Cargando…

A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours

BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). METHODS: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate ca...

Descripción completa

Detalles Bibliográficos
Autores principales: Wilky, B A, Rudek, M A, Ahmed, S, Laheru, D A, Cosgrove, D, Donehower, R C, Nelkin, B, Ball, D, Doyle, L A, Chen, H, Ye, X, Bigley, G, Womack, C, Azad, N S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453594/
https://www.ncbi.nlm.nih.gov/pubmed/25268371
http://dx.doi.org/10.1038/bjc.2014.515
_version_ 1782374480789635072
author Wilky, B A
Rudek, M A
Ahmed, S
Laheru, D A
Cosgrove, D
Donehower, R C
Nelkin, B
Ball, D
Doyle, L A
Chen, H
Ye, X
Bigley, G
Womack, C
Azad, N S
author_facet Wilky, B A
Rudek, M A
Ahmed, S
Laheru, D A
Cosgrove, D
Donehower, R C
Nelkin, B
Ball, D
Doyle, L A
Chen, H
Ye, X
Bigley, G
Womack, C
Azad, N S
author_sort Wilky, B A
collection PubMed
description BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). METHODS: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. RESULTS: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg(−1) every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.
format Online
Article
Text
id pubmed-4453594
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-44535942016-01-06 A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours Wilky, B A Rudek, M A Ahmed, S Laheru, D A Cosgrove, D Donehower, R C Nelkin, B Ball, D Doyle, L A Chen, H Ye, X Bigley, G Womack, C Azad, N S Br J Cancer Clinical Study BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). METHODS: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. RESULTS: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg(−1) every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition. Nature Publishing Group 2015-01-06 2014-09-30 /pmc/articles/PMC4453594/ /pubmed/25268371 http://dx.doi.org/10.1038/bjc.2014.515 Text en Copyright © 2015 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Clinical Study
Wilky, B A
Rudek, M A
Ahmed, S
Laheru, D A
Cosgrove, D
Donehower, R C
Nelkin, B
Ball, D
Doyle, L A
Chen, H
Ye, X
Bigley, G
Womack, C
Azad, N S
A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours
title A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours
title_full A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours
title_fullStr A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours
title_full_unstemmed A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours
title_short A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours
title_sort phase i trial of vertical inhibition of igf signalling using cixutumumab, an anti-igf-1r antibody, and selumetinib, an mek 1/2 inhibitor, in advanced solid tumours
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453594/
https://www.ncbi.nlm.nih.gov/pubmed/25268371
http://dx.doi.org/10.1038/bjc.2014.515
work_keys_str_mv AT wilkyba aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT rudekma aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT ahmeds aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT laheruda aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT cosgroved aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT donehowerrc aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT nelkinb aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT balld aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT doylela aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT chenh aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT yex aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT bigleyg aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT womackc aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT azadns aphaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT wilkyba phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT rudekma phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT ahmeds phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT laheruda phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT cosgroved phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT donehowerrc phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT nelkinb phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT balld phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT doylela phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT chenh phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT yex phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT bigleyg phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT womackc phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours
AT azadns phaseitrialofverticalinhibitionofigfsignallingusingcixutumumabanantiigf1rantibodyandselumetinibanmek12inhibitorinadvancedsolidtumours