Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792).

ER Plummer; Emma Dean; J Evans; A Greystoke; K Herbschleb; M Ranson; J Brown; Y Zhang; S Karan; J Pollard; MS Penney; M Asmal; MR Middleton

Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792).

ER Plummer, Emma Dean, J Evans, A Greystoke, K Herbschleb, M Ranson, J Brown, Y Zhang, S Karan, J Pollard, MS Penney, M Asmal, MR Middleton

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution › peer-review

Abstract

ackground: ATR is a regulator of the cellular response to replication stress, where it signals DNA damage repair through the homologous recombination pathway.Many cancer cells depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with marked preclinical anticancer activity in combination with DNA-damaging chemotherapy in preclinical models. A multicenter phase I study of VX-970 in combination with Gem was performed. Methods: Patients (pts) with advanced solid tumors measurable by RECIST 1.1 received IV VX-970 in combination with Gem in a 3+3 dose-escalation design. Gem was administered on days 1 and 8 and VX-970 on days 2, 9 and 16 of each 21-day cycle. Results: 50 pts were treated (28 M/22 F), median age 62 yrs (range 28-79 yrs), ECOG PS 0/1: 15/35. Primary tumors were colorectal (n=15), NSCLC (n=6), breast (n=4), pancreatic (n=2) and other (n=23). Gr 3/4 treatment-related AEs occurred in 25 pts. Maximum tolerated dose was not reached. VX-970 exposure was approximately linear based on Cmax and AUC0-∞ ; terminal T1/2 was ≈16 h. Best response was PR in 4 pts (breast, NPC, NSCLC, and CUP). Two pts with cancers not typically responsive to chemotherapy had prolonged SD: PFS was 415 days (papillary ca) and >191 days (GIST). Exposures achieved at ≈90mg/m2 correlated to those showing maximum preclinical activity. In a parallel phase I study this dose blocked ATR activity by ≈75% in patient tumor biopsies. Preliminary data from a non-randomized comparison of cohorts 1-4 (VX-970 < 90mg/m2 with Gem 875 mg/m2) and 5-7 (VX-970 ≥ 90mg/m2 with Gem 500mg/m2) showed median PFS of 8.3 and 29.3 weeks, respectively. Conclusions: The recommended phase II dose is VX-970 210 mg/m2 and Gem 1000 mg/m2. Preliminary evidence of activity was observed. Studies in biomarker-defined NSCLC and SCLC are ongoing, as are additional studies with VX-970 and platinum in TNBC. Clinical trial information: NCT02157792

Original language	English
Title of host publication	Journal of Clinical Oncology
Volume	34
Edition	15_suppl 2513
Publication status	Published - 2016
Event	ASCO annual conference 2016 - Chicago, United States Duration: 3 Jun 2016 → 7 Jun 2016

Conference

Conference	ASCO annual conference 2016
Country/Territory	United States
City	Chicago
Period	3/06/16 → 7/06/16

Cite this

@inproceedings{ccb48dea97d2490a91d34dfb5c485355,

title = "Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792).",

abstract = "ackground: ATR is a regulator of the cellular response to replication stress, where it signals DNA damage repair through the homologous recombination pathway.Many cancer cells depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with marked preclinical anticancer activity in combination with DNA-damaging chemotherapy in preclinical models. A multicenter phase I study of VX-970 in combination with Gem was performed. Methods: Patients (pts) with advanced solid tumors measurable by RECIST 1.1 received IV VX-970 in combination with Gem in a 3+3 dose-escalation design. Gem was administered on days 1 and 8 and VX-970 on days 2, 9 and 16 of each 21-day cycle. Results: 50 pts were treated (28 M/22 F), median age 62 yrs (range 28-79 yrs), ECOG PS 0/1: 15/35. Primary tumors were colorectal (n=15), NSCLC (n=6), breast (n=4), pancreatic (n=2) and other (n=23). Gr 3/4 treatment-related AEs occurred in 25 pts. Maximum tolerated dose was not reached. VX-970 exposure was approximately linear based on Cmax and AUC0-∞ ; terminal T1/2 was ≈16 h. Best response was PR in 4 pts (breast, NPC, NSCLC, and CUP). Two pts with cancers not typically responsive to chemotherapy had prolonged SD: PFS was 415 days (papillary ca) and >191 days (GIST). Exposures achieved at ≈90mg/m2 correlated to those showing maximum preclinical activity. In a parallel phase I study this dose blocked ATR activity by ≈75% in patient tumor biopsies. Preliminary data from a non-randomized comparison of cohorts 1-4 (VX-970 < 90mg/m2 with Gem 875 mg/m2) and 5-7 (VX-970 ≥ 90mg/m2 with Gem 500mg/m2) showed median PFS of 8.3 and 29.3 weeks, respectively. Conclusions: The recommended phase II dose is VX-970 210 mg/m2 and Gem 1000 mg/m2. Preliminary evidence of activity was observed. Studies in biomarker-defined NSCLC and SCLC are ongoing, as are additional studies with VX-970 and platinum in TNBC. Clinical trial information: NCT02157792",

author = "ER Plummer and Emma Dean and J Evans and A Greystoke and K Herbschleb and M Ranson and J Brown and Y Zhang and S Karan and J Pollard and MS Penney and M Asmal and MR Middleton",

year = "2016",

language = "English",

volume = "34",

booktitle = "Journal of Clinical Oncology",

edition = "15_suppl 2513",

note = "ASCO annual conference 2016 ; Conference date: 03-06-2016 Through 07-06-2016",

}

Plummer, ER, Dean, E, Evans, J, Greystoke, A, Herbschleb, K, Ranson, M, Brown, J, Zhang, Y, Karan, S, Pollard, J, Penney, MS, Asmal, M & Middleton, MR 2016, Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792). in Journal of Clinical Oncology. 15_suppl 2513 edn, vol. 34, ASCO annual conference 2016, Chicago, United States, 3/06/16.

TY - GEN

T