Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies.
Adult
Aged
Aged, 80 and over
Antineoplastic Agents
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Benzimidazoles
/ administration & dosage
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Mitogen-Activated Protein Kinase Kinases
/ antagonists & inhibitors
Neoplasms
/ drug therapy
Quinazolines
/ administration & dosage
Vascular Endothelial Growth Factors
/ antagonists & inhibitors
AZD2171
AZD6244
Cediranib
MEK
Selumetinib
VEGF
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
16
08
2021
accepted:
30
08
2021
pubmed:
14
9
2021
medline:
8
3
2022
entrez:
13
9
2021
Statut:
ppublish
Résumé
Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.
Identifiants
pubmed: 34515877
doi: 10.1007/s10637-021-01175-6
pii: 10.1007/s10637-021-01175-6
pmc: PMC8766914
mid: NIHMS1761544
doi:
Substances chimiques
AZD 6244
0
Antineoplastic Agents
0
Benzimidazoles
0
Quinazolines
0
Vascular Endothelial Growth Factors
0
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
cediranib
NQU9IPY4K9
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
115-123Subventions
Organisme : NCI NIH HHS
ID : K12 CA086913
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA069912
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186686
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Gynecol Oncol. 2015 Sep;138(3):507-12
pubmed: 26186911
J Clin Oncol. 2011 Jun 10;29(17):2357-63
pubmed: 21519026
J Clin Oncol. 2013 Sep 10;31(26):3212-8
pubmed: 23940216
Space Med Med Eng (Beijing). 2001 Dec;14(6):439-43
pubmed: 11887896
J Clin Oncol. 2012 Oct 10;30(29):3596-603
pubmed: 22965965
J Thorac Oncol. 2011 Nov;6(11):1938-45
pubmed: 21964533
Eur J Cancer. 2010 Mar;46(5):901-11
pubmed: 20061136
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
J Clin Oncol. 2009 Nov 20;27(33):5601-6
pubmed: 19826113
Am J Clin Oncol. 1982 Dec;5(6):649-55
pubmed: 7165009
Eur J Cancer. 2012 Mar;48(4):527-37
pubmed: 22285180
Eur J Cancer. 2013 Dec;49(18):3780-7
pubmed: 24012098
Nat Rev Cancer. 2008 Aug;8(8):579-91
pubmed: 18596824
Invest New Drugs. 2012 Oct;30(5):1962-71
pubmed: 21989836
Invest New Drugs. 2013 Oct;31(5):1307-10
pubmed: 23812905
JAMA. 2014 Jun 18;311(23):2397-405
pubmed: 24938562
Cancer Chemother Pharmacol. 2009 Nov;64(6):1165-72
pubmed: 19308410
J Clin Oncol. 2010 Jun 10;28(17):2817-23
pubmed: 20458050
J Clin Oncol. 2010 Jan 1;28(1):49-55
pubmed: 19917841
Br J Cancer. 2013 Aug 20;109(4):943-9
pubmed: 23868004
Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
pubmed: 11252954
Invest New Drugs. 2011 Oct;29(5):1021-8
pubmed: 20127139
J Clin Oncol. 2008 May 1;26(13):2139-46
pubmed: 18390968
Lancet Oncol. 2013 Jan;14(1):38-47
pubmed: 23200175
Cancer. 2014 Jul 15;120(14):2164-73
pubmed: 24752867
J Clin Oncol. 2007 Jul 20;25(21):3045-54
pubmed: 17634482
Clin Cancer Res. 2013 Sep 1;19(17):4816-23
pubmed: 23833308
Invest New Drugs. 2007 Oct;25(5):445-51
pubmed: 17458505
J Biopharm Stat. 2009;19(3):509-23
pubmed: 19384692
Nat Rev Cancer. 2008 Aug;8(8):592-603
pubmed: 18650835
Pediatr Blood Cancer. 2019 Dec;66(12):e27987
pubmed: 31502400
N Engl J Med. 2020 Apr 9;382(15):1430-1442
pubmed: 32187457
Invest New Drugs. 2012 Jun;30(3):1216-23
pubmed: 21594619
JAMA. 2017 May 9;317(18):1844-1853
pubmed: 28492898
J Clin Oncol. 2013 Jun 20;31(18):2296-302
pubmed: 23630200
Br J Cancer. 2013 Feb 19;108(3):493-502
pubmed: 23299530
Clin Cancer Res. 2010 Mar 1;16(5):1613-23
pubmed: 20179232
Clin Cancer Res. 2007 Mar 1;13(5):1576-83
pubmed: 17332304
J Clin Oncol. 2008 Aug 1;26(22):3709-14
pubmed: 18669456
Lancet Oncol. 2014 Oct;15(11):1207-14
pubmed: 25218906
Cancer Chemother Pharmacol. 2014 Jul;74(1):77-84
pubmed: 24817603
Biometrics. 2007 Mar;63(1):173-9
pubmed: 17447942
Lancet Oncol. 2019 Jul;20(7):1023-1034
pubmed: 31160249
J Clin Oncol. 2012 Oct 10;30(29):3588-95
pubmed: 22965961
Cancer Res. 2005 May 15;65(10):4389-400
pubmed: 15899831
Gynecol Oncol. 2015 Jul;138(1):55-61
pubmed: 25895616
Clin Cancer Res. 2012 Mar 15;18(6):1641-54
pubmed: 22275507
Clin Cancer Res. 2013 Apr 15;19(8):2257-64
pubmed: 23444215
Eur J Cancer. 2014 Mar;50(4):706-12
pubmed: 24360368
Ann Oncol. 2019 Apr 1;30(4):551-557
pubmed: 30753272
Clin Cancer Res. 2012 Apr 1;18(7):2056-65
pubmed: 22241789
BJU Int. 2013 Jun;111(8):1269-80
pubmed: 23419134