Selumetinib (Sel) and cisplatin/gemcitabine (CisGem) for advanced biliary tract cancer (BTC): A randomized trial

Mark Doherty; Vincent Tam; Mairead Mcnamara; David Hedley; Neesha Dhani; Eric Chen; Raymond Jang; Patricia Tang; Hao-Wen Sim; Grainne O'Kane; Stephanie DeLuca; Lisa Wang; Kelly Brooks; Jennifer J Knox

Abstract

Background: Sel (AZD6244, ARR142886) is an oral MEK inhibitor, with preclinical evidence of synergy with Gem in BTC. CisGem is standard first-line treatment for advanced BTC. This trial assessed the efficacy of Sel in continuous or sequential combination with CisGem in first-line advanced BTC. Methods: This randomized multicentre phase II trial (NCT02151084) enrolled patients (pts) with advanced cholangiocarcinoma (CC) or gallbladder cancer (GBC). CisGem was given at standard doses. Sel started at 75mg BID, daily (continuous – Arm A) or day 1-5, 8-19 every 21 days (sequential – Arm B). Arm C was CisGem alone. Sel starting dose was reduced to 50mg BID for toxicity concerns after 32 enrolled pts (protocol amendment). Primary endpoint was % change in RECIST tumor size of 48 evaluable pts: Arm A or B vs Arm C at 10 wks. Secondary endpoints: PFS, OS, ORR, disease control rate (DCR) and toxicity. Results: 57 pts were enrolled: 29 female; 22 intrahepatic CC, 16 extrahepatic CC and 19 GBC. Baseline characteristics were similar across arms. Mean change in tumor size was not significantly different between either Sel arm and the control arm (Arm A p = 0.37, Arm B p = 0.53 [Table]). There were no significant differences in other efficacy endpoints. Toxicities appeared more frequent in Arm A; dose intensity of Gem and Sel were lower. More pts in Arms A and B stopped treatment due to toxicity than Arm C. Conclusions: Adding Sel to CisGem failed to improve tumor response at 10 wks, or prolong survival, but added toxicity and led to lower dose intensity. Exploration of biomarkers may identify a group deriving benefit, but it should not be studied further in unselected BTC. Clinical trial information: NCT02151084

Arm A
(N = 19)

Arm B
(N = 19)

Arm C
(N = 19)

overall p-value

Mean % change in tumor size at 10 wks
(95% CI) -7.3
(-24.3,+9.7) -16.3
(-26.2,-6.4) -13.2
(-25.2,-1.3) 0.80
ORR (%) 36 29 29 0.91
DCR (%) 86 88 88 0.95
Median PFS (months) 6.0 6.6 6.4 0.58
Median OS (months) 10.9 14.8 12.7 0.76
Treatment discontinuation reason
Disease progression 7 7 13
Toxicity 4 6 0
Death 0 0 2
Withdrawn consent 1 3 1
Non-protocol surgery 0 1 0
Toxicity Events (Grade [G])
G 3 63 52 40
G 4 8 13 10
G 5 2 1 0
Non-hematologic G3-5 55 34 34
Relative Dose Intensity C1-3, %
Cis 92.2 94.5 93.2 0.21
Gem 85.7 93.8 94.1 0.10
Sel 74.1 85.6 - 0.28

Original language	English
Publication status	Published - 3 Jun 2018
Event	ASCO 2018 - Chicago, Chicago, United States Duration: 1 Jun 2018 → 5 Jun 2018

Conference

Conference	ASCO 2018
Country/Territory	United States
City	Chicago
Period	1/06/18 → 5/06/18

Keywords

Biliary tract cancer
Advanced disease
Cisplatin
selumetinib
Gemcitabine

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

http://abstracts.asco.org/214/AbstView_214_223951.html

Cite this

Doherty, M., Tam, V., Mcnamara, M., Hedley, D., Dhani, N., Chen, E., Jang, R., Tang, P., Sim, H.-W., O'Kane, G., DeLuca, S., Wang, L., Brooks, K., & Knox, J. J. (2018). Selumetinib (Sel) and cisplatin/gemcitabine (CisGem) for advanced biliary tract cancer (BTC): A randomized trial. Abstract from ASCO 2018, Chicago, United States. http://abstracts.asco.org/214/AbstView_214_223951.html

