A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB
- Conditions
- RhabdomyosarcomaAstrocytomaHepatoblastomaGliomaMedulloblastomaNeuroblastoma
- Interventions
- Registration Number
- NCT01125800
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 76
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description LDE225 425 mg/m2 daily dose LDE225 Pediatric dose. LDE225 233mg/m2 daily dose LDE225 Pediatric dose. LDE225 680 mg/m2 daily dose LDE225 Pediatric dose. LDE225 372mg/m2 daily dose LDE225 Pediatric dose. LDE225 800 mg/m2 daily dose LDE225 Adult dose
- Primary Outcome Measures
Name Time Method Number of Participants With Dose-limiting Toxicities (DLT) in Phase I 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 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 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.
- Secondary Outcome Measures
Name Time Method 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 Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration time data.
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) An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs were defined as AEs that were suspected to be related to study treatment as per investigator. On-treatment deaths were deaths which occurred up to 30 days after last date of study treatment.
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 Maximum observed plasma concentration following drug administration was calculated from the raw plasma concentration time data.
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 AUC(0-24h) was defined as the area under the drug concentration time curve calculated using linear trapezoidal summation from time zero to 24 hours after dosing.
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) ORR was determined in the participants with mutations on Hh gene (Hh positive) and the participants without mutations on Hh gene (Hh negative).
Duration of Response by Treatment Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose) Duration of overall response (complete response (CR) or partial response (PR)) was calculated for those participants whose best overall response was CR or PR. The start date was the date of the first documented tumor response (CR or PR) and the end date was the date of the event defined as the first documented progression or death due to underlying cancer or after the same treatment line. If a participant did not have a progression or death, the duration of response was censored at the date of last adequate tumor assessment in that treatment line.
Trial Locations
- Locations (5)
Seattle Children's Hospital CPKC412A2114
🇺🇸Seattle, Washington, United States
Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. John Hopkins
🇺🇸Baltimore, Maryland, United States
Dana Farber Cancer Institute DFCI (3)
🇺🇸Boston, Massachusetts, United States
Novartis Investigative Site
🇬🇧Newcastle Upon Tyne, United Kingdom
Children's Healthcare of Atlanta Childern Hosp - ATL
🇺🇸Atlanta, Georgia, United States