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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

Primary Purpose

Medulloblastoma, Rhabdomyosarcoma, Neuroblastoma

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LDE225
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Medulloblastoma focused on measuring Recurrent,, refractory,, medulloblastoma,, rhabdomyosarcoma,, neuroblastoma,, hepatoblastoma,, astrocytoma,, children,, pediatric,, hedgehog pathway inhibitor, adult

Eligibility Criteria

12 Months - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Healthcare of Atlanta Childern Hosp - ATL
  • Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. John Hopkins
  • Dana Farber Cancer Institute DFCI (3)
  • Seattle Children's Hospital CPKC412A2114
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

LDE225 233mg/m2 daily dose

LDE225 372mg/m2 daily dose

LDE225 425 mg/m2 daily dose

LDE225 680 mg/m2 daily dose

LDE225 800 mg/m2 daily dose

Arm Description

Pediatric dose.

Pediatric dose.

Pediatric dose.

Pediatric dose.

Adult dose

Outcomes

Primary Outcome Measures

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.
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
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.

Secondary Outcome Measures

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.
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.
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.
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.
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).
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.

Full Information

First Posted
May 12, 2010
Last Updated
February 13, 2017
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01125800
Brief 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
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

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Completed
Study Start Date
February 2011 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Medulloblastoma, Rhabdomyosarcoma, Neuroblastoma, Hepatoblastoma, Glioma, Astrocytoma
Keywords
Recurrent,, refractory,, medulloblastoma,, rhabdomyosarcoma,, neuroblastoma,, hepatoblastoma,, astrocytoma,, children,, pediatric,, hedgehog pathway inhibitor, adult

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
76 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LDE225 233mg/m2 daily dose
Arm Type
Experimental
Arm Description
Pediatric dose.
Arm Title
LDE225 372mg/m2 daily dose
Arm Type
Experimental
Arm Description
Pediatric dose.
Arm Title
LDE225 425 mg/m2 daily dose
Arm Type
Experimental
Arm Description
Pediatric dose.
Arm Title
LDE225 680 mg/m2 daily dose
Arm Type
Experimental
Arm Description
Pediatric dose.
Arm Title
LDE225 800 mg/m2 daily dose
Arm Type
Experimental
Arm Description
Adult dose
Intervention Type
Drug
Intervention Name(s)
LDE225
Other Intervention Name(s)
sonidegib
Intervention Description
LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.
Primary Outcome Measure Information:
Title
Number of Participants With Dose-limiting Toxicities (DLT) in Phase I
Description
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)
Title
Maximum Tolerated Dose (MTD) of Sonidegib for Prolonged Use
Description
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)
Title
Percentage of Participants With Objective Response Rate (ORR) by Treatment
Description
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)
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs and Death During the Study
Description
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)
Title
Area Under the Drug Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24h) of Sonidegib in Phase I
Description
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
Title
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sonidegib in Phase I
Description
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
Title
Maximum Observed Plasma Concentration (Cmax) of Sonidegib in Phase I
Description
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
Title
Percentage of Pediatric Participants With Objective Response Rate (ORR) by Hedgehog (Hh) Signaling Pathway Status
Description
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)
Title
Duration of Response by Treatment
Description
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Children's Healthcare of Atlanta Childern Hosp - ATL
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. John Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
Dana Farber Cancer Institute DFCI (3)
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Seattle Children's Hospital CPKC412A2114
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Novartis Investigative Site
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Novartis Investigative Site
City
Paris
ZIP/Postal Code
75231
Country
France
Facility Name
Novartis Investigative Site
City
Villejuif Cedex
ZIP/Postal Code
94805
Country
France
Facility Name
Novartis Investigative Site
City
Bologna
State/Province
BO
ZIP/Postal Code
40139
Country
Italy
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20133
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00168
Country
Italy
Facility Name
Novartis Investigative Site
City
Sutton
State/Province
Surrey
ZIP/Postal Code
SM2 5PT
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Newcastle Upon Tyne
ZIP/Postal Code
NE1 4LP
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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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