A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day;...

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Main Authors: Filippo de Braud, Jean-Pascal H. Machiels, Daniela Boggiani, Sylvie W.H. Rottey, Matteo Duca, Marie Laruelle, Stefania Salvagni, Silvia Damian, Lore D.F. Lapeire, Marcello Tiseo, Alexandre Dermine, Mahmoud Ould-Kaci, Juergen Braunger, Juliane Rascher, Daniela Fischer, Josef Hoefler, Gabriella L. Mariani, Sara Cresta
Format: Article
Language:English
Published: MDPI AG 2020-05-01
Series:Cancers
Subjects:
Online Access:https://www.mdpi.com/2072-6694/12/6/1425
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author Filippo de Braud
Jean-Pascal H. Machiels
Daniela Boggiani
Sylvie W.H. Rottey
Matteo Duca
Marie Laruelle
Stefania Salvagni
Silvia Damian
Lore D.F. Lapeire
Marcello Tiseo
Alexandre Dermine
Mahmoud Ould-Kaci
Juergen Braunger
Juliane Rascher
Daniela Fischer
Josef Hoefler
Gabriella L. Mariani
Sara Cresta
author_facet Filippo de Braud
Jean-Pascal H. Machiels
Daniela Boggiani
Sylvie W.H. Rottey
Matteo Duca
Marie Laruelle
Stefania Salvagni
Silvia Damian
Lore D.F. Lapeire
Marcello Tiseo
Alexandre Dermine
Mahmoud Ould-Kaci
Juergen Braunger
Juliane Rascher
Daniela Fischer
Josef Hoefler
Gabriella L. Mariani
Sara Cresta
author_sort Filippo de Braud
collection DOAJ
description This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m<sup>2</sup>/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (<i>n</i> = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (<i>n</i> = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.
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spelling doaj.art-192ed59c772e4e4f8e15c11087db92c92023-11-20T02:21:18ZengMDPI AGCancers2072-66942020-05-01126142510.3390/cancers12061425A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid TumorsFilippo de Braud0Jean-Pascal H. Machiels1Daniela Boggiani2Sylvie W.H. Rottey3Matteo Duca4Marie Laruelle5Stefania Salvagni6Silvia Damian7Lore D.F. Lapeire8Marcello Tiseo9Alexandre Dermine10Mahmoud Ould-Kaci11Juergen Braunger12Juliane Rascher13Daniela Fischer14Josef Hoefler15Gabriella L. Mariani16Sara Cresta17Fondazione IRCCS Istituto Nazionale dei Tumori, Medical Oncology Department, University of Milan, via G. Venezian, 1, 20133 Milan, ItalyInstitut Roi Albert II, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Avenue Hippocrate 10, 200 Woluwe-Saint-Lambert, 1200 Brussels, BelgiumMedical Oncology Unit, University Hospital of Parma, Via Antonio Gramsci 14, 43126 Parma, ItalyDrug Research Unit Ghent, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, BelgiumMedical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian, 1, 20133 Milan, ItalyInstitut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université catholique de Louvain, Avenue Hippocrate 10, 200 Woluwe-Saint-Lambert, 1200 Brussels, BelgiumPoliclinico S. Orsola Malphigi, via Giuseppe Massarenti, 13, 40138 Bologna, ItalyMedical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian, 1, 20133 Milan, ItalyDrug Research Unit Ghent, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, BelgiumMedical Oncology Unit, University Hospital of Parma, Via Antonio Gramsci 14, 43126 Parma, ItalyInstitut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université catholique de Louvain, Avenue Hippocrate 10, 200 Woluwe-Saint-Lambert, 1200 Brussels, BelgiumBoehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877, USABoehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riß, GermanyBoehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riß, GermanyBoehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riß, GermanyStaburo GmbH, Aschauer Str. 26b, 81549 Munich, Germany, on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GermanyBoehringer Ingelheim, via Giovanni Lorenzini, 8, 20139 Milan, ItalyMedical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian, 1, 20133 Milan, ItalyThis phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m<sup>2</sup>/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (<i>n</i> = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (<i>n</i> = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.https://www.mdpi.com/2072-6694/12/6/1425mTOR serine-threonine kinasesBI 860585clinical trialphase 1maximum tolerated dosepharmacokinetics
spellingShingle Filippo de Braud
Jean-Pascal H. Machiels
Daniela Boggiani
Sylvie W.H. Rottey
Matteo Duca
Marie Laruelle
Stefania Salvagni
Silvia Damian
Lore D.F. Lapeire
Marcello Tiseo
Alexandre Dermine
Mahmoud Ould-Kaci
Juergen Braunger
Juliane Rascher
Daniela Fischer
Josef Hoefler
Gabriella L. Mariani
Sara Cresta
A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
Cancers
mTOR serine-threonine kinases
BI 860585
clinical trial
phase 1
maximum tolerated dose
pharmacokinetics
title A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
title_full A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
title_fullStr A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
title_full_unstemmed A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
title_short A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
title_sort phase 1 study of mtorc1 2 inhibitor bi 860585 as a single agent or with exemestane or paclitaxel in patients with advanced solid tumors
topic mTOR serine-threonine kinases
BI 860585
clinical trial
phase 1
maximum tolerated dose
pharmacokinetics
url https://www.mdpi.com/2072-6694/12/6/1425
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