A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma

Basal Cell Carcinoma Clinical Trial

— BOLT  

Official title:

Phase II, Randomized Double-blind Study of Efficacy and Safety of Two Dose Levels of LDE225 in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01327053
• Other study ID #: CLDE225A2201
• Secondary ID: 2010-022629-14
• Status: Completed
• Phase: Phase 2
• Start date: June 29, 2011
• Est. completion date: June 29, 2018

Study information

• Verified date: August 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study assessed the efficacy and safety of oral treatment with two dose levels of LDE225 in patients with locally advanced or metastatic BCC.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 230
• Est. completion date: June 29, 2018
• Est. primary completion date: June 28, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with locally advanced BCC and metastatic BCC

• Patients with adequate bone marrow, liver, and renal function

Exclusion Criteria:

• Patients who had had major surgery within 4 weeks of initiation of study medication

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

• Patients with concurrent medical conditions that may interfere or potentially affect the interpretation of the study.

• Patients with neuromuscular disorders or are on concurrent treatment with drugs that may cause muscle damage.

• Patients who were on concurrent therapy with other anti-neoplastic agents.

• Patients who had taken part in an experimental drug within 4 weeks of initiation of study medication.

• Pregnant or nursing (lactating) women

• Women of child bearing potential unwilling to use 2 forms of highly effective contraception throughout the study and for 3 months after the last treatment

• Fertile males not willing to use condoms throughout the study and for 3 months after the last treatment.

• Patients who were unwilling or unable to comply with the protocol.

