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Study Title and Description

Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial.



Key Questions Addressed
1 Comparison of interventions
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Primary Publication Information
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TitleData
Title Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial.
Author Migden MR., Guminski A., Gutzmer R., Dirix L., Lewis KD., Combemale P., Herd RM., Kudchadkar R., Trefzer U., Gogov S., Pallaud C., Yi T., Mone M., Kaatz M., Loquai C., Stratigos AJ., Schulze HJ., Plummer R., Chang AL., Cornélis F., Lear JT., Sellami D., Dummer R.
Country Mohs Surgery Center, Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mrmigden@mdanderson.org.
Year 2015
Numbers Pubmed ID: 25981810

Secondary Publication Information
UI Title Author Country Year
The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. Dummer R., Guminski A., Gutzmer R., Dirix L., Lewis KD., Combemale P., Herd RM., Kaatz M., Loquai C., Stratigos AJ., Schulze HJ., Plummer R., Gogov S., Pallaud C., Yi T., Mone M., Chang AL., Cornélis F., Kudchadkar R., Trefzer U., Lear JT., Sellami D., Migden MR. UniversitätsSpital Zürich-Skin Cancer Center, University Hospital, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. 2016
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Investigator-assessed efficacy and safety of sonidegib in patients with locally advanced basal cell carcinoma and metastatic basal cell carcinoma: results of the BOLT 30-month analysis R. Dummer, M. Migden, A. Guminski, R. Gutzmer, R. Kudchadkar, K. Lewis, L. Dirix, P. Combemale, U. Trefzer, C. Loquai, M. Kaatz, A.L. Chang, A. Stratigos, R. Plummer, M. Mone, H.Castro, T. Yi, D. Sellami and J. Lear 2016
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Sonidegib for patients with advanced basal cell carcinoma: long-term efficacy and safety results in the BOLT 30-month analysis M. R. Migden, R. Dummer, A. Guminski, R. Gutzmer, R. Kudchadkar, K. D. Lewis, L. Dirix, P. Combemale, U. Trefzer, C. Loquai, M. Kaatz, A. L. S. Chang, A. Stratigos, R. Plummer, M. Mone, H. Castro, T. Yi, D. Sellami, J. Lear 2017
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Extraction Form: Comparative studies
Arms
Number Title Description Comments
1 sonidegib 200
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2 sonidegib 800
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Design Details
Question... Follow Up Answer Follow-up Answer
Publication or abstract? Publication
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Study design RCT
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Multicenter etc. Multicenter
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Country/Region worldwide
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Funding Industry funded
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Inclusion criteria >= 18 years, with histologically confirmed, locally advanced basal cell carcinoma not amenable to radiotherapy or curative surgery, adequate bone marrow (absolute neutrophil count 1·5 × 10⁹ cells per L or higher, haemoglobin 90 g/L or higher, and platelet count of 100 × 10⁹ cells per L or higher), liver function (total bilirubin concentration in serum no greater than 1·5 times the upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase no greater than 2·5 times the ULN or no more than 5·0 times the ULN in patients with liver metastases), and renal function (creatine kinase concentration in serum no greater than 1·5 times the ULN; creatinine concentration in serum no greater than 1·5 times the ULN or 24 h creatinine clearance of 0·84 mL/s per m² or greater).
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Exclusion criteria previous treatment with sonidegib or another Hedgehog pathway inhibitor, major surgery, other antineoplastic therapy, having taken an investigational agent within 4 weeks before the start of the study or currently taking strong inhibitors or inducers of CYP3A4 or CYP3A5 expression or drugs metabolised by CYP2B6 or CYP2C9; gastrointestinal dysfunction or known malabsorption syndromes, neuromuscular disorders, or other uncontrolled medical disorders; treatment with drugs known to cause rhabdomyolysis (eg, statins), although use of pravastatin was allowed with extra caution; and pregnancy or breastfeeding
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N Enrolled/Randomized/Analyzed 269
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230
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230
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Notes/Comments 27% of the entire cohort is recurrent, but analysis was done separately on metastatic vs advanced, so I'm leaning toward keeping anyway.
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Method of diagnosis ... Describe Biopsy/pathologic confirmation ...
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Preoperative assessment of clinical size of the tumor ... visual ... standard annotated photography
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Percent non-primary (recurrent) 27%
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Secondary size assessment Tumour assessments were done by the central review committee and investigators at baseline and at weeks 5 and 9 after treatment start, then every 8 weeks during year 1, every 12 weeks thereafter
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Baseline Characteristics
Question sonidegib 200 sonidegib 800 Total Comments
AnswerFollow-up AnswerFollow-up AnswerFollow-up
Continuous baselines 67 65 12.1 cm²
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25, 92 24, 93 0.7, 639.3 cm²
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Gender/Racial descent 31 55
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39 36
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0 1
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0 145
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71 96
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90 5
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8 3
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10
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Lesion location No data entered.
Skin type (Fitzpatrick score) No data entered.
Number of lesions per patient 30 57
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38 38
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49 93
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62 62
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>=2 >=2
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Previous treatments 60 127
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76 84
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Surgical excision without intraoperative evaluation of the margins Surgical excision without intraoperative evaluation of the margins
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19 49
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24 32
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Radiation Radiation
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Immunocompromized status No data entered.
Number of patients/lesions 79 151
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40 104
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16 adverse events 15 disease progression 5 withdrew consent 3 physician’s decision 1 lost to follow-up 48 adverse events 6 disease progression 28 withdrew consent 10 physician’s decision 4 lost to follow-up 4 died* 3 non-adherence 1 protocol deviation
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55 116
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Lesion extent number of people 151 79
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38 (1 type missing)
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nodular and superfi cial basal cell carcinoma. 68
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40 nodular and superfi cial basal cell carcinoma.
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micronodular, infi ltrative, multifocal, basosquamous, or sclerosing 76
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14 micronodular, infi ltrative, multifocal, basosquamous, or sclerosing
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Metastasis 23
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Metastasis
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Lesion extent number of people No data entered.



