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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: vismodegib
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: combination of vismodegib with temozolomide<br>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<br>* Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day<br>Drug: Temozolomide<br>* 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<br>* Other names: temodal;|
| Active Comparator: temozolomide alone<br>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<br>* 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<br>* Other names: temodal;|
| Other: vismodegib alone<br>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<br>* Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day<br>|

What is the study measuring?
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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 | 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 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) | 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) | measure by objective response rate | after 6 months of treatment | 
| To estimate in the two study arms the duration of treatment response (phase II) | treatment response | 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) | measure of progression free rate | one year | 
| To estimate in the two study arms the time to treatment failure (phase II) |  | one year | 
| frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade | In the combination arm (vismodegib + temozolomide): to further evaluate the safety of the combination | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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medulloblastoma, sonic hedgehog pathway, vismodegib