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

NCT01601184 | Terminated Phase 1 DMC

• 2 other identifiers: MEVITEM2011-003372-37
• Study Type: interventional
• Target: 24
• Locations: 4 countries
• Sites: 15

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.

Conditions

Histologically Confirmed Medulloblastoma; Activation of the Sonic Hedgehog (SHH) Pathway

Keywords

medulloblastoma; sonic hedgehog pathway; vismodegib

Outcome Measures

Primary Outcomes (2)

• 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

  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)

  the 6-month progression-free rate

  6 months after start of treatment

Secondary Outcomes (7)

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

  6 months after start of treatment

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

  after 6 months of treatment

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

  one year

• 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

Study Arms (3)

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)

Drug: vismodegib; Drug: Temozolomide

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).

Drug: Temozolomide

vismodegib alone

OTHER

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

Interventions

vismodegib DRUG

Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day

combination of vismodegib with temozolomide; vismodegib alone

Temozolomide DRUG

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

Also known as: temodal

combination of vismodegib with temozolomide; temozolomide alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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.)

Sponsors & Collaborators

• Centre Leon Berard: lead
• Ministry of Health, France: collaborator

Study Sites (15)

CHU La Timone

Marseille, Bouches Du Rhône, 13385, France

Location

Institut Claudius Régaud (iuct-oncopole)

Toulouse, Haute-Garonne, 31059, France

Location

Institut de Cancérologie de l'Ouest - René Gauducheau

Saint-Herblain, Loire Atlantique, 44805, France

Location

Hopital Central de Nancy

Nancy, Meurthe Et Moselle, 54035, France

Location

CHBS Hôpital du Scorff

Lorient, Morbihan, 56322, France

Location

CHRU de Lille

Lille, Nord, 59037, France

Location

Centre Léon Bérard

Lyon, Rhone, 69373, France

Location

Institut de Cancérologie de l'Ouest - Paul Papin

Angers, 49933, France

Location

Institut Bergonié

Bordeaux, 33076, France

Location

Hopital de La Pitié Salpétrière

Paris, Île-de-France Region, 75013, France

Location

BELLARIA Ospedale

Bologna, 40139, Italy

Location

University of Turin

Torino, 10126, Italy

Location

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, CH-8091, Switzerland

Location

University Hospital Zurich

Zurich, CH-8091, Switzerland

Location

University College London Hospital - Mount Vernon Cancer Centre - Mount Vernon hospital

London, London-NW1-2PG, United Kingdom

Location

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MeSH Terms

Conditions

Microphthalmia, Isolated, with Coloboma 5; Medulloblastoma

Interventions

HhAntag691; Temozolomide

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• didier frappaz

  Centre Léon Bérard, Lyon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2012
• First Posted: May 17, 2012
• Study Start: June 1, 2012
• Primary Completion: September 1, 2017
• Study Completion: October 1, 2017
• Last Updated: May 21, 2019

Record last verified: 2019-05

Locations

CH (2); FR (10); IT (2); GB (1)