Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial

William D. Tap, Hans Gelderblom, Emanuela Palmerini, Jayesh Desai, Sebastian Bauer, Jean Yves Blay, Thierry Alcindor, Kristen Ganjoo, Javier Martín-Broto, Christopher Ryan, David M. Thomas, Charles Peterfy, John H. Healey, Michiel van de Sande, Heather L. Gelhorn, Dale E. Shuster, Q. Wang, Antoine Yver, Henry H. Hsu, Paul S. LinSandra Tong-Starksen, Silvia Stacchiotti, Andrew J. Wagner

    Research output: Contribution to journalArticle

    5 Citations (Scopus)

    Abstract

    Background: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. Methods: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. Findings: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27–53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. Interpretation: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. Funding: Daiichi Sankyo.

    Original languageEnglish (US)
    Pages (from-to)478-487
    Number of pages10
    JournalThe Lancet
    Volume394
    Issue number10197
    DOIs
    StatePublished - Aug 10 2019

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    Placebos
    Macrophage Colony-Stimulating Factor
    Giant Cell Tumor of Tendon Sheath
    Clinical Trials Data Monitoring Committees
    Colony-Stimulating Factor Receptors
    Dysgeusia
    Hair Color
    Therapeutics
    Aspartate Aminotransferases
    Transaminases
    Alanine Transaminase
    Bilirubin
    Double-Blind Method
    Nausea
    Fatigue
    Alkaline Phosphatase
    Neoplasms
    Morbidity
    Biopsy
    Safety

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Tap, W. D., Gelderblom, H., Palmerini, E., Desai, J., Bauer, S., Blay, J. Y., ... Wagner, A. J. (2019). Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. The Lancet, 394(10197), 478-487. https://doi.org/10.1016/S0140-6736(19)30764-0

    Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN) : a randomised phase 3 trial. / Tap, William D.; Gelderblom, Hans; Palmerini, Emanuela; Desai, Jayesh; Bauer, Sebastian; Blay, Jean Yves; Alcindor, Thierry; Ganjoo, Kristen; Martín-Broto, Javier; Ryan, Christopher; Thomas, David M.; Peterfy, Charles; Healey, John H.; van de Sande, Michiel; Gelhorn, Heather L.; Shuster, Dale E.; Wang, Q.; Yver, Antoine; Hsu, Henry H.; Lin, Paul S.; Tong-Starksen, Sandra; Stacchiotti, Silvia; Wagner, Andrew J.

    In: The Lancet, Vol. 394, No. 10197, 10.08.2019, p. 478-487.

    Research output: Contribution to journalArticle

    Tap, WD, Gelderblom, H, Palmerini, E, Desai, J, Bauer, S, Blay, JY, Alcindor, T, Ganjoo, K, Martín-Broto, J, Ryan, C, Thomas, DM, Peterfy, C, Healey, JH, van de Sande, M, Gelhorn, HL, Shuster, DE, Wang, Q, Yver, A, Hsu, HH, Lin, PS, Tong-Starksen, S, Stacchiotti, S & Wagner, AJ 2019, 'Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial', The Lancet, vol. 394, no. 10197, pp. 478-487. https://doi.org/10.1016/S0140-6736(19)30764-0
    Tap, William D. ; Gelderblom, Hans ; Palmerini, Emanuela ; Desai, Jayesh ; Bauer, Sebastian ; Blay, Jean Yves ; Alcindor, Thierry ; Ganjoo, Kristen ; Martín-Broto, Javier ; Ryan, Christopher ; Thomas, David M. ; Peterfy, Charles ; Healey, John H. ; van de Sande, Michiel ; Gelhorn, Heather L. ; Shuster, Dale E. ; Wang, Q. ; Yver, Antoine ; Hsu, Henry H. ; Lin, Paul S. ; Tong-Starksen, Sandra ; Stacchiotti, Silvia ; Wagner, Andrew J. / Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN) : a randomised phase 3 trial. In: The Lancet. 2019 ; Vol. 394, No. 10197. pp. 478-487.
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    abstract = "Background: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. Methods: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. Findings: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39{\%}] of 61 vs none of 59; absolute difference 39{\%} [95{\%} CI 27–53]; p<0·0001). Serious adverse events occurred in eight (13{\%}) of 61 patients in the pexidartinib group and one (2{\%}) of 59 patients in the placebo group. Hair colour changes (67{\%}), fatigue (54{\%}), aspartate aminotransferase increase (39{\%}), nausea (38{\%}), alanine aminotransferase increase (28{\%}), and dysgeusia (25{\%}) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. Interpretation: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. Funding: Daiichi Sankyo.",
    author = "Tap, {William D.} and Hans Gelderblom and Emanuela Palmerini and Jayesh Desai and Sebastian Bauer and Blay, {Jean Yves} and Thierry Alcindor and Kristen Ganjoo and Javier Mart{\'i}n-Broto and Christopher Ryan and Thomas, {David M.} and Charles Peterfy and Healey, {John H.} and {van de Sande}, Michiel and Gelhorn, {Heather L.} and Shuster, {Dale E.} and Q. Wang and Antoine Yver and Hsu, {Henry H.} and Lin, {Paul S.} and Sandra Tong-Starksen and Silvia Stacchiotti and Wagner, {Andrew J.}",
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    language = "English (US)",
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    TY - JOUR

    T1 - Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN)

    T2 - a randomised phase 3 trial

    AU - Tap, William D.

    AU - Gelderblom, Hans

    AU - Palmerini, Emanuela

    AU - Desai, Jayesh

    AU - Bauer, Sebastian

    AU - Blay, Jean Yves

    AU - Alcindor, Thierry

    AU - Ganjoo, Kristen

    AU - Martín-Broto, Javier

    AU - Ryan, Christopher

    AU - Thomas, David M.

    AU - Peterfy, Charles

    AU - Healey, John H.

    AU - van de Sande, Michiel

    AU - Gelhorn, Heather L.

    AU - Shuster, Dale E.

    AU - Wang, Q.

    AU - Yver, Antoine

    AU - Hsu, Henry H.

    AU - Lin, Paul S.

    AU - Tong-Starksen, Sandra

    AU - Stacchiotti, Silvia

    AU - Wagner, Andrew J.

    PY - 2019/8/10

    Y1 - 2019/8/10

    N2 - Background: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. Methods: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. Findings: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27–53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. Interpretation: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. Funding: Daiichi Sankyo.

    AB - Background: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection. Methods: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369. Findings: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27–53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy. Interpretation: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery. Funding: Daiichi Sankyo.

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