Activation of the Sonic Hedgehog (SHH) Pathway, Histologically Confirmed Medulloblastoma
Conditions
Keywords
medulloblastoma, sonic hedgehog pathway, vismodegib
Brief summary
The purpose of this study is to evaluate the safety of vismodegib in combination with temozolomide (primary objective - phase I) and to estimate the efficacy of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory medulloblastomas to standard therapy measured by the 6-month progression-free rate (phase II). This study is an open-label Phase I/II, international, randomized. 38 patients will be included in the study.
Detailed description
Secondary objectives are : phase I : to collect preliminary results on the 6-month progression-free rate of the combination vismodegib + temozolomide PHASE II To estimate in the two study arms: * the objective response rate (Complete response + Partial Response according to WHO criteria) after 6 months of treatment * the duration of treatment response * the best overall response obtained during the study * the progression-free survival (PFS) * the time to progression (TTP) * the time to treatment failure (TTF) * In the combination arm (vismodegib + temozolomide): to further evaluate the safety of the combination.
Interventions
DRUGvismodegib
Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day
DRUGTemozolomide
alkylating agent Dosage: Dose in Cycle 1 is 150 mg/m2 orally once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200mg/m2 orally once daily for 5 days
Sponsors
Ministry of Health, France
Centre Leon Berard
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Patients must have histologically confirmed medulloblastoma (including posterior fossa primitive neuroectodermal tumor) for which no known curative therapy exists * Patients must have recurrent or refractory disease * 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. * Activation of the SHH pathway validated by IHC. * ECOG performance status 0, 1 or 2 * Life expectancy ≥ 12 weeks * Patients must have normal organ and marrow function as defined below: Neutrophils ≥ 1. 5 G/L Platelets ≥ 100 G /L Hemoglobin ≥ 10g/dL Creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula or MDRD formula for patients older than 65 years ) or serum creatinine within normal limits or less than 1.5 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 ULN ALAT and ASAT ≤ 2.5 ULN Serum albumin ≥ 25 g/L. * Patients recovered from prior treatment-related toxicity (persistent treatment related toxicity \<Grade 2 are allowed (NCI-CTCAE v4.0). * Prior therapy: No prior hedgehog antagonist vismodegib or other antagonists of the hedgehog pathway, and no prior temozolomide treatment for patients to be randomized in Arm A or B. Patients previously treated with temozolomide are eligible for enrollment in study arm C on a case by case basis and following sponsor agreement 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) * 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). \*: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential: ≥50 years old and naturally amenorrheic for ≥ 1 year Permanent premature ovarian failure confirmed by a specialist gynaecologist Previous bilateral salpingo-oophorectomy 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. * 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 4 for acceptable method of contraception) at least 4 weeks prior to study entry, during the study period and for at least 24 months post-treatment for women and 2 months post-treatment for men. Prior to dispensing vismodegib, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of vismodegib. * Ability to understand and willingness to comply to follow-up visits. * Covered by a medical insurance (in countries where applicable)
Exclusion criteria
* Tumor tissue sample not available for biological studies (from the initial diagnosis and/or relapse) * Pregnant or breastfeeding women are not eligible. * History of allergic reactions attributed to compounds of similar chemical composition to vismodegib. * Any contraindications to temozolomide treatment as per Temodal® SPC (see Appendix 5). * Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption. Patients must be able to swallow capsules. * Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation. * History of congestive heart failure. * History of ventricular arrhythmia requiring medication. * Congenital long QT syndrome. * Clinically significant unrelated systemic illness (e.g., serious infection or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results. * Patients using prohibited concomitant and/or concurrent medications (see section Prohibited concomitant/concurrent treatments.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the safety of a fixed dose of vismodegib in combination with (phase I)temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma | during the first three months follow up | number of severe toxicities occurring during the first 3 months of follow-up : * Toxic death * Grade 4 toxicity * Any grade 3 AE leading to study treatment interruption for more than 7 days or discontinuation. |
| To estimate the efficacy of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma (phase II) | 6 months after start of treatment | the 6-month progression-free rate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To estimate in the two study arms the duration of treatment response (phase II) | one year | treatment response |
| To estimate in the two study arms the best overall response obtained during the study (phase II) | one year | — |
| To collect preliminary results on the 6-month progression-free rate of the combination vismodegib + temozolomide (phase I) | 6 months after start of treatment | measurement of progression free rate |
| To estimate in the two study arms the time to treatment failure (phase II) | one year | — |
| frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade | one year | In the combination arm (vismodegib + temozolomide): to further evaluate the safety of the combination |
| To estimate in the two study arms the progression-free survival (PFS)(phase II) | one year | measure of progression free rate |
| To estimate in the two study arms the objective response rate after 6 months of treatment (phase II) | after 6 months of treatment | measure by objective response rate |
Countries
France, Italy, Switzerland, United Kingdom
Outcome results
None listed