Results & Comparisons


Results Data
Outcome: Lack of clinical clearance      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 42 93
Counts 40 93
Outcome: Lack of clinical clearance      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 42 93
Counts 39 81
Outcome: Lack of clinical clearance      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 66 128
Counts 64 128
Outcome: Lack of clinical clearance      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 66 128
Counts 61 113
Outcome: Lack of clinical clearance      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 42 93
Counts 24 58
Outcome: Lack of clinical clearance      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 66 128
Counts 35 83


30 months

N Analyzed 66 128
Counts 19 52
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 110
Counts 22 35
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 110
Counts 51 73
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 109
Counts 16 22
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 109
Counts 56 97
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 110
Counts 19 36
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 110
Counts 55 88
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 109
Counts 23 21
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 61 109
Counts 49 76
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 58 110
Counts 25 33
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 58 110
Counts 52 101
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 60 112
Counts 11 21
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 60 112
Counts 58 98
Outcome: Quality of life (generic)      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 58 110
Counts 58 97
Outcome: Adverse events: other      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


13.9 months

N Analyzed 79 150
Counts 75 150
Outcome: Long-term Mortality      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


30 months

N Analyzed 66 128
Counts 5 11
Outcome: Adverse events: Any leading to discontinuation      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


30 months

N Analyzed 66 128
Counts 20 51.2
Outcome: Adverse events: Any serious/severe      Population: All Participants
Time Point Measure sonidegib 200 sonidegib 800


30 months

N Analyzed 66 128
Counts 28 90


Quality Dimensions
Dimension Value Notes Comments
RCT:....Adequate generation of a randomized sequence reported Yes
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RCT:....Adequate allocation concealment reported Yes
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RCT:....Adequate blinding of PATIENTS reported Yes
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RCT:....Adequate blinding of PROVIDERS reported Yes
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ALL....Adequate blinding of OUTCOME ASSESSORS reported Yes
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ALL.....Incomplete results data: are more than 20% missing for any eligible outcome in any group? No Very high dropout rate; most due to adverse events. Bounding analysis suggest there is high risk of bias due to dropouts
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ALL.....Selective Reporting (judgement - put directly into notes field). Possible; only a small number (7) of QOL results reported; NCT record does not call for any QOL results.
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RCT.....Is the treatment effect by Intention to treat? Yes both ITT and as treated results reported
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ALL....Group similarity at baseline. Yes
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ALL....Additional Bias: Bias due to problems not covered elsewhere. (judgement - put directly into notes field) followup time is a median
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ALL (with AE results)....Were reported adverse events (of interest) precisely defined Yes
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Overall, by outcome (judgement - put directly into notes field) Overall moderate RoB due to dropouts
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ALL.....Incomplete results data: Is there differential missingness (more than 20%) between arms for any eligible outcome? No dropout rates and reasons were similar across arms
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Quality Rating
No quality rating data was found.