Clinical trial NCT01125800: 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
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Medulloblastoma
Rhabdomyosarcoma
Neuroblastoma
Hepatoblastoma
Glioma
Astrocytoma
Keywords: Recurrent,
refractory,
medulloblastoma,
rhabdomyosarcoma,
neuroblastoma,
hepatoblastoma,
astrocytoma,
children,
pediatric,
hedgehog pathway inhibitor, adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-05-18
Enrollment: 76
Sex: ALL
Minimum age (years): 12
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLT) in Phase I
timeFrame: Baseline, End of dose escalation part (Day 42)
measure: Maximum Tolerated Dose (MTD) of Sonidegib for Prolonged Use
timeFrame: Baseline, End of dose escalation part (Day 42)
measure: Percentage of Participants With Objective Response Rate (ORR) by Treatment
timeFrame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs and Death During the Study
timeFrame: Baseline (start of study treatment) up to End of treatment (Within 14 days of last dose)
measure: Area Under the Drug Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24h) of Sonidegib in Phase I
timeFrame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sonidegib in Phase I
timeFrame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1
measure: Maximum Observed Plasma Concentration (Cmax) of Sonidegib in Phase I
timeFrame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1
measure: Percentage of Pediatric Participants With Objective Response Rate (ORR) by Hedgehog (Hh) Signaling Pathway Status
timeFrame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)
measure: Duration of Response by Treatment
timeFrame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta Childern Hosp - ATL
state: Georgia
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. John Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute DFCI (3)
state: Massachusetts
city: Seattle
country: United States
facility: Seattle Children's Hospital CPKC412A2114
state: Washington
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Paris
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Newcastle Upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: