A Phase I/II Study of LDE225 in Pediatric Patients With Recurrent or Refractory Medulloblastoma or Other Tumors Potentially Dependent on the Hedgehog-signaling Pathway and Adult Patients With Recurrent or Refractory Medulloblastoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 76
- 试验地点
- 5
- 主要终点
- Number of Participants With Dose-limiting Toxicities (DLT) in Phase I
研究概览
简要总结
Phase I dose-escalation study to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of LDE225 given orally on a daily dosing schedule in children with recurrent or refractory medulloblastoma, or other tumors potentially dependent on Hedgehog signaling pathway.
Phase II study is to assess preliminary efficacy in both adult and pediatric patients with recurrent or refractory MB.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Phase I - Patients aged ≥12 months and <18 years, Phase II - Patients ≥12 months
- •Phase I - Histologically confirmed diagnosis of medulloblastoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high grade glioma, or osteosarcoma, that has progressed despite treatment with standard therapies, or for which no standard treatments are available (patients with brainstem gliomas are excluded). Phase II - Histologically confirmed diagnosis of recurrent or relapsed medulloblastoma with at least one measurable lesion.
- •Performance Status: Karnofsky ≥60% for patients >10 yrs, Lansky ≥50 for patients less than or equal to 10 yrs
- •Protocol-defined renal , liver and bone marrow function
- •Negative pregnancy test before starting study treatment. If of child bearing potential must use 'highly effective' methods of contraception.
- •All patients must consent to provide a tumor sample
排除标准
- •Systemic anti-cancer treatment within 2 weeks prior to first dose (6 weeks for nitrosourea, mitomycin and monoclonal antibodies).
- •Focal radiotherapy within 4 weeks prior to first dose, or full spinal radiotherapy within 3 months of first dose.
- •Unresolved toxicity greater than CTCAE grade 1 from previous anti-cancer therapy or radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia or other specifications in the eligibility criteria for this study), or incomplete recovery from previous surgery, unless agreed by Novartis and the Principal Investigator (PI) and documented.
- •Major surgery, serious illness or traumatic injury within 2 weeks of starting study therapy. Patients anticipated to require major surgery within the first 2 cycles of treatment.
- •Patients requiring a nasogastric tube for drug administration (G-tubes are permitted)
- •Impaired cardiac function
- •Pregnant or breast-feeding females
- •Impairment of gastrointestinal (GI) function or GI disease
- •Other protocol-defined inclusion/exclusion criteria may apply
研究组 & 干预措施
LDE225 233mg/m2 daily dose
Pediatric dose.
干预措施: LDE225 (Drug)
LDE225 372mg/m2 daily dose
Pediatric dose.
干预措施: LDE225 (Drug)
LDE225 425 mg/m2 daily dose
Pediatric dose.
干预措施: LDE225 (Drug)
LDE225 680 mg/m2 daily dose
Pediatric dose.
干预措施: LDE225 (Drug)
LDE225 800 mg/m2 daily dose
Adult dose
干预措施: LDE225 (Drug)
结局指标
主要结局
Number of Participants With Dose-limiting Toxicities (DLT) in Phase I
时间窗: Baseline, End of dose escalation part (Day 42)
DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications. DLT included any grade 3 or 4 clinically-evident toxicity, Hematology: ≥ CTCAE grade 3 neutropenia (ANC \<1.0x10\^9/L); ≥ CTCAE grade 3 thrombocytopenia (platelets \<50x10\^9/L); ≥ CTCAE grade 3 anemia (Hgb \<80 g/L); Febrile neutropenia (ANC \<1x10\^9/L, fever ‡ 38.5°C), Renal: ≥ CTCAE grade 3 serum creatinine (\>3xULN), Hepatic: ≥ CTCAE grade 3 total bilirubin (\>3xULN); ≥ 10xULN ALT elevation; grade 2 total bilirubin (\>1.5ULN) together with ≥ grade 3 ALT elevation (\>5xULN), Cardiac: ≥ CTCAE grade 3, Other AEs: ≥ CTCAE grade 3 vomiting or nausea despite optimal antiemetic therapy, diarrhea despite optimal antidiarrheal treatment.
Maximum Tolerated Dose (MTD) of Sonidegib for Prolonged Use
时间窗: Baseline, End of dose escalation part (Day 42)
MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose-limiting toxicity (DLT), based on Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications.k
Percentage of Participants With Objective Response Rate (ORR) by Treatment
时间窗: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)
The tumor response to the sonidegib treatment was measured by ORR. The ORR was defined as the percentage of participants with partial response or complete response as their best overall response. Participants with stable disease, progressive disease tumor assessment were considered as non-responders. Response evaluation criteria was gadolinium chelate-enhanced brain tumor magnetic resonance imaging (Gd-MRI) for Medulloblastoma and central nervous system (CNS) tumors and response evaluation criteria in solid tumors (RECIST) version 1.0 for non-CNS tumors assessed by MRI. Complete Response (CR), Progressive Disease (PD) and Incomplete Response/Stable Disease (SD) were defined as disappearance of all non-target lesions, unequivocal progression of existing non-target lesions and Neither CR nor PD, respectively.
次要结局
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sonidegib in Phase I(Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1)
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs and Death During the Study(Baseline (start of study treatment) up to End of treatment (Within 14 days of last dose))
- Maximum Observed Plasma Concentration (Cmax) of Sonidegib in Phase I(Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1)
- Area Under the Drug Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24h) of Sonidegib in Phase I(Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1)
- Percentage of Pediatric Participants With Objective Response Rate (ORR) by Hedgehog (Hh) Signaling Pathway Status(Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose))
- Duration of Response by Treatment(Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose))