Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours

Hester van Cruijsen; Emile E. Voest; Cornelis J. A. Punt; Klaas Hoekman; Petronella O. Witteveen; Martijn R. Meijerink; Thomas A. Puchalski; Jane Robertson; Owain Saunders; Juliane M. Jürgensmeier; Carla M. L. van Herpen; Giuseppe Giaccone

doi:10.1016/j.ejca.2009.12.023

Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours

Hester van Cruijsen
, Emile E. Voest
, Cornelis J. A. Punt
, Klaas Hoekman
, Petronella O. Witteveen
, Martijn R. Meijerink
, Thomas A. Puchalski
, Jane Robertson
, Owain Saunders
, Juliane M. Jürgensmeier
, Carla M. L. van Herpen
, Giuseppe Giaccone

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours. Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics. Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment. Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration

Original language	English
Pages (from-to)	901-911
Journal	European journal of cancer (Oxford, England
Volume	46
Issue number	5
DOIs	https://doi.org/10.1016/j.ejca.2009.12.023
Publication status	Published - 2010

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SDG 3 Good Health and Well-being

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10.1016/j.ejca.2009.12.023

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van Cruijsen, H., Voest, E. E., Punt, C. J. A., Hoekman, K., Witteveen, P. O., Meijerink, M. R., Puchalski, T. A., Robertson, J., Saunders, O., Jürgensmeier, J. M., van Herpen, C. M. L., & Giaccone, G. (2010). Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. European journal of cancer (Oxford, England, 46(5), 901-911. https://doi.org/10.1016/j.ejca.2009.12.023

@article{5a88a4d2ff224e04858624f0582fd13f,

title = "Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours",

abstract = "Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours. Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics. Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93\%]), anorexia (63 [70\%]) and fatigue (60 [67\%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9\%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42\%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment. Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration",

author = "\{van Cruijsen\}, Hester and Voest, \{Emile E.\} and Punt, \{Cornelis J. A.\} and Klaas Hoekman and Witteveen, \{Petronella O.\} and Meijerink, \{Martijn R.\} and Puchalski, \{Thomas A.\} and Jane Robertson and Owain Saunders and J{\"u}rgensmeier, \{Juliane M.\} and \{van Herpen\}, \{Carla M. L.\} and Giuseppe Giaccone",

year = "2010",

doi = "10.1016/j.ejca.2009.12.023",

language = "English",

volume = "46",

pages = "901--911",

journal = "European journal of cancer (Oxford, England",

issn = "0959-8049",

publisher = "Elsevier Limited",

number = "5",

}

van Cruijsen, H, Voest, EE, Punt, CJA, Hoekman, K, Witteveen, PO, Meijerink, MR, Puchalski, TA, Robertson, J, Saunders, O, Jürgensmeier, JM, van Herpen, CML & Giaccone, G 2010, 'Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours', European journal of cancer (Oxford, England, vol. 46, no. 5, pp. 901-911. https://doi.org/10.1016/j.ejca.2009.12.023

Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. / van Cruijsen, Hester; Voest, Emile E.; Punt, Cornelis J. A. et al.
In: European journal of cancer (Oxford, England, Vol. 46, No. 5, 2010, p. 901-911.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours

AU - van Cruijsen, Hester

AU - Voest, Emile E.

AU - Punt, Cornelis J. A.

AU - Hoekman, Klaas

AU - Witteveen, Petronella O.

AU - Meijerink, Martijn R.

AU - Puchalski, Thomas A.

AU - Robertson, Jane

AU - Saunders, Owain

AU - Jürgensmeier, Juliane M.

AU - van Herpen, Carla M. L.

AU - Giaccone, Giuseppe

PY - 2010

Y1 - 2010

N2 - Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours. Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics. Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment. Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration

AB - Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours. Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics. Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment. Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration

U2 - 10.1016/j.ejca.2009.12.023

DO - 10.1016/j.ejca.2009.12.023

M3 - Article

C2 - 20061136

SN - 0959-8049

VL - 46

SP - 901

EP - 911

JO - European journal of cancer (Oxford, England

JF - European journal of cancer (Oxford, England

IS - 5

ER -

Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours

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