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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Medulloblastoma, Rhabdomyosarcoma, Neuroblastoma, Hepatoblastoma, Glioma, Astrocytoma

Intervention / Treatment
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* Drug: LDE225


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDE225 233mg/m2 daily dose<br>Pediatric dose. | Drug: LDE225<br>* LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.<br>* Other names: sonidegib;|
| Experimental: LDE225 372mg/m2 daily dose<br>Pediatric dose. | Drug: LDE225<br>* LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.<br>* Other names: sonidegib;|
| Experimental: LDE225 425 mg/m2 daily dose<br>Pediatric dose. | Drug: LDE225<br>* LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.<br>* Other names: sonidegib;|
| Experimental: LDE225 680 mg/m2 daily dose<br>Pediatric dose. | Drug: LDE225<br>* LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.<br>* Other names: sonidegib;|
| Experimental: LDE225 800 mg/m2 daily dose<br>Adult dose | Drug: LDE225<br>* LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.<br>* Other names: sonidegib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLT) in Phase I | 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. | Baseline, End of dose escalation part (Day 42) | 
| Maximum Tolerated Dose (MTD) of Sonidegib for Prolonged Use | 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 | Baseline, End of dose escalation part (Day 42) | 
| Percentage of Participants With Objective Response Rate (ORR) by Treatment | 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. | Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs and Death During the Study | 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. | Baseline (start of study treatment) up to End of treatment (Within 14 days of last dose) | 
| Area Under the Drug Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24h) of Sonidegib in Phase I | 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. | Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sonidegib in Phase I | Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration time data. | 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 (Cmax) of Sonidegib in Phase I | Maximum observed plasma concentration following drug administration was calculated from the raw plasma concentration time data. | 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 | ORR was determined in the participants with mutations on Hh gene (Hh positive) and the participants without mutations on Hh gene (Hh negative). | Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose) | 
| Duration of Response by Treatment | 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. | Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent,, refractory,, medulloblastoma,, rhabdomyosarcoma,, neuroblastoma,, hepatoblastoma,, astrocytoma,, children,, pediatric,, hedgehog pathway inhibitor, adult