Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE)

a randomised, regimen-controlled, double-blind, phase 2 trial

Brigitte Dréno, Rainer Kunstfeld, Axel Hauschild, Scott Fosko, David Zloty, Bruno Labeille, Jean Jacques Grob, Susana Puig, Frank Gilberg, Daniel Bergström, Damian R. Page, Gary Rogers, Dirk Schadendorf

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. Methods In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. Findings Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Interpretation Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. Funding F Hoffmann-La Roche.

Original languageEnglish (US)
Pages (from-to)404-412
Number of pages9
JournalThe Lancet Oncology
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2017

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HhAntag691
Basal Cell Nevus Syndrome
Therapeutics
Basal Cell Carcinoma
Multiple basal cell carcinoma

ASJC Scopus subject areas

  • Oncology

Cite this

Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE) : a randomised, regimen-controlled, double-blind, phase 2 trial. / Dréno, Brigitte; Kunstfeld, Rainer; Hauschild, Axel; Fosko, Scott; Zloty, David; Labeille, Bruno; Grob, Jean Jacques; Puig, Susana; Gilberg, Frank; Bergström, Daniel; Page, Damian R.; Rogers, Gary; Schadendorf, Dirk.

In: The Lancet Oncology, Vol. 18, No. 3, 01.03.2017, p. 404-412.

Research output: Contribution to journalArticle

Dréno, B, Kunstfeld, R, Hauschild, A, Fosko, S, Zloty, D, Labeille, B, Grob, JJ, Puig, S, Gilberg, F, Bergström, D, Page, DR, Rogers, G & Schadendorf, D 2017, 'Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial', The Lancet Oncology, vol. 18, no. 3, pp. 404-412. https://doi.org/10.1016/S1470-2045(17)30072-4
Dréno, Brigitte ; Kunstfeld, Rainer ; Hauschild, Axel ; Fosko, Scott ; Zloty, David ; Labeille, Bruno ; Grob, Jean Jacques ; Puig, Susana ; Gilberg, Frank ; Bergström, Daniel ; Page, Damian R. ; Rogers, Gary ; Schadendorf, Dirk. / Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE) : a randomised, regimen-controlled, double-blind, phase 2 trial. In: The Lancet Oncology. 2017 ; Vol. 18, No. 3. pp. 404-412.
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abstract = "Background Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. Methods In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. Findings Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7{\%} (95{\%} CI 53·0–72·3) in treatment group A and 54·0{\%} (43·6–64·4) in treatment group B. 216 (95{\%}) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94{\%}] of 114 in treatment group A and 109 [97{\%}] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4{\%}] patients in treatment group A vs 12 [11{\%}] in treatment group B), increased blood creatine phosphokinase (one [1{\%}] vs four [4{\%}]), and hypophosphataemia (zero vs three [3{\%}]). Serious treatment-emergent events were noted in 22 (19{\%}) patients in treatment group A and 19 (17{\%}) patients in treatment group B. Four (2{\%}) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Interpretation Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. Funding F Hoffmann-La Roche.",
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TY - JOUR

T1 - Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE)

T2 - a randomised, regimen-controlled, double-blind, phase 2 trial

AU - Dréno, Brigitte

AU - Kunstfeld, Rainer

AU - Hauschild, Axel

AU - Fosko, Scott

AU - Zloty, David

AU - Labeille, Bruno

AU - Grob, Jean Jacques

AU - Puig, Susana

AU - Gilberg, Frank

AU - Bergström, Daniel

AU - Page, Damian R.

AU - Rogers, Gary

AU - Schadendorf, Dirk

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Background Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. Methods In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. Findings Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Interpretation Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. Funding F Hoffmann-La Roche.

AB - Background Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. Methods In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. Findings Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Interpretation Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. Funding F Hoffmann-La Roche.

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