Erivedge (Vismodegib) in the Treatment of Pediatric Patients With Refractory Pontine Glioma

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate an investigational drug (Vismodegib) for Pontine Glioma that is growing or has come back (reoccurred). This study will look at the tumors response to the study drug, Vismodegib, and will also look at the safety and tolerability of Vismodegib. Vismodegib has been tested in multiple adult clinical trials and one pediatric trial. Laboratory testing in pontine gliomas suggests that this drug may be effective in treating this disease.

Official Title
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A Phase II, Open-label, Multi-center Study of Erivedge (Vismodegib) in the Treatment of Pediatric Patients With Refractory Pontine Glioma.

Conditions
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Pontine Glioma

Intervention / Treatment
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* Drug: Vismodegib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have radiographically proven diffuse intrinsic pontine glioma and confirmation of residual disease after initial therapy or at the time of recurrence/progression as confirmed by MRI of the brain Subjects must be age ≥3 years and ≤ 18 years Diffuse intrinsic pontine glioma with measurable disease after receiving radiotherapy either concurrent with or followed by ≤ 2 prior courses of chemotherapy Measurable disease as defined by: Measurable tumor >10mm by MRI Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age) Body surface area > 0.67 m2 and ≤ 2.21 m2 Life expectancy of at least 2 months A negative urine pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses) Acceptable liver function as defined by: Bilirubin ≤ 1.5 times upper limit of normal AST (SGOT), ALT (SGPT) and Alkaline phosphatase ≤ 2.5 times upper limit of normal Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age as follows: 0.8 mg/dL (for patients ≤ 5 years of age) 1.0 mg/dL (for patients 6 to 10 years of age) 1.2 mg/dL (for patients 11 to 15 years of age) 1.5 mg/dL (for patients > 15 years of age) Acceptable hematologic status as defined by: Granulocyte ≥ 1500 cells/mm3 Platelet count ≥ 100,000 (plt/mm3) Serum albumin ≥ 2.5 g/dL Urinalysis: a. No clinically significant abnormalities Acceptable coagulation status as defined by: PT/INR less than 1.5 PTT within normal limits Subjects must be able to swallow and retain oral medication Female post-pubertal study subjects need to agree to use one of the more effective birth control methods during treatment and for 7 (seven) months after treatment is stopped. These methods include total abstinence (no sex), oral contraceptives (the pill), an intrauterine device (IUD), levonorgestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). Male post-pubertal study subjects need to agree to use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with Erivedge capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to Vismodegib. Voluntarily signed and dated a written IRB-approved informed consent by parent or legal guardian of subject Exclusion Criteria: Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, biologic therapy) other than the ones specified in the protocol. Patients must have discontinued the above cancer therapies for generally about 3 weeks (8 weeks for radiotherapy) prior to the first dose of study medication, as well as recovered from toxicity (to ≤ than grade 2 except for alopecia) induced by previous treatments. Currently receiving another investigational medicinal product. Uncontrolled concurrent illness including, but not limited to: Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy Diarrhea of any cause ≥ CTCAE grade 2 Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary Any kind of malabsorption syndrome significantly affecting gastrointestinal function Pregnant or nursing female patients. NOTE: If a female patient becomes pregnant or suspects that she is pregnant while participating in this study, she should stop taking study drug and immediately inform her treating physician immediately. Prior therapy with a Hedgehog inhibitor Unwillingness or inability to comply with procedures required in this protocol Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor. History of Congestive Heart Failure (CHF) or ventricular arrhythmia requiring medication.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vismodegib<br>Vismodegib will be dosed at 150mg-300mg orally (max dose: 300mg) once a day on days 1 to 28 of a 28-day cycle. In the absence of unacceptable toxicity or disease progression, treatment may continue for as long as tolerated. | Drug: Vismodegib<br> <br> * Other names: Erivedge;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days Participants Experienced Progression Free Survival (PFS) | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | To determine the safety and tolerability of Vismodegib as a single agent in pediatric and young adult patients with refractory or recurrent pontine glioma | 2 years | 
| Determine the Median Overall Survival (OS) of Participants | Overall Survival (OS) and clinical benefit (ORR + stable disease, SD) | 2 years | 
| Evaluate the Impact of Quality of Life of Children Receiving Vismodegib Using PedsQL Questionnaires | Evaluate the impact of Quality of Life of children receiving Vismodegib using PedsQL questionnaires | 2 years | 
| Determine the Response Rates of Participants Based on Activation (or no Activation) of Their Hedgehog Signaling Pathway | To determine the objective response rates (partial and complete response) for patients without and with evidence of activation of Hedgehog signaling pathway in their tumors | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DIPG