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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Centre Leon Berard
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Centre Leon Berard
ClinicalTrials.gov Identifier:
NCT01601184
First received: May 15, 2012
Last updated: July 9, 2014
Last verified: July 2014
  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.


Condition Intervention Phase
Histologically Confirmed Medulloblastoma
Activation of the Sonic Hedgehog (SHH) Pathway
Drug: vismodegib
Drug: Temozolomide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Centre Leon Berard:

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 [ Time Frame: during the first three months follow up ] [ Designated as safety issue: Yes ]

    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.

  • 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 ] [ Designated as safety issue: No ]
    the 6-month progression-free rate


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    measurement of progression free rate

  • To estimate in the two study arms the objective response rate after 6 months of treatment (phase II) [ Time Frame: after 6 months of tratment ] [ Designated as safety issue: No ]
    measure by objective response rate

  • To estimate in the two study arms the duration of treatment response (phase II) [ Time Frame: one year ] [ Designated as safety issue: No ]
    treatment response

  • To estimate in the two study arms the best overall response obtained during the study (phase II) [ Time Frame: one year ] [ Designated as safety issue: No ]
  • To estimate in the two study arms the progression-free survival (PFS)(phase II) [ Time Frame: one year ] [ Designated as safety issue: No ]
    measure of progression free rate

  • To estimate in the two study arms the time to treatment failure (phase II) [ Time Frame: one year ] [ Designated as safety issue: No ]
  • frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade [ Time Frame: one year ] [ Designated as safety issue: Yes ]
    In the combination arm (vismodegib + temozolomide): to further evaluate the safety of the combination


Estimated Enrollment: 38
Study Start Date: June 2012
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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 Name: temodal
No Intervention: 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

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01601184

Contacts
Contact: Didier Frappaz + 33 478 78 28 81 didier.frappaz@lyon.unicancer.fr

Locations
France
Institut de Cancérologie de l'Ouest - Paul Papin Active, not recruiting
Angers, France, 49933
Centre Léon Bérard Recruiting
Lyon, France
Contact: didier frappaz    +33 4 78 782 881    didier.frappaz@lyon.unicancer.fr   
Principal Investigator: Didier Frappaz         
Sub-Investigator: Marie-Pierre Sunyach         
Sub-Investigator: Yves Devaux         
Sub-Investigator: Alice LEVARD, MD         
Sub-Investigator: Philippe CASSIER, MD         
Sub-Investigator: Louis TASSY, MD         
CHU La Timone Recruiting
Marseille, France, 13385
Contact: olivier chinot       olivier.chinot@ap-hm.fr   
Principal Investigator: Olivier Chinot         
Sub-Investigator: Maryline Barrié         
Sub-Investigator: Mona Matta         
Hopital Central de Nancy Active, not recruiting
Nancy, France
Hopital de La Pitié Salpétrière Recruiting
Paris, France
Contact: Florence Laigle-Donadey    +33 1 42 16 03 81    florence.laigle-donadey@psl.aphp.fr   
Principal Investigator: Florence Laigle-Donadey         
Sub-Investigator: Jean-Yves DELATTRE, MD         
Sub-Investigator: Khê HOANG-XUAN, MD         
Sub-Investigator: Marc SANSON, MD         
Sub-Investigator: Sophie TAILLIBERT, MD         
Sub-Investigator: Caroline DEHAIS, MD         
Sub-Investigator: Dimitri PSIMARAS         
Sub-Investigator: Caroline HOUILLER         
Sub-Investigator: Ahmed IDBAIH         
Institut de Cancérologie de l'Ouest René Gauducheau Recruiting
St Herblain, France
Contact: Mario Campone    +33 2 40 67 99 77    mario.campone@ico.unicancer.fr   
Principal Investigator: Mario Campone         
Sub-Investigator: Jean Sébastien Frenel         
Sub-Investigator: Carole Gourmelon         
Switzerland
Centre Hospitalier Universitaire Vaudois (CHUV) Active, not recruiting
Lausanne, Switzerland, CH-8091
Sponsors and Collaborators
Centre Leon Berard
Ministry of Health, France
Investigators
Principal Investigator: didier frappaz Centre Léon Bérard, Lyon
  More Information

Publications:

Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT01601184     History of Changes
Other Study ID Numbers: MEVITEM, 2011-003372-37
Study First Received: May 15, 2012
Last Updated: July 9, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Centre Leon Berard:
medulloblastoma
sonic hedgehog pathway
vismodegib

Additional relevant MeSH terms:
Medulloblastoma
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
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 24, 2014