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title = "Selumetinib (Sel) and cisplatin/gemcitabine (CisGem) for advanced biliary tract cancer (BTC): A randomized trial",

abstract = "Background: Sel (AZD6244, ARR142886) is an oral MEK inhibitor, with preclinical evidence of synergy with Gem in BTC. CisGem is standard first-line treatment for advanced BTC. This trial assessed the efficacy of Sel in continuous or sequential combination with CisGem in first-line advanced BTC. Methods: This randomized multicentre phase II trial (NCT02151084) enrolled patients (pts) with advanced cholangiocarcinoma (CC) or gallbladder cancer (GBC). CisGem was given at standard doses. Sel started at 75mg BID, daily (continuous – Arm A) or day 1-5, 8-19 every 21 days (sequential – Arm B). Arm C was CisGem alone. Sel starting dose was reduced to 50mg BID for toxicity concerns after 32 enrolled pts (protocol amendment). Primary endpoint was % change in RECIST tumor size of 48 evaluable pts: Arm A or B vs Arm C at 10 wks. Secondary endpoints: PFS, OS, ORR, disease control rate (DCR) and toxicity. Results: 57 pts were enrolled: 29 female; 22 intrahepatic CC, 16 extrahepatic CC and 19 GBC. Baseline characteristics were similar across arms. Mean change in tumor size was not significantly different between either Sel arm and the control arm (Arm A p = 0.37, Arm B p = 0.53 [Table]). There were no significant differences in other efficacy endpoints. Toxicities appeared more frequent in Arm A; dose intensity of Gem and Sel were lower. More pts in Arms A and B stopped treatment due to toxicity than Arm C. Conclusions: Adding Sel to CisGem failed to improve tumor response at 10 wks, or prolong survival, but added toxicity and led to lower dose intensity. Exploration of biomarkers may identify a group deriving benefit, but it should not be studied further in unselected BTC. Clinical trial information: NCT02151084Arm A (N = 19)Arm B (N = 19)Arm C (N = 19)overall p-valueMean % change in tumor size at 10 wks(95% CI) -7.3 (-24.3,+9.7) -16.3 (-26.2,-6.4) -13.2 (-25.2,-1.3) 0.80 ORR (%) 36 29 29 0.91 DCR (%) 86 88 88 0.95 Median PFS (months) 6.0 6.6 6.4 0.58 Median OS (months) 10.9 14.8 12.7 0.76 Treatment discontinuation reason Disease progression 7 7 13 Toxicity 4 6 0 Death 0 0 2 Withdrawn consent 1 3 1 Non-protocol surgery 0 1 0 Toxicity Events (Grade [G]) G 3 63 52 40 G 4 8 13 10 G 5 2 1 0 Non-hematologic G3-5 55 34 34 Relative Dose Intensity C1-3, % Cis 92.2 94.5 93.2 0.21 Gem 85.7 93.8 94.1 0.10 Sel 74.1 85.6 - 0.28 ",

keywords = "Biliary tract cancer, Advanced disease, Cisplatin, selumetinib, Gemcitabine",

author = "Mark Doherty and Vincent Tam and Mairead Mcnamara and David Hedley and Neesha Dhani and Eric Chen and Raymond Jang and Patricia Tang and Hao-Wen Sim and Grainne O'Kane and Stephanie DeLuca and Lisa Wang and Kelly Brooks and Knox, {Jennifer J}",

year = "2018",

month = jun,

day = "3",

language = "English",

note = "ASCO 2018 ; Conference date: 01-06-2018 Through 05-06-2018",

}

Doherty, M, Tam, V, Mcnamara, M, Hedley, D, Dhani, N, Chen, E, Jang, R, Tang, P, Sim, H-W, O'Kane, G, DeLuca, S, Wang, L, Brooks, K & Knox, JJ 2018, 'Selumetinib (Sel) and cisplatin/gemcitabine (CisGem) for advanced biliary tract cancer (BTC): A randomized trial', ASCO 2018, Chicago, United States, 1/06/18 - 5/06/18. <http://abstracts.asco.org/214/AbstView_214_223951.html>

TY - CONF

T1 - Selumetinib (Sel) and cisplatin/gemcitabine (CisGem) for advanced biliary tract cancer (BTC)

