A Study to Evaluate Neoadjuvant Sonidegib Followed by Surgery or Imiquimod in the Management of Basal Cell Carcinoma

Study Overview
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Brief Summary
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In this study, patients with BCC will be given neoadjuvant treatment with a drug called sonidegib. Sonidegib is a daily tablet usually given for BCC that cannot be removed by surgery or that has spread through the body. The study aims to see if sonidegib given for 12 weeks will reduce the size of tumours so surgery results in less scarring or may be avoided, with only short term topical treatment required to treat remaining tumour.

Detailed Description
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Surgery is the first line treatment for most basal cell carcinomas (BCCs) with cure rates of 88 to 96%. However, excision of large lesions in sensitive locations such as the face and scalp may result in disfigurement and impairment of function. Neoadjuvant drug treatment given before surgery aims to reduce tumour size so that surgery and recovery is easier. In this study, patients with BCC will be given neoadjuvant treatment with a drug called sonidegib. Sonidegib is a daily tablet usually given for BCC that cannot be removed by surgery or that has spread through the body. The study aims to see if sonidegib given for 12 weeks will reduce the size of tumours so surgery results in less scarring or may be avoided, with only short term topical treatment required to treat remaining tumour. This approach may also reduce the risk of recurrence. To assess response to treatment, we will use a new technology for skin tumours called optical coherence technology (OCT). This is like an ultrasound scan and is non invasive. OCT can detect the extent and nature of the tumour and build a 3D image with great accuracy. OCT will be used together with pathological analysis of tumour tissue to determine response to sonidegib.

Official Title
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A Pilot Study to Evaluate Short Term Neoadjuvant Sonidegib Followed by Surgery or Imiquimod in the Management of Basal Cell Carcinomas in Cosmetically Challenging Locations

Conditions
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Basal Cell Carcinoma, Basal Cell Carcinoma of Skin, Site Unspecified, Skin Cancer, Invasive Carcinoma

Intervention / Treatment
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* Drug: Sonidegib
* Drug: Imiquimod
* Procedure: Surgery
* Other: Best supportive care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age. Written informed consent. Histologically confirmed, resectable, invasive basal cell carcinoma. Site and size of BCC considered to be in a cosmetically challenging position for surgery. Patient has expressed concerns of the cosmetic outcome of surgery. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Ability to swallow and retain oral medication. Anticipated life expectancy of > 12 months. Adequate organ function as demonstrated by blood tests. Willing to abstain from blood donations for 20 months from the last dose of sonidegib. Men with female partner of childbearing potential to use effective contraception from 14 days prior to study treatment until 6 months after the last dose. Female patients with active contraception or no menstrual cycle for >12 months Exclusion Criteria: Inoperable basal cell carcinoma tumours. A concurrent cancer diagnosis requiring any systemic anti-cancer therapy. Serious or unstable pre-existing medical conditions or other conditions or laboratory abnormalities that could interfere with the patient's safety, consent, or compliance. History of malabsorption or other conditions that would interfere with the absorption of sonidegib. Known psychiatric or substance abuse disorders that would interfere with cooperation and compliance with the requirements of the trial. Prior treatment with hedgehog pathway inhibitors. Concomitant medications that may result in increased or decreased bioavailability of sonidegib. Patients with neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, rhabdomyolysis, amyotrophic lateral sclerosis and spinal muscular atrophy) due to an increased risk of muscle toxicity with sonidegib. Male patients expecting to father children or donate sperm during the 12 weeks of sonidegib treatment and for a further 6 months from the end of treatment. Pregnant or breastfeeding women

