Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Patients With Medulloblastomas With an Activation of the Sonic Hedgehog Pathway
NCT ID: NCT01601184
Last Updated: 2019-05-21
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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TERMINATED
PHASE1/PHASE2
24 participants
INTERVENTIONAL
2012-06-30
2017-10-31
Brief Summary
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This study is an open-label Phase I/II, international, randomized.
38 patients will be included in the study.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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combination of vismodegib with 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)
vismodegib
Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day
Temozolomide
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
temozolomide alone
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).
Temozolomide
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
vismodegib alone
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
vismodegib
Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day
Interventions
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vismodegib
Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day
Temozolomide
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
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.)
18 Years
ALL
No
Sponsors
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Ministry of Health, France
OTHER_GOV
Centre Leon Berard
OTHER
Responsible Party
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Principal Investigators
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didier frappaz
Role: PRINCIPAL_INVESTIGATOR
Centre Léon Bérard, Lyon
Locations
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CHU La Timone
Marseille, Bouches Du Rhône, France
Institut Claudius Régaud (iuct-oncopole)
Toulouse, Haute-Garonne, France
Institut de Cancérologie de l'Ouest - René Gauducheau
Saint-Herblain, Loire Atlantique, France
Hopital Central de Nancy
Nancy, Meurthe Et Moselle, France
CHBS Hôpital du Scorff
Lorient, Morbihan, France
CHRU de Lille
Lille, Nord, France
Centre Léon Bérard
Lyon, Rhone, France
Institut de Cancérologie de l'Ouest - Paul Papin
Angers, , France
Institut Bergonié
Bordeaux, , France
Hopital de La Pitié Salpétrière
Paris, Île-de-France Region, France
BELLARIA Ospedale
Bologna, , Italy
University of Turin
Torino, , Italy
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, , Switzerland
University Hospital Zurich
Zurich, , Switzerland
University College London Hospital - Mount Vernon Cancer Centre - Mount Vernon hospital
London, , United Kingdom
Countries
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References
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Other Identifiers
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2011-003372-37
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
MEVITEM
Identifier Type: -
Identifier Source: org_study_id
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