T2 - ASCO 2018

AU - Doherty, Mark

AU - Tam, Vincent

AU - Mcnamara, Mairead

AU - Hedley, David

AU - Dhani, Neesha

AU - Chen, Eric

AU - Jang, Raymond

AU - Tang, Patricia

AU - Sim, Hao-Wen

AU - O'Kane, Grainne

AU - DeLuca, Stephanie

AU - Wang, Lisa

AU - Brooks, Kelly

AU - Knox, Jennifer J

PY - 2018/6/3

Y1 - 2018/6/3

N2 - Background: Sel (AZD6244, ARR142886) is an oral MEK inhibitor, with preclinical evidence of synergy with Gem in BTC. CisGem is standard first-line treatment for advanced BTC. This trial assessed the efficacy of Sel in continuous or sequential combination with CisGem in first-line advanced BTC. Methods: This randomized multicentre phase II trial (NCT02151084) enrolled patients (pts) with advanced cholangiocarcinoma (CC) or gallbladder cancer (GBC). CisGem was given at standard doses. Sel started at 75mg BID, daily (continuous – Arm A) or day 1-5, 8-19 every 21 days (sequential – Arm B). Arm C was CisGem alone. Sel starting dose was reduced to 50mg BID for toxicity concerns after 32 enrolled pts (protocol amendment). Primary endpoint was % change in RECIST tumor size of 48 evaluable pts: Arm A or B vs Arm C at 10 wks. Secondary endpoints: PFS, OS, ORR, disease control rate (DCR) and toxicity. Results: 57 pts were enrolled: 29 female; 22 intrahepatic CC, 16 extrahepatic CC and 19 GBC. Baseline characteristics were similar across arms. Mean change in tumor size was not significantly different between either Sel arm and the control arm (Arm A p = 0.37, Arm B p = 0.53 [Table]). There were no significant differences in other efficacy endpoints. Toxicities appeared more frequent in Arm A; dose intensity of Gem and Sel were lower. More pts in Arms A and B stopped treatment due to toxicity than Arm C. Conclusions: Adding Sel to CisGem failed to improve tumor response at 10 wks, or prolong survival, but added toxicity and led to lower dose intensity. Exploration of biomarkers may identify a group deriving benefit, but it should not be studied further in unselected BTC. Clinical trial information: NCT02151084Arm A (N = 19)Arm B (N = 19)Arm C (N = 19)overall p-valueMean % change in tumor size at 10 wks(95% CI) -7.3 (-24.3,+9.7) -16.3 (-26.2,-6.4) -13.2 (-25.2,-1.3) 0.80 ORR (%) 36 29 29 0.91 DCR (%) 86 88 88 0.95 Median PFS (months) 6.0 6.6 6.4 0.58 Median OS (months) 10.9 14.8 12.7 0.76 Treatment discontinuation reason Disease progression 7 7 13 Toxicity 4 6 0 Death 0 0 2 Withdrawn consent 1 3 1 Non-protocol surgery 0 1 0 Toxicity Events (Grade [G]) G 3 63 52 40 G 4 8 13 10 G 5 2 1 0 Non-hematologic G3-5 55 34 34 Relative Dose Intensity C1-3, % Cis 92.2 94.5 93.2 0.21 Gem 85.7 93.8 94.1 0.10 Sel 74.1 85.6 - 0.28

AB - Background: Sel (AZD6244, ARR142886) is an oral MEK inhibitor, with preclinical evidence of synergy with Gem in BTC. CisGem is standard first-line treatment for advanced BTC. This trial assessed the efficacy of Sel in continuous or sequential combination with CisGem in first-line advanced BTC. Methods: This randomized multicentre phase II trial (NCT02151084) enrolled patients (pts) with advanced cholangiocarcinoma (CC) or gallbladder cancer (GBC). CisGem was given at standard doses. Sel started at 75mg BID, daily (continuous – Arm A) or day 1-5, 8-19 every 21 days (sequential – Arm B). Arm C was CisGem alone. Sel starting dose was reduced to 50mg BID for toxicity concerns after 32 enrolled pts (protocol amendment). Primary endpoint was % change in RECIST tumor size of 48 evaluable pts: Arm A or B vs Arm C at 10 wks. Secondary endpoints: PFS, OS, ORR, disease control rate (DCR) and toxicity. Results: 57 pts were enrolled: 29 female; 22 intrahepatic CC, 16 extrahepatic CC and 19 GBC. Baseline characteristics were similar across arms. Mean change in tumor size was not significantly different between either Sel arm and the control arm (Arm A p = 0.37, Arm B p = 0.53 [Table]). There were no significant differences in other efficacy endpoints. Toxicities appeared more frequent in Arm A; dose intensity of Gem and Sel were lower. More pts in Arms A and B stopped treatment due to toxicity than Arm C. Conclusions: Adding Sel to CisGem failed to improve tumor response at 10 wks, or prolong survival, but added toxicity and led to lower dose intensity. Exploration of biomarkers may identify a group deriving benefit, but it should not be studied further in unselected BTC. Clinical trial information: NCT02151084Arm A (N = 19)Arm B (N = 19)Arm C (N = 19)overall p-valueMean % change in tumor size at 10 wks(95% CI) -7.3 (-24.3,+9.7) -16.3 (-26.2,-6.4) -13.2 (-25.2,-1.3) 0.80 ORR (%) 36 29 29 0.91 DCR (%) 86 88 88 0.95 Median PFS (months) 6.0 6.6 6.4 0.58 Median OS (months) 10.9 14.8 12.7 0.76 Treatment discontinuation reason Disease progression 7 7 13 Toxicity 4 6 0 Death 0 0 2 Withdrawn consent 1 3 1 Non-protocol surgery 0 1 0 Toxicity Events (Grade [G]) G 3 63 52 40 G 4 8 13 10 G 5 2 1 0 Non-hematologic G3-5 55 34 34 Relative Dose Intensity C1-3, % Cis 92.2 94.5 93.2 0.21 Gem 85.7 93.8 94.1 0.10 Sel 74.1 85.6 - 0.28

KW - Biliary tract cancer

KW - Advanced disease

KW - Cisplatin

KW - selumetinib

KW - Gemcitabine

M3 - Abstract

Y2 - 1 June 2018 through 5 June 2018

ER -