Related Conditions & MeSH terms

• Basal Cell Carcinoma
• Carcinoma
• Carcinoma, Basal Cell

Intervention

Drug:
• LDE225
LDE225 was administered orally, on a continuous once daily dosing schedule and was supplied as 200 mg hard gelatin capsules in bottles. Every 4 weeks on the day of study visit, patients received a prescription of an adequate drug supply for self-administration at home. The 800 mg dose patients received 4 capsules of LDE225 and 200 mg dose arm patients received 1 LDE225 capsule + 3 placebo capsules.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Geelong	Victoria
Australia	Novartis Investigative Site	St Leonards	New South Wales
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Wilrijk
Canada	Novartis Investigative Site	Sainte-Foy	Quebec
Canada	Novartis Investigative Site	Waterloo	Ontario
France	Novartis Investigative Site	Lyon Cedex
France	Novartis Investigative Site	Marseille Cedex 05
France	Novartis Investigative Site	Pierre Benite Cedex
France	Novartis Investigative Site	Toulouse Cedex 9
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Gera
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	Stade
Greece	Novartis Investigative Site	Athens
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szeged
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Torino	TO
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Geneve
Switzerland	Novartis Investigative Site	Zürich
United Kingdom	Novartis Investigative Site	Cardiff
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	High Heaton	Newcastle Upon Tyne
United Kingdom	Novartis Investigative Site	Leicester
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Yeovil	Somerset
United States	University of Colorado School of Medicine UC	Aurora	Colorado
United States	Dana Farber Cancer Institute DFCI - MA	Boston	Massachusetts
United States	NorthwesternUniv.Med.School/Robert H. Lurie Comp.Cancer Ctr Study coordinator	Chicago	Illinois
United States	Baylor Health Care System/Sammons Cancer Center Baylor Texas Oncology	Dallas	Texas
United States	Texas Oncology Tex Onc 3	Dallas	Texas
United States	Texas Oncology Texas Onc - Amarillo	Dallas	Texas
United States	Henry Ford Hospital Henry Ford	Detroit	Michigan
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Hackensack University Medical Center Hackensack (SC)	Hackensack	New Jersey
United States	Penn State University / Milton S. Hershey Medical Center Hershey Medical	Hershey	Pennsylvania
United States	University of Texas MD Anderson Cancer Center MD Anderson	Houston	Texas
United States	Comprehensive Cancer Centers of Nevada CCC of Nevada- Southwest (2)	Las Vegas	Nevada
United States	University of California at Los Angeles UCLA 3	Los Angeles	California
United States	New York University Medical Center SC-2	New York	New York
United States	University of Pittsburgh Medical Center UPMC	Pittsburgh	Pennsylvania
United States	Washington University School Of Medicine-Siteman Cancer Ctr Siteman	Saint Louis	Missouri
United States	University of Utah / Huntsman Cancer Institute Huntsman/Univ UT	Salt Lake City	Utah
United States	Stanford University Medical Center Stanford Univ 2	Stanford	California
United States	H Lee Moffitt Cancer Center and Research Institute Cutaneous Onc Dept	Tampa	Florida
United States	Texas Oncology Cancer Care & Research Center	Waco	Texas
United States	Washington Hospital Center Wash Hospital	Washington	District of Columbia
United States	Texoma Cancer Center Texoma Cancer Center	Wichita Falls	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Greece,  Hungary,  Italy,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) Based on Central Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (for Metastatic Basal Cell Carcinoma (mBCC)) Per Primary Efficacy Analysis Set (pEAS)	ORR is the percentage of patient's objective response (ORR) by 6 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 6 months after starting LDE225 treatment.Treatment with sonidegib was considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	6 months
Primary	Objective Response Rate (ORR) Based on Central Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (Metastatic Basal Cell Carcinoma (mBCC)) Per Full Analysis Set (FAS)	ORR is the percentage of patient's objective response (ORR) by 6 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 6 months after starting LDE225 treatment.Treatment with sonidegib was to be considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	6 months
Secondary	Duration of Response (DoR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	Duration of response is the time from the first observed confirmed response (CR or PR) to disease progression or death due to any reason.; Duration of response was for participants with ORR. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.; Progressive disease (PD): At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm2.	42 months
Secondary	Duration of Response (DoR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	Duration of response is the time from the first observed confirmed response (CR or PR) to disease progression or death due to any reason.; Median DoR for patients with laBCC was non-estimable for both treatment arms. Duration of response was for participants with ORR. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Complete Response Rate (CRR) Per Central Review (pEAS)	Rate of complete response is the percentage of patients with best overall response of complete response (CR) after starting LDE225 treatment. The rate of CR was determined according to mRECIST for laBCC and RECIST 1.1 for mBCC. Patients with best overall response of 'Unknown" were treated as non responders. Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Complete Response Rate (CRR) Per Central Review (FAS)	Rate of complete response is the proportion of patients with best overall response of complete response (CR) after starting LDE225 treatment. The rate of CR will be determined according to mRECIST for laBCC and RECIST 1.1 for mBCC. Patients with best overall response of 'Unknown" will be treated as non responders	6 months
Secondary	Progression-free Survival (PFS) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.	42 months
Secondary	Progression-free Survival (PFS) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, PFS is censored at the date of last adequate tumor assessment.	42 months
Secondary	Time to Tumor Response (TTR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	Time to tumor response (TTR) is defined as the time from date of enrollment to the date of first documented tumor response (CR or PR). PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Time to Tumor Response (TTR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	Time to tumor response (TTR) is defined as the time from date of enrollment to the date of first documented tumor response (CR or PR). PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Objective Response Rate (ORR) Based on Site Investigator Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (for Metastatic Basal Cell Carcinoma (mBCC)) Per Primary Efficacy Analysis Set (pEAS)	ORR is the percentage of patient's objective response (ORR) by 42 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 42 months after starting LDE225 treatment. Treatment with sonidegib was considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Objective Response Rate (ORR) Based on Site Investigator Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (Metastatic Basal Cell Carcinoma (mBCC)) Per Full Analysis Set (FAS)	ORR is the percentage of patient's objective response (ORR) by 6 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 42 months after starting LDE225 treatment.Treatment with sonidegib was to be considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Duration of Response (DoR) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	Duration of response is the time from the first observed confirmed response (CR or PR) to disease progression or death due to any reason.; Duration of response was for participants with ORR. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.; Progressive disease (PD): At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm2.	42 months
Secondary	Duration of Response (DoR) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	Duration of response is the time from the first observed confirmed response (CR or PR) to disease progression or death due to any reason. Duration of response was for participants with ORR. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Progression-free Survival (PFS) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.	42 months
Secondary	Time to Tumor Response (TTR) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	Time to tumor response (TTR) is defined as the time from date of enrollment to the date of first documented tumor response (CR or PR). PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.	42 months
Secondary	Plasma Concentration of Sonidegib (LDE225)	Blood PK samples were collected either by direct venipuncture or an indwelling cannula inserted in a forearm vein for the determination of trough (Cmin) plasma concentrations of sonidegib and its main circulating metabolite, LGE899, from all patients who enrolled in the study. Blood was collected in Weeks 1, 3, 5, 9 (pre-dose), and subsequently pre-dose every 4 weeks up to Week 21, and every 12 weeks thereafter up to week 69.	Weeks 1, 3, 5, 9, 13, 17, 21, 33, 45, 57, 69
Secondary	Overall Survival (OS)	OS is defined as the time from date of randomization to date of death due to any cause or the last date that a patient was known to be alive (censored observation) as of the data cut-off.	42 months