Pilot LDE225 in Locally Advanced or Metastatic BCC + Previously Tx Non-LDE225 Smoothened Inhibitors

A Pilot Open-Label Study to Examine the Safety and Efficacy of Oral LDE225 in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma Who Have Been Previously Treated With Non-LDE225 Smoothened Inhibitor(s)

This is a prospective single-center, open label, pilot study to investigate the safety and efficacy of LDE225 in patients with locally advanced or metastatic basal cell carcinoma.

Primary Objectives:

• To explore the effects of oral LDE225 on the Progression Free Survival (PFS) of individuals with locally advanced or metastatic BCC who have been previously treated with a non-LDE225 Smo inhibitor.

Secondary Objectives:

• To evaluate the effect of oral LDE225 on tumor tissue biomarkers of BCC activation (Gii 1, 2, Patched 1,2 and Ki67) in individuals which are non-na"ive to Smo inhibitors other than LDE225, at baseline and at end-of-treatment
• To describe adverse effects of oral LDE225 in individuals with a history of non-LDE225 Smo inhibitor usage
• To assess the overall survival rates of individuals with locally advanced BCC or metastatic BCC who have previously taken a non-LDE225 Smo inhibitor after treatment with LDE225

Study Overview

• Status: Completed
• Conditions: Basal Cell Carcinoma
• Intervention / Treatment: Drug: LDE225

Detailed Description

This is a prospective single-center, open label, pilot study to investigate the safety and efficacy of LDE225 in patients with locally advanced or metastatic basal cell carcinoma.

Primary Objectives:

• To explore the effects of oral LDE225 on the Progression Free Survival (PFS) of individuals with locally advanced or metastatic BCC who have been previously treated with a non-LDE225 Smo inhibitor.

Secondary Objectives:

• To evaluate the effect of oral LDE225 on tumor tissue biomarkers of BCC activation (e.g. Gli and Ki67) in individuals which are non-naive to Smo inhibitors other than LDE225, at baseline and at end-of-treatment
• To describe adverse effects of oral LDE225 in individuals with a history of non-LDE225 Smo inhibitor usage

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University, School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 years or older.
2. Histologically documented diagnosis of basal cell carcinoma deemed to be locally advanced or metastatic who have previously received a non-LDE225 Smo inhibitor.
3. World Health Organization (WHO) performance status <= 2
4. At least one measurable site of disease (as defined by Response Evaluation Criteria in Solid Tumors), or other disease specific response assessment criteria, as appropriate. State age restriction and/or gender/race-ethnic restrictions.

5. Patients with adequate bone marrow, liver and renal function, as specified below:

   • Absolute Neutrophil Count (ANC) >= 1.5 x 10^9/L
   • Hemoglobin (Hgb) >= 9 g/dL
   • Platelets >= 80 x 10^9/L
   • Serum total bilirubin <= 1.5 x upper limit of normal (ULN)
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 x ULN or <= 5 x ULN if liver metastases are present
   • Plasma creatine phosphokinase (CK) < 1.5 x ULN
   • Serum creatinine <= 1.5 x ULN or 24-hour clearance >= 50ml/min
6. Written informed consent obtained prior to any screening procedures

Exclusion Criteria:

1. Patients who have had major surgery within 4 weeks of initiation of study medication.

2. Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data.

   State restrictions regarding use of other Investigational Agents.

3. Patients unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes.

   State exclusion requirements due to co-morbid disease or incurrent illness, as needed.

4. Patients who have previously been treated with systemic LDE225.

5. Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) inhibitors (statins), clofibrate and gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting LDE225 treatment. If it is essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may be used with extra caution.

   b) Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment. Note: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided whilst on LDE225 treatment.

6. Patients who have taken part in an experimental drug study within 4 weeks of initiating treatment with LDE225.
7. Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted therapy or radiotherapy) concurrently or within 2 weeks of starting treatment with LDE225.
8. Patients who are receiving treatment with medications known to be moderate and strong inhibitors or inducers of cytochrome (CYP)3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment with LDE225.
9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL).

10 Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include:

• Diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.

• Reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation.

  11 Patients unwilling or unable to comply with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Refractory Group; Patients previously treated with non-LDE225 Smo inhibitor who were refractory.	Drug: LDE225; 800-mg (4 200-mg capsules/day) capsule; Other Names: NVP-LDE225
ACTIVE_COMPARATOR: Resistance Developed Group; Patients previously treated with non-LDE225 Smo inhibitor who were initially responsive but became resistant with progressive disease.	Drug: LDE225; 800-mg (4 200-mg capsules/day) capsule; Other Names: NVP-LDE225

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival (PFS) of All Participants	End of treatment or at time of disease progression (up to 58 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular Markers Associated With Clinical Response	Following consent, historical biopsy samples were analyzed for molecular markers associated with clinical response. Tumors were analyzed and present of Smooth mutation (SMO [genetic changes which influence Ki 67 and Gli levels]). was determined. The number of participants with and without SMO were reported by clinical outcome (SD = stable disease; PD = progressive disease).	Assessed on day 1

Collaborators and Investigators

• Sponsor: Anne Chang
• Collaborators: Novartis
• Investigators: Principal Investigator: Anne Chang, MD, Stanford University

Publications and helpful links

General Publications

• Danial C, Sarin KY, Oro AE, Chang AL. An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib. Clin Cancer Res. 2016 Mar 15;22(6):1325-9. doi: 10.1158/1078-0432.CCR-15-1588. Epub 2015 Nov 6.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (ACTUAL): August 1, 2013
• Study Completion (ACTUAL): August 1, 2013

Study Registration Dates

• First Submitted: October 11, 2011
• First Submitted That Met QC Criteria: February 6, 2012
• First Posted (ESTIMATE): February 8, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): January 16, 2017
• Last Update Submitted That Met QC Criteria: November 23, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: basal cell carcinoma, sonidegib, smoothened inhibitor, hedgehog
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Basal Cell; Carcinoma; Carcinoma, Basal Cell
• Other Study ID Numbers: SKIN0009; SU-09022011-8371 (OTHER: Stanford University); 21759 (OTHER: Stanford IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO