Clinical Trials /

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

NCT01601184

Description:

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.

Related Conditions:
  • Medulloblastoma
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Study of <span class="go-doc-concept go-doc-intervention">Vismodegib</span> in Combination With <span class="go-doc-concept go-doc-intervention">Temozolomide</span> Versus <span class="go-doc-concept go-doc-intervention">Temozolomide</span> Alone in Patients With Medulloblastomas With an Activation of the Sonic <span class="go-doc-concept go-doc-biomarker">Hedgehog</span> Pathway

Title

  • Brief Title: 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
  • Clinical Trial IDs

    NCT ID: NCT01601184

    ORG ID: MEVITEM

    NCI ID: 2011-003372-37

    Trial Conditions

    Histologically Confirmed Medulloblastoma

    Activation of the Sonic Hedgehog (SHH) Pathway

    Trial Interventions

    Drug Synonyms Arms
    vismodegib combination of vismodegib with temozolomide
    Temozolomide temodal temozolomide alone

    Trial Purpose

    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
    to standard therapy medulloblastoma 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

    Trial Arms

    Name Type Description Interventions
    combination of vismodegib with temozolomide Experimental 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
    temozolomide alone Active Comparator 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
    vismodegib alone No Intervention 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

    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 (Appendix 4).

    - 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 5 for
    acceptable method of contraception) at least 4 weeks prior to study entry, during the
    study period and for at least 7 months post-treatment. 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 6).

    - 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.)

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    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

    To estimate the efficacy of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma (phase II)

    Secondary Outcome Measures

    To collect preliminary results on the 6-month progression-free rate of the combination vismodegib + temozolomide (phase I)

    To estimate in the two study arms the objective response rate after 6 months of treatment (phase II)

    To estimate in the two study arms the duration of treatment response (phase II)

    To estimate in the two study arms the best overall response obtained during the study (phase II)

    To estimate in the two study arms the progression-free survival (PFS)(phase II)

    To estimate in the two study arms the time to treatment failure (phase II)

    frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade

    Trial Keywords

    medulloblastoma

    sonic hedgehog pathway

    vismodegib