: Combination Dose-finding
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
干预措施: Lenvatinib (Drug)
Cohort 3A: Combination Dose-finding
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
干预措施: Ifosfamide (Drug)
Cohort 3A: Combination Dose-finding
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
干预措施: Etoposide (Drug)
Cohort 3B: Combination Expansion
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
干预措施: Lenvatinib (Drug)
Cohort 3B: Combination Expansion
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
干预措施: Ifosfamide (Drug)
Cohort 3B: Combination Expansion
Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
干预措施: Etoposide (Drug)
结局指标
主要结局
Cohort 1: Recommended Dose (RD) of Lenvatinib
时间窗: Cycle 1 (28 days)
RD was defined as the dose that had a dose limiting toxicity (DLT) rate closest to the targeted 20% rate. DLT was an adverse drug reaction and was assessed according to common terminology criteria for adverse events (CTCAE) version (v) 4.03 defined as 1) Grade 4 neutropenia for greater than or equal to (\>=) 7 days, 2) Grade \>=3 thrombocytopenia with bleeding, or lasting greater than (\>) 7 days, 3) Grade \>=3 febrile neutropenia, 4) Next course of chemotherapy delayed for \>=7 days, 5) Grade \>=3 non-hematologic toxicity persisting \>7 days optimal supportive care, 6) Grade 4 hypertension, confirmed systolic or diastolic blood pressure \>25 millimeters of mercury (mmHg) above the 95th percentile for age, or an elevated diastolic blood pressure (that is, \>95th percentile for age) not controlled by a single antihypertensive medication within 14 days of use, 7) Grade 3 proteinuria, 8) Any recurrent Grade 2 non-hematological toxicity requiring \>=2 interruption and dose reductions.
Cohort 2A: Number of Participants With Best Overall Response (BOR)
时间窗: From first dose of study drug until PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)
BOR was defined as the best response of CR or PR for \>4 weeks or SD for \>=7 weeks recorded from the start of the treatment until PD or death, whichever occurred first based on RECIST v1.1. CR: 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 \<10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Cohort 2A: Number of Participants With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)
时间窗: From date of first dose of study drug until first documentation of PD or death, whichever occurred first (until the data cut-off date, 31 May 2019)
OR was defined as participants with best overall response (BOR) of CR or PR as assessed by investigator based on response evaluation criteria in solid tumors (RECIST) version (v) 1.1. For OR, the BOR was defined as the best response (CR or PR for \>4 weeks) recorded from the start of the treatment until PD or death whichever occurred first. CR was defined as the 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 \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
Cohorts 2B and 3B: Progression-free Survival (PFS) Rate at Month 4
时间窗: At Month 4
Progression free survival at Month 4 (PFS-4) rate was defined as the percentage of participants who were alive and without PD at Month 4 after the first dose of study drug, based on RECIST v1.1, using a binomial proportion with corresponding 95% confidence interval (CI). PD: \>= 20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of \>=5 mm. Appearance of \>=1 new lesions also considered PD.
Cohort 3A: Recommended Dose (RD) of Lenvatinib When Given in Combination With Etoposide and Ifosfamide
时间窗: Cycle 1 (21 days)
RD of lenvatinib when given in combination with ifosfamide and etoposide was defined as dose that resulted in no more than 1 DLT per 6 participants,or hematologic DLT in 1 participant and nonhematologic DLT in another participant per 6 participants,upon repeating same dose level.DLT was adverse drug reaction and assessed per CTCAE v4.03 defined as 1)Grade 4 neutropenia for \>=10 days,2)Grade \>=3 thrombocytopenia with bleeding,or lasting \>=10 days,3)Grade \>=3 febrile neutropenia lasting \>=7 days,4)Next course of chemotherapy delayed for \>=7 days,5)Grade \>=3 nonhematologic toxicity persisting \>7 days despite optimal supportive care,6)Grade 4 hypertension,confirmed systolic or diastolic blood pressure \>25 mmHg above 95th percentile for age,or elevated diastolic blood pressure(\>95th percentile for age)not controlled by single antihypertensive medication within 14 days use,7)Grade 3 proteinuria,8)Any recurrent Grade 2 nonhematological toxicity requiring \>=2 interruption and dose reductions.
次要结局
- Cohorts 1, 2B, 3A, and 3B: Number of Participants With Best Overall Response (BOR)(From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohorts 1, 2B, 3A, and 3B: Objective Response Rate (ORR)(From date of first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohorts 1, 2A, 2B, 3A and 3B: Duration of Response (DOR)(First documentation of CR/PR until first documentation of PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Who Experienced Disease Control(From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohorts 1, 2A, 2B, 3A, and 3B: Number of Participants With Shift From Baseline to Worst Post Baseline Measurements on Urine DipStick for Proteinuria(Baseline up to approximately 4 years 7 months)
- Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(From the date of first dose of study drug up to 30 days after the last dose (up to approximately 7 years))
- Cohorts 1, 2A, 2B, 3A, and 3B: Plasma Concentrations of Lenvatinib(Cohorts 1, 2A, 2B: Cycle(C)1 Day(D)1: 0.5-4 hours (h), 6-10 h post-dose, C1D15: pre-dose, 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose; Cohorts 3A, 3B: C1D1: 0.5-4 h, 6-10 h post-dose, C2D1: pre-dose, 2-12 h post-dose)
- Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Categorized Based on Overall Acceptability Questionnaire Responses for Suspension of Lenvatinib(Cycle 1 Day 1 (Cycle length=28 days for Cohorts 1, 2A, 2B; Cycle length=21 days for Cohorts 3A, 3B))
- Cohorts 1, 2A, 2B, 3A and 3B: Overall Survival (OS)(From first dose of study drug until death (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohort 2B, 3B: Percent Change From Baseline in Serum Biomarkers Level(Cohort 2B: Baseline, Cycle 2-3 Day 1 (Duration of each cycle=28 days); Cohort 3B: Baseline, Cycle 2 Day 1, Cycle 4 Day 1 (Duration of each cycle=21 days))
- Cohorts 1, 2A, 2B, 3A and 3B: Progression-free Survival (PFS)(From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohorts 1, 2A, 2B, 3A and 3B: Time to Progression (TTP)(From first dose of study drug until PD (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants Experienced Clinical Benefit(From first dose of study drug until PD or death, whichever occurred first (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))
- Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Shift From Baseline to Worst Post Baseline Score in Lansky Performance Play Score(Baseline up to approximately 4 years 7 months)
- Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Shift From Baseline to Worst Post Baseline Score in Karnofsky Performance Status (KPS) Scores(Baseline up to approximately 4 years 7 months)
- Cohorts 1, 2A, 2B, 3A and 3B: Number of Participants With Most Frequent Treatment-emergent Adverse Events (TEAEs) Related to Lenvatinib Exposure(First dose of study drug until 30 days after last dose of study drug (Cohort 1, Cohort 2A, Cohort 2B: until the data cut-off date, 31 May 2019; Cohort 3A, Cohort 3B: until the data cut-off date, 18 July 2019))