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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01125800
Registration number
NCT01125800
Ethics application status
Date submitted
12/05/2010
Date registered
18/05/2010
Date last updated
20/03/2017
Titles & IDs
Public title
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
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Scientific title
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
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Secondary ID [1]
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2010-019348-37
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Secondary ID [2]
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CLDE225X2104
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Medulloblastoma
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Rhabdomyosarcoma
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Neuroblastoma
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Hepatoblastoma
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Glioma
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Astrocytoma
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Condition category
Condition code
Cancer
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Neuroendocrine tumour (NET)
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Cancer
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Children's - Other
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Cancer
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Brain
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Cancer
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Children's - Brain
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Cancer
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Sarcoma (also see 'Bone') - soft tissue
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Cancer
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Bone
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Cancer
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Liver
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - LDE225
Experimental: LDE225 233mg/m2 daily dose - Pediatric dose.
Experimental: LDE225 372mg/m2 daily dose - Pediatric dose.
Experimental: LDE225 425 mg/m2 daily dose - Pediatric dose.
Experimental: LDE225 680 mg/m2 daily dose - Pediatric dose.
Experimental: LDE225 800 mg/m2 daily dose - Adult dose
Treatment: Drugs: LDE225
LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Dose-limiting Toxicities (DLT) in Phase I
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline, End of dose escalation part (Day 42)
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Primary outcome [2]
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Maximum Tolerated Dose (MTD) of Sonidegib for Prolonged Use
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Assessment method [2]
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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
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Timepoint [2]
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Baseline, End of dose escalation part (Day 42)
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Primary outcome [3]
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Percentage of Participants With Objective Response Rate (ORR) by Treatment
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)
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Secondary outcome [1]
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Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs and Death During the Study
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline (start of study treatment) up to End of treatment (Within 14 days of last dose)
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Secondary outcome [2]
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Area Under the Drug Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24h) of Sonidegib in Phase I
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Assessment method [2]
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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.
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Timepoint [2]
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Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1
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Secondary outcome [3]
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Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sonidegib in Phase I
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Assessment method [3]
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Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration time data.
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Timepoint [3]
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Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1
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Secondary outcome [4]
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Maximum Observed Plasma Concentration (Cmax) of Sonidegib in Phase I
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Assessment method [4]
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Maximum observed plasma concentration following drug administration was calculated from the raw plasma concentration time data.
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Timepoint [4]
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Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1
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Secondary outcome [5]
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Percentage of Pediatric Participants With Objective Response Rate (ORR) by Hedgehog (Hh) Signaling Pathway Status
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Assessment method [5]
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ORR was determined in the participants with mutations on Hh gene (Hh positive) and the participants without mutations on Hh gene (Hh negative).
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Timepoint [5]
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Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)
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Secondary outcome [6]
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Duration of Response by Treatment
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Assessment method [6]
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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.
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Timepoint [6]
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Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)
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Eligibility
Key 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
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Minimum age
12
Months
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Maximum age
18
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/02/2011
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/10/2014
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Sample size
Target
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Accrual to date
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Final
76
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Parkville
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Recruitment postcode(s) [1]
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3052 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Georgia
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Country [2]
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United States of America
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State/province [2]
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Maryland
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Country [3]
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United States of America
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State/province [3]
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Massachusetts
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Country [4]
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United States of America
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State/province [4]
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Washington
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Country [5]
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Canada
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State/province [5]
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Ontario
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Country [6]
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France
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State/province [6]
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Paris
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Country [7]
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France
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State/province [7]
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Villejuif Cedex
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Country [8]
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Italy
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State/province [8]
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BO
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Country [9]
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Italy
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State/province [9]
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MI
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Country [10]
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Italy
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State/province [10]
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RM
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Country [11]
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United Kingdom
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State/province [11]
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Surrey
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Country [12]
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United Kingdom
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State/province [12]
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Newcastle Upon Tyne
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01125800
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01125800
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