Clinical trial NCT01601184: Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Patients With Medulloblastomas With an Activation of the Sonic Hedgehog Pathway
Official title: An International, Randomized, Open-label Phase I/II Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Adult Patients With Recurrent or Refractory Medulloblastomas Presenting an Activation of the Sonic Hedgehog (SHH) Pathway
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Histologically Confirmed Medulloblastoma
Activation of the Sonic Hedgehog (SHH) Pathway
Keywords: medulloblastoma
sonic hedgehog pathway
vismodegib
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2012-05-17
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.)

Primary outcomes:
measure: 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
timeFrame: during the first three months follow up
measure: To estimate the efficacy of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma (phase II)
timeFrame: 6 months after start of treatment
Secondary outcomes:
measure: To collect preliminary results on the 6-month progression-free rate of the combination vismodegib + temozolomide (phase I)
timeFrame: 6 months after start of treatment
measure: To estimate in the two study arms the objective response rate after 6 months of treatment (phase II)
timeFrame: after 6 months of treatment
measure: To estimate in the two study arms the duration of treatment response (phase II)
timeFrame: one year
measure: To estimate in the two study arms the best overall response obtained during the study (phase II)
timeFrame: one year
measure: To estimate in the two study arms the progression-free survival (PFS)(phase II)
timeFrame: one year
measure: To estimate in the two study arms the time to treatment failure (phase II)
timeFrame: one year
measure: frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade
timeFrame: one year
Other outcomes:
Locations:
city: Marseille
country: France
facility: CHU La Timone
state: Bouches Du Rhône
city: Toulouse
country: France
facility: Institut Claudius Régaud (iuct-oncopole)
state: Haute-Garonne
city: Paris
country: France
facility: Hopital de La Pitié Salpétrière
state: Ile De France
city: St Herblain
country: France
facility: Institut de Cancérologie de l'Ouest - René Gauducheau
state: Loire Atlantique
city: Nancy
country: France
facility: Hopital Central de Nancy
state: Meurthe Et Moselle
city: Lorient
country: France
facility: CHBS Hôpital du Scorff
state: Morbihan
city: Lille
country: France
facility: CHRU de Lille
state: Nord
city: Lyon
country: France
facility: Centre Léon Bérard
state: Rhone
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest - Paul Papin
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bologna
country: Italy
facility: BELLARIA Ospedale
city: Torino
country: Italy
facility: University of Turin
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
city: Zurich
country: Switzerland
facility: University Hospital Zurich
city: London
country: United Kingdom
facility: University College London Hospital - Mount Vernon Cancer Centre - Mount Vernon hospital
Study officials:
affiliation: Centre Léon Bérard, Lyon
name: didier frappaz
role: PRINCIPAL_INVESTIGATOR
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