Relationship Between Pharmacokinetics and Safety of Vismodegib - OPTIVISMO-1

Study Overview
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Brief Summary
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Vismodegib (ERIVEDGE®) at the standard dose of 150 mg/day orally is indicated for the treatment of advanced Basal Cell Carcinoma (BCC) and is associated with many adverse effects. Cramps, alopecia, dysgeusia, weight loss and others observed in clinical practice, compromize compliance and often lead to treatment discontinuation. Currently, it is the only drug available in this indication. Our main objective is to assess the relationship between plasma concentrations of vismodegib, and the occurrence of adverse effects within 6 months of inclusion in the study.

Detailed Description
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In patients treated with the Hedgehog (Hh) signaling pathway inhibitor, vismodegib, for Basal Cell Carcinoma (BCC), intolerance to this drug is a cause of non-compliance to treatment and often requires therapy discontinuation in spite of its potent anticarcinomic action. Indeed, vismodegib, at the standard dose of 150 mg/day, leads to many heavy side effects often 1 month after therapy initiation. The major side effects are daily or multiple daily cramps (associated with hypometabolism) in 60% of patients, dysgeusia, ageusia and alopecia (related to stem cells), and tiredness. Currently, there is no recommendation for dose adjustment against the occurrence of these adverse effects, so that clinicians propose temporary or definitive therapeutic discontinuation for around 30% of patients. The management of these therapeutic pauses is a challenge for clinicians, as no data are available on their impact on treatment long-term response. We hypothesize that vismodegib side effects are related to high plasma concentrations of drug in many patients. To date, there is no data from phase 3 study, sparse pharmacokinetic data emanating from Phase 1 and 2 studies in various solid tumors. Patients included are treated with vismodegib (Hedgehog (Hh) pathway inhibitor) for symptomatic metastatic BCC, or for advanced BCC when surgery and radiotherapy are not appropriate. Included patients are new patients initiating a treatment with vismodegib or patients already on vismodegib. The study of the relationship between plasma concentrations of vismodegib and tolerance, requires at each monthly follow-up visits, monitoring of: concentrations of free (unbound to the α1-GPA) and total (bound and unbound) forms of vismodegib, α1-GPA plasma concentrations, patient's status, data on safety and efficacy, and clinical and biological data (covariates that may modulate the vismodegib pharmacokinetics resulting in increased plasma concentrations). Patients will be followed for 6 months.

Official Title
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Study of the Relationship Between the Pharmacokinetics of Vismodegib and Safety Data: a Pilot Study to Therapeutic Optimization in Patients With Basal Cell Carcinoma - OPTIVISMO-1

Conditions
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Metastatic Basal Cell Carcinoma, Locally Advanced Basal Cell Carcinoma

Intervention / Treatment
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* Drug: Treatment with vismodegib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with BCC and annexial carcinoma histologically proven under treatment or new patients under vismodegib or patients who restarted treatment 18 years-old or older Complete medical record Members or beneficiaries of a social security system, Patients must have given informed consent, free and written. Exclusion Criteria: Patients with or without BCC and not treated with vismodegib BCC patients who stopped treatment with vismodegib due to non-response or progression on treatment Patients under 18 years-old Patients whose medical record is incomplete Unaffiliated subjects or not beneficiaries of a security system social, Patients who have not been informed and have not given their consent, free and written, Pregnant and childbearing women without effective contraceptive method Patients with confusional state

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with BCC and annexial carcinoma<br>Patients with BCC and annexial carcinoma histologically proven under treatment or new patients under vismodegib | Drug: Treatment with vismodegib<br>* Vismodegib 150 mg capsules is administered daily with or without food until disease progression or unacceptable toxicity. Patients are followed in the dermatologic unit of Bordeaux University Hospital (Saint André Hospital) every month. At each consultation, clinical and biological datas, and two blood samples are collected just before taking the drug. One sample is for vismodegib quantification (pharmacokinetic protocol), and the other for the determination of alpha-1 glycoprotein acid level<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious side effects (grade 2 or more) during the clinical response follow-up to vismodegib | Patients already on vismodegib will be monitored at inclusion and for 6 months (M0, M1, M2, M3, M4, M5). New patients will be monitored from the end of the first month after inclusion and during 6 months (M1, M2, M3, M4, M5, M6) | Occurrence from inclusion to 6 months visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between the plasma concentrations of free and/or total vismodegib, and covariates |  | From inclusion to 6 months visit | 
| Clinical response to vismodegib in term of efficacy | Classification into 4 categories: progression, stabilité, partial response and complete response according to RECIST criteria | at least at each visit, from inclusion to 6 months visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vismodegib, Pharmacokinetic, LC-MS/MS-MRM, Human plasma concentrations, Adverse events