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

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

Time frame: Baseline, End of dose escalation part (Day 42)

Population: The MTD for the pediatric population was not established in this study. MTD was not achieved since 1 or no DLT was observed. The recommended phase II dose was established based on the safety, pharmacokinetics, and clinical responses observed.

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.

Time frame: Baseline, End of dose escalation part (Day 42)

Population: The analysis was performed in full analysis set (FAS), defined as all the participants who received at least one dose of sonidegib.

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.

Time frame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)

Population: The analysis was performed in full analysis set (FAS), defined as all the participants who received at least one dose of sonidegib.

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.

Time frame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1

Population: The analysis was performed in pharmacokinetic analysis set (PAS), defined as all the participants who received at least one (full or partial) dose of sonidegib and provided at least one evaluable pharmacokinetic (PK) blood sample. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

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.

Time frame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)

Population: The analysis was performed in FAS population. Here Number of participants analysed signifies treatment responders for the specified reporting group.

Maximum observed plasma concentration following drug administration was calculated from the raw plasma concentration time data.

Time frame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1

Population: The analysis was performed in PAS population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

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.

Time frame: Baseline (start of study treatment) up to End of treatment (Within 14 days of last dose)

Population: The analysis was performed in safety set (SS), defined as all the participants who received at least 1 dose of sonidegib.

ORR was determined in the participants with mutations on Hh gene (Hh positive) and the participants without mutations on Hh gene (Hh negative).

Time frame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)

Population: 60 patients with known (Hedgehog) Hh pathway activation status were analyzed, 10 patients, including all 5 patients with an objective response (3 with pediatric) , were Hh-positive (+). No Hh-negative patient had an objective response.

Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration time data.

Time frame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1

Population: The analysis was performed in PAS population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.