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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01125800
First received: May 12, 2010
Last updated: February 4, 2016
Last verified: February 2016
  Purpose

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.


Condition Intervention Phase
Medulloblastoma,
Rhabdomyosarcoma,
Neuroblastoma,
Hepatoblastoma,
Glioma,
Astrocytoma
Drug: LDE225
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of Participants With Dose-limiting Toxicities (DLT) in Phase I [ Time Frame: Baseline, End of dose escalation part (Day 42) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, End of dose escalation part (Day 42) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline (start of study treatment) up to End of treatment (Within 14 days of last dose) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose) ] [ Designated as safety issue: No ]
    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.


Enrollment: 76
Study Start Date: February 2011
Study Completion Date: October 2014
Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LDE225 233mg/m2 daily dose
Pediatric dose.
Drug: LDE225
LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.
Other Name: sonidegib
Experimental: LDE225 372mg/m2 daily dose
Pediatric dose.
Drug: LDE225
LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.
Other Name: sonidegib
Experimental: LDE225 425 mg/m2 daily dose
Pediatric dose.
Drug: LDE225
LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.
Other Name: sonidegib
Experimental: LDE225 680 mg/m2 daily dose
Pediatric dose.
Drug: LDE225
LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.
Other Name: sonidegib
Experimental: LDE225 800 mg/m2 daily dose
Adult dose
Drug: LDE225
LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.
Other Name: sonidegib

  Eligibility

Ages Eligible for Study:   12 Months to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01125800

Locations
United States, Georgia
Children's Healthcare of Atlanta Childern Hosp - ATL
Atlanta, Georgia, United States, 30342
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. John Hopkins
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Dana Farber Cancer Institute DFCI (3)
Boston, Massachusetts, United States, 02115
United States, Washington
Seattle Children's Hospital CPKC412A2114
Seattle, Washington, United States, 98105
Australia, Victoria
Novartis Investigative Site
Parkville, Victoria, Australia, 3052
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 1X8
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 2M9
France
Novartis Investigative Site
Paris, France, 75231
Novartis Investigative Site
Villejuif Cedex, France, 94805
Italy
Novartis Investigative Site
Bologna, BO, Italy, 40139
Novartis Investigative Site
Milano, MI, Italy, 20133
Novartis Investigative Site
Roma, RM, Italy, 00168
United Kingdom
Novartis Investigative Site
Sutton, Surrey, United Kingdom, SM2 5PT
Novartis Investigative Site
Newcastle Upon Tyne, United Kingdom, NE1 4LP
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01125800     History of Changes
Other Study ID Numbers: CLDE225X2104  2010-019348-37 
Study First Received: May 12, 2010
Results First Received: September 29, 2015
Last Updated: February 4, 2016
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Australia: Department of Health and Ageing Therapeutic Goods Administration
Italy: Ministry of Health
Spain: Spanish Agency of Medicines
Canada: Health Canada

Keywords provided by Novartis:
Recurrent,
refractory,
medulloblastoma,
rhabdomyosarcoma,
neuroblastoma,
hepatoblastoma,
astrocytoma,
children,
pediatric,
hedgehog pathway inhibitor, adult

Additional relevant MeSH terms:
Neuroblastoma
Astrocytoma
Rhabdomyosarcoma
Medulloblastoma
Hepatoblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Glioma
Myosarcoma
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma
Neoplasms, Complex and Mixed

ClinicalTrials.gov processed this record on July 28, 2016