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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a pilot study which will evaluate the efficacy and safety of short term neoadjuvant sonidegib followed by surgery or imiquimod in the management of basal cell carcinomas in cosmetically challenging locations, assessed by optical coherence tomography and histopathology. The data from this pilot study may lead to the design of larger scale trials of neoadjuvant targeted therapy with the aim to decrease the morbidity of surgical treatment and increase the probability of a curative resection in larger patient populations.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sonidegib followed by imiquimod<br>Sonidegib 200mg taken orally once a day for 12 weeks. COMPLETE OR PARTIAL RESPONSE WITH SUPERFICAL REMNANT LESION For patients with a complete response or a partial response resulting in a superficial lesion, treatment with topical imiquimod for 5 days a week for 6 weeks will be prescribed. | Drug: Sonidegib<br>* Sonidegib is a selective and orally bioavailable Smoothened (Smo) antagonist. The dose will be 200mg taken once a day for 12 weeks.<br>* Other names: Odomzo;Drug: Imiquimod<br>* Imiquimod is an immune response modifier that promotes NF-kappa-B-mediated secretion of pro-inflammatory cytokines, chemokines and other mediators. These immune responses produce cytotoxic effects that are antiproliferative and anti-tumour. Imiquimod treatment requires an extended treatment period of 6 weeks for superficial BCC. Imiquimod is an option for the treatment of small, low-risk superficial BCC when surgery, curettage or cryotherapy are inappropriate. Treatment with imiquimod will be for 5 days a week for a total of 6 weeks.<br>* Other names: Aldara;|
| Experimental: Sonidegib followed by surgery<br>Sonidegib 200mg taken orally once a day for 12 weeks. PARTIAL RESPONSE WITH REMNANT INVASIVE LESION For patients with a no change on BCC size / depth or patients with a partial response but a remaining invasive lesion, will have surgical excscion of the remaining lesion. | Drug: Sonidegib<br>* Sonidegib is a selective and orally bioavailable Smoothened (Smo) antagonist. The dose will be 200mg taken once a day for 12 weeks.<br>* Other names: Odomzo;Procedure: Surgery<br>* Although most BCCs are amenable to surgery, excision of large tumours in aesthetically sensitive sites may compromise function or cosmesis. Patients whose BCC has not shrunk in size or depth following 12 weeks of sonidegib will undergo surgical excision of the remaining tumour.<br>* Other names: Excision of remnant invasive basal cell carcinoma;|
| Other: Sonidegib then best supportive care<br>Sonidegib 200mg taken orally once a day for 12 weeks. PROGRESSIVE DISEASE Patients with lesions that have progressed in size and/or depth will receive the best supportive care deemed appropriate by the treating clinician. This may be surgery, imiquimod, a clinical trial treatment, radiotherapy or any combination of these interventions. | Drug: Sonidegib<br>* Sonidegib is a selective and orally bioavailable Smoothened (Smo) antagonist. The dose will be 200mg taken once a day for 12 weeks.<br>* Other names: Odomzo;Other: Best supportive care<br>* Patients with lesions that have progressed in size and/or depth will receive the best supportive care deemed appropriate by the treating clinician. This may be surgery, imiquimod, a clinical trial treatment, radiotherapy or any combination of these interventions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neoadjuvant treatment response determined by optical coherence tomography | The size and spread of abnormal skin structures associated with basal cell carcinoma detected by optical coherence tomography. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neoadjuvant treatment response determined by histopathology | The size and spread of basal cell carcinoma tumour in a biopsy taken from the known worse affected area of disease demonstrated by histopathologic analysis. | 12 weeks | 
| Histologic response to neoadjuvant treatment in basal cell carcinoma sub types | The amount and spread of basal cell carcinoma tumour cells and structures detected at histopathology analysis in nodular and in infiltrative sub types of BCC. | 12 weeks | 
| Response to neoadjuvant treatment in basal cell carcinoma sub types measured with optical coherence tomography. | The amount and spread of basal cell carcinoma tumour cells and structures detected at histopathology analysis in nodular and in infiltrative sub types of BCC. | 12 weeks | 
| Recurrence rate | The number of patients who have a recurrence of basal cell carcinoma at the original site of disease after having surgery or 6 weeks of topical treatment with imiquimod. | 6 and 12 months after surgery or at the end of 6 weeks of treatment with imiquimiod. | 
| Drug related adverse reactions | The proportion of patients experiencing any adverse drug reactions graded according to CTCAE version 4. | 12 weeks | 
| Discontinuation of sonidegib due to adverse reactions | The proportion of patients who discontinue sonideigb because of adverse drug reactions. | 12 weeks | 
| Quality of life based on SKINDEX-16 | The scores obtained from the validated SKINDEX-16 quality of life questionnaire compared to baseline. | Weeks 12 and 18 and months 6 and 12. | 
| Patient rated cosmetic outcome after neoadjuvant treatment followed by surgery | Scores from a 3 likert scale questions assessing the patient's agreement with statements about the appearance of their surgical scar for patients who need surgery after neoadjuvant treatment. | Week 12 | 
| Surgeon rated cosmetic outcome after neoadjuvant treatment followed by surgery | Scores from a 3 likert scale questions assessing the surgeon's agreement with statements about the appearance of their surgical scar for patients who need surgery after neoadjuvant treatment. | Week 12 | 
| Patient rated cosmetic outcome after neoadjuvant treatment | Scores from a 3 likert scale questions assessing the patient's agreement with statements about the appearance of the remmant BCC area for patients who did not need surgery after neoadjuvant treatment. | Week 12 | 
| Surgeon rated cosmetic outcome after neoadjuvant treatment | Scores from a 3 likert scale questions assessing the surgeons's agreement with statements about the appearance of the remmant BCC area for patients who did not need surgery after neoadjuvant treatment. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant, Sonidegib