A Phase III Study of Oral LDE225 Versus (vs) Temozolomide (TMZ) in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB) - Full Text View

Purpose

This Phase III study evaluates the safety and efficacy of LDE225 vs TMZ in adult and pediatric patients with Hh-pathway activated, relapsed MB. This study also allows the evaluation of LDE225 in 2 separate subgroups of patients with Hh-pathway activated relapsed MB: in children ≤ 6 years of age who may or may not have previously been treated with TMZ but who have not received prior radiotherapy and in adult and pediatric patients who may have received prior RT and TMZ.

Condition	Intervention	Phase
Medulloblastoma	Drug: LDE225 Drug: TMZ	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase III, Multi-center, Open-label, Randomized, Controlled Study of the Efficacy and Safety of Oral LDE225 Versus Temozolomide in Patients With Hh-pathway Activated Relapsed Medulloblastoma

Resource links provided by NLM:

Drug Information available for: Temozolomide

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:

Overall response rate (ORR) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR). (As per Tumor response guidelines and criteria for Medulloblastoma.

ORR will be done by independent central review.

Secondary Outcome Measures:

Progression free survival (PFS) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
PFS is defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause
Overall response rate (ORR) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
As per Tumor response guidelines and criteria for Medulloblastoma. ORR will be done by local investigator assessment.
Duration of response (DoR) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
DoR is defined as the time from the first documented onset of confirmed PR or CR to the date of PD/relapse or death due to medulloblastoma.
Overall survival (OS) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
OS is defined as the time from date of randomization to date of death due to any cause.
Safety and tolerability of LDE225 treatment [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
Adverse and serious adverse events, clinically significant changes in hematology and chemistry values, assessment of physical and/or neurological examinations, vital signs, electrocardiograms, bone x-rays, dental x-rays (e.g., panorex or age appropriate dental x-ray), and dental exams (as appropriate for age)
Pharmacokinetics (Pk) - Cmin [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
PK of LDE225 and any relevant metabolites

Estimated Enrollment:	109
Study Start Date:	March 2013
Estimated Study Completion Date:	November 2016
Estimated Primary Completion Date:	August 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: LDE225 (no prior TMZ and relapsed after radiation therapy (RT)	Drug: LDE225
Active Comparator: TMZ (no prior TMZ and relapsed after RT	Drug: TMZ Other Name: temozolomide, temodar
Experimental: LDE225 (RT naive +/- TMZ)	Drug: LDE225
Experimental: LDE225 (RT+TMZ pretreated)	Drug: LDE225

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with histologically confirmed diagnosis of MB, who have experienced relapse or progression after standard-of-care therapy including radiotherapy with no prior exposure to TMZ therapy. Patients currently receiving steroids must have been on a stable (or decreasing) dose for at least 5 days before initiating study therapy.
Only patients with a test result, using the 5-gene Hh signature assay, indicating Hhpathway activated MB are eligible for this study. All available tumor material obtained at any time during the course of the patient's disease should be submitted for these analyses
At least one measurable lesion defined as lesion(s) that can be accurately measured in at least two dimensions and is ≥ 10 mm in each dimension by Gadolinium (Gd)-MRI, irrespective of slice thickness/reconstruction interval, for CNS lesions and CT or MRI (with or without contrast) for non-CNS lesions. All patients with CNS lesions must have a brain MRI with and without gadolinium and a spine MRI with gadolinium within 2 weeks prior to first dose of study treatment.
Performance Status corresponding to ECOG score of 0, 1, or 2:
1. Karnofsky performance status score ≥ 50 for patients >16 years of age
2. Lansky performance status score ≥ 50 for patients ≤ 16 years of age
Adequate bone marrow function as defined as:
1. Peripheral absolute neutrophil count (ANC) ≥ 1.5 x 109/L
2. Platelet count ≥ 100 x 109/L
3. Hemoglobin (Hgb) ≥ 9 g/dL
Serum CK ≤1.5 ULN

Exclusion Criteria:

Prior treatment with a Smoothened inhibitor Systemic anticancer treatment within 2 weeks before first dose of study treatment (6 weeks for nitrosourea, mitomycin, and monoclonal antibodies).
Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months before first dose of study treatment.
Patients who have neuromuscular disorders that are associated with elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
Patients receiving treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5 or are metabolized by CYP2B6 and CYP2C9, that have narrow therapeutic indices that cannot be discontinued at least 2 weeks before first dose of study treatment and for the duration of the study
Patients receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms, dose must have been stabilized (or decreasing) for at least 5 days before first dose of study treatment.
History of hypersensitivity reaction to dacarbazine (DTIC), TMZ or any of its components.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01708174

Contacts

Contact: Novartis Pharmaceuticals

+1(800)340-6843

Show 59 Study Locations

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:

Novartis Pharmaceuticals

More Information

No publications provided

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01708174 History of Changes
Other Study ID Numbers:	CLDE225C2301
Study First Received:	October 11, 2012
Last Updated:	December 18, 2012
Health Authority:	United States: Food and Drug Administration Canada: Health Canada Spain: Spanish Agency of Medicines

Keywords provided by Novartis:

medulloblastoma,
relapsed,
pediatric,
children,

adults,
Hh pathway inhibitor,
temozolomide,
LDE225

Additional relevant MeSH terms:

Medulloblastoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors, Primitive
Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 16, 2013