Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Patients With Medulloblastomas With an Activation of the Sonic Hedgehog Pathway

May 20, 2019 updated by: Centre Leon Berard

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Angers, France, 49933
        • Institut de Cancerologie de l'Ouest - Paul Papin
      • Bordeaux, France, 33076
        • Institut Bergonie
    • Bouches Du Rhône
      • Marseille, Bouches Du Rhône, France, 13385
        • CHU La Timone
    • Haute-Garonne
      • Toulouse, Haute-Garonne, France, 31059
        • Institut Claudius Régaud (iuct-oncopole)
    • Ile De France
      • Paris, Ile De France, France, 75013
        • Hopital de la Pitie Salpetriere
    • Loire Atlantique
      • St Herblain, Loire Atlantique, France, 44805
        • Institut de Cancérologie de l'Ouest - René Gauducheau
    • Meurthe Et Moselle
      • Nancy, Meurthe Et Moselle, France, 54035
        • Hôpital Central de Nancy
    • Morbihan
      • Lorient, Morbihan, France, 56322
        • CHBS Hôpital du Scorff
    • Nord
      • Lille, Nord, France, 59037
        • CHRU de Lille
    • Rhone
      • Lyon, Rhone, France, 69373
        • Centre Leon Berard
  • Italy
      • Bologna, Italy, 40139
        • BELLARIA Ospedale
      • Torino, Italy, 10126
        • University of Turin
  • Switzerland
      • Lausanne, Switzerland, CH-8091
        • Centre Hospitalier Universitaire Vaudois (CHUV)
      • Zurich, Switzerland, CH-8091
        • University Hospital Zurich
  • United Kingdom
      • London, United Kingdom, London-NW1-2PG
        • University College London Hospital - Mount Vernon Cancer Centre - Mount Vernon hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: 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)
Drug: vismodegib
Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day
Drug: 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 Names:
  • temodal
ACTIVE_COMPARATOR: 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).
Drug: 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 Names:
  • temodal
OTHER: 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
Drug: vismodegib
Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: 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.
during the first three months follow up
To estimate the efficacy of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma (phase II)
Time Frame: 6 months after start of treatment
the 6-month progression-free rate
6 months after start of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To collect preliminary results on the 6-month progression-free rate of the combination vismodegib + temozolomide (phase I)
Time Frame: 6 months after start of treatment
measurement of progression free rate
6 months after start of treatment
To estimate in the two study arms the objective response rate after 6 months of treatment (phase II)
Time Frame: after 6 months of treatment
measure by objective response rate
after 6 months of treatment
To estimate in the two study arms the duration of treatment response (phase II)
Time Frame: one year
treatment response
one year
To estimate in the two study arms the best overall response obtained during the study (phase II)
Time Frame: one year
one year
To estimate in the two study arms the progression-free survival (PFS)(phase II)
Time Frame: one year
measure of progression free rate
one year
To estimate in the two study arms the time to treatment failure (phase II)
Time Frame: one year
one year
frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade
Time Frame: one year
In the combination arm (vismodegib + temozolomide): to further evaluate the safety of the combination
one year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Leon Berard

Collaborators

Ministry of Health, France

Investigators

  • Principal Investigator: didier frappaz, Centre Léon Bérard, Lyon

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2012

Primary Completion (ACTUAL)

September 1, 2017

Study Completion (ACTUAL)

October 1, 2017

Study Registration Dates

First Submitted

May 15, 2012

First Submitted That Met QC Criteria

May 16, 2012

First Posted (ESTIMATE)

May 17, 2012

Study Record Updates

Last Update Posted (ACTUAL)

May 21, 2019

Last Update Submitted That Met QC Criteria

May 20, 2019

Last Verified

May 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MEVITEM
  • 2011-003372-37 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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