Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Patients With Medulloblastomas With an Activation of the Sonic Hedgehog Pathway
- Conditions
- Activation of the Sonic Hedgehog (SHH) PathwayHistologically Confirmed Medulloblastoma
- Interventions
- Registration Number
- NCT01601184
- Lead Sponsor
- Centre Leon Berard
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 24
- 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)
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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.
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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.
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Ability to understand and willingness to comply to follow-up visits.
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Covered by a medical insurance (in countries where applicable)
- 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.)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description temozolomide alone Temozolomide In the first step of the study (Phase I), 9 adult patients with relapsing or refractory medulloblastoma will be randomized (randomization ratio 2:1) to receive Arm B: temozolomide alone (150 mg/m2 day1 to day 5/ 28 day-cycle during Cycle 1 and 200 mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles) (3 patients). combination of vismodegib with temozolomide Temozolomide In the first step of the study (Phase I), 9 adult patients with relapsing or refractory medulloblastoma will be randomized (randomization ratio 2:1) to receive - Arm A: the combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 during Cycle 1 \[day 1 to day 5/ 28 day-cycle\] and 200 mg/m2 during subsequent cycles) (6 patients) combination of vismodegib with temozolomide vismodegib In the first step of the study (Phase I), 9 adult patients with relapsing or refractory medulloblastoma will be randomized (randomization ratio 2:1) to receive - Arm A: the combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 during Cycle 1 \[day 1 to day 5/ 28 day-cycle\] and 200 mg/m2 during subsequent cycles) (6 patients) vismodegib alone vismodegib Considering the rarity of the disease, the few therapeutic options available and the promising results reported with vismodegib in adult medulloblastoma : the Sponsor will consider (on case by case basis) the enrolment of patients previously treated by temozolomide in a 3rd independent and parallel study arm
- Primary Outcome Measures
Name Time Method 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
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.
- Secondary Outcome Measures
Name Time Method 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
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 duration of treatment response (phase II) one year treatment response
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
To estimate in the two study arms the best overall response obtained during the study (phase II) one year 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 time to treatment failure (phase II) one year
Trial Locations
- Locations (15)
Institut de Cancérologie de l'Ouest - René Gauducheau
🇫🇷St Herblain, Loire Atlantique, France
Institut Bergonié
🇫🇷Bordeaux, France
Institut Claudius Régaud (iuct-oncopole)
🇫🇷Toulouse, Haute-Garonne, France
Hopital de La Pitié Salpétrière
🇫🇷Paris, Ile De France, France
CHU La Timone
🇫🇷Marseille, Bouches Du Rhône, France
Centre Léon Bérard
🇫🇷Lyon, Rhone, France
CHRU de Lille
🇫🇷Lille, Nord, France
Hopital Central de Nancy
🇫🇷Nancy, Meurthe Et Moselle, France
CHBS Hôpital du Scorff
🇫🇷Lorient, Morbihan, France
Institut de Cancérologie de l'Ouest - Paul Papin
🇫🇷Angers, France
BELLARIA Ospedale
🇮🇹Bologna, Italy
University of Turin
🇮🇹Torino, Italy
University College London Hospital - Mount Vernon Cancer Centre - Mount Vernon hospital
🇬🇧London, United Kingdom
Centre Hospitalier Universitaire Vaudois (CHUV)
🇨🇭Lausanne, Switzerland
University Hospital Zurich
🇨🇭Zurich, Switzerland