CLDE225C2301: 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
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 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.
Inclusion Criteria:ï¿½Patients 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.ï¿½Only 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 analysesï¿½At least one measurable lesion defined as lesion(s) that can be accurately measured in at least two dimensions and is ï¿½ 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.ï¿½Performance Status corresponding to ECOG score of 0, 1, or 2:a.Karnofsky performance status score ï¿½ 50 for patients greater than 16 years of ageb.Lansky performance status score ï¿½ 50 for patients ï¿½ 16 years of ageï¿½Adequate bone marrow function as defined as:a.Peripheral absolute neutrophil count (ANC) ï¿½ 1.5 x 109/Lb.Platelet count ï¿½ 100 x 109/Lc.Hemoglobin (Hgb) ï¿½ 9 g/dLï¿½Serum CK ï¿½1.5 ULNExclusion Criteria:ï¿½Prior 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).ï¿½Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months before first dose of study treatment.ï¿½Patients who have neuromuscular disorders that are associated with elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).ï¿½Patients 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 studyï¿½Patients 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.ï¿½History of hypersensitivity reaction to dacarbazine (DTIC), TMZ or any of its components.
Study drug - LDE225 administered as an oral suspensionDose for patients greater than 4 months to less than 18 years of age is 500mg/m2 (capped at 600 mgmaximum) QDDose for patients greater than 18 years of age is 600 mg QDComparator drug ï¿½ TMZ administered as oral capsulesC1 dose for adults and children is 150 mg/m2 QD day 1-5 (every 4 weeks). At thestart of C2 the dose may be escalated to 200mg/m2 QD day 1-5 (every week)provided C1 is well tolerated.MRI of the brain and spine with iv contrast every 8 weeks during treatment/ followup phase. CT or MRI (with or without contrast) may be used for non-CNS lesions and patients with CNS lesions and contra-indication for MRI, may be assessed with CT (with contrast).Overall neurological status and steroid use at each response assessmentSafety assessments Physical examination including vital signs, height and weightPerformance statusLaboratory evaluations (hematology, clinical chemistry, urinalysis, pregnancy and assessments of fertility)Knee and wrist x-rays ( less than 18 years only)Dental evaluations ( less than 18 years only)Cardiac assessmentsOther assessments: Pharmacokinetics- For determining the pharmacokinetics of LDE225/ any relevant metabolite(s)BiomarkersArchival or fresh tumor samples as part of molecular pre-screening Additionaloptional tumor samples may be used to analyze 5-gene Hh activation assay, Smo,Ptch, SUFU mutations and gli2 amplificationWhole blood sample for analysis of germline mutation status of Ptch and SmogenesTaste questionnaire- For evaluating the acceptability and palatability of LDE225 oral suspension using a Likert scaleSurvival Follow up- Survival status, and growth/developmental assessments for children ( less than 18 years only)
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