Recurrent, progressive or refractory medulloblastoma with activation of the SHH pathway MedDRA version: 14.1 Level: PT Classification code 10066594 Term: Medulloblastoma recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: GDC-0449
Pharmaceutical Form: Capsule
Sponsors
CENTRE LEON BERARD
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: I1. Age = 18 years. I2. Patients must have histologically confirmed medulloblastoma (including posterior fossa primitive neuroectodermal tumor) for which no known curative therapy exists. I3. Patients must have recurrent or refractory disease I4. Patients must have evidence of measurable disease or lesion in pre-inclusion MRI. Patients with measurable spinal disease are eligible. NB: Patients with complete resection for recurrence are not eligible. I5. The activation of the SHH pathway must be validated by IHC before initiation of treatment. I6. ECOG performance status 0, 1 or 2 (Appendix 4). I7. Life expectancy = 12 weeks (as determined by treating physician). I8. Patients must have normal organ and marrow function as defined below: ? Neutrophils = 1. 5 G/L ? Platelets = 100 G /L (transfusion-independent) ? Hemoglobin = 10g/dL (RBC transfusions allowed) ? Creatinine clearance = 50 mL/min (calculated by Cockcroft-Gault formula or MDRD formula for patients older than 65 years ) or serum within normal limits or less than 1.5 x upper limit of normal (ULN) ? Total bilirubin = 1.5 times ULN ? ALT and AST = 2.5 times ULN ? Serum albumin = 25 g/L. I9. Recovered from prior treatment-related toxicity (persistent treatment related toxicity <Grade 2 are allowed). I10. Prior therapy: ? No prior hedgehog antagonist vismodegib or other antagonists of the hedgehog pathway, and no prior temozolomide treatment. ? More than 4 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas, 6 months after high dose therapy) or immunotherapy ? At least 3 months since prior craniospinal irradiation (= 23 Gy) ? At least 8 weeks since prior local irradiation to primary tumor ? At least 2 weeks since prior focal irradiation for symptomatic metastatic sites. ? At least 1 week since prior colony-stimulating factors (e.g., G-CSF, GM-CSF, or erythropoietin) I11. Women of childbearing potential* are required to have a negative serum pregnancy test within 72 hours prior to study treatment initiation (i.e. Cycle 1 Day 1). o *: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential: o =50 years old and naturally amenorrheic for = 1 year o Permanent premature ovarian failure confirmed by a specialist gynaecologist o Previous bilateral salpingo-oophrectomy o XY genotype, Turner’s syndrome, or uterine agenesis Female patient who do not meet at least of the above criteria are defined as women of childbearing potential. I12. An embryo-fetal development study in rats has confirmed the teratogenic potential of vismodegib. Therefore, women of child-bearing potential and men must use two forms of effective contraception (including one barrier method- refer to Appendix 5 for acceptable method of contraception) at least 4 weeks prior to study entry, during the study participation and for at least 7 months post-treatment. Prior to dispensing vismodegib, the investigator m
Exclusion criteria
Exclusion criteria: - Tumor Tissue samples (either from the initial diagnosis and/or relapse) not available for biological studies. - Pregnant or breastfeeding women. - History of allergic reactions attributed to compounds of similar chemical or biologic composition to vismodegib. - Any contraindications to Temozolomide treatment as per Temodal SPC (i.e. hypersensitivity to the active substance or to any of the excipients, Hypersensitivity to dacarbazine (DTIC)).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: to evaluate the safety of a fixed dose of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma. Phase II: to estimate the efficacy of vismodegib in combination with concomitant temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma. ; Secondary Objective: Phase I: - to determine the pharmacokinetic profile of the vismodegib in combination with temozolomide - to collect preliminary results on 6-month progression-free rate of the combination vismodegib + temozolomide Phase II: to estimate in the 2 study arms: - the objective tumor response rate (complete response + partial response + stable disease) - the duration of treatment response - the best overall response obtained during the study - the progression-free survival - the time to progression In the combination arm: to further evaluate the safety of the combination. ; Primary end point(s): Phase I: number of adverse events Phase II: progression-free rate ; Timepoint(s) of evaluation of this end point: Phase I: 3 months Phase II: 6 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - objective response rate - duration of treatment response - best overall response - progression-free survival - time to progression - time to treatment failure ; Timepoint(s) of evaluation of this end point: - progression-free rate preliminary results: 6 months - all the endpoints will be assessed 1 year after the last patient enrollment. | — |
Countries
France, Switzerland
Contacts
Public ContactDidier FRAPPAZ
CENTRE LEON BERARD
Outcome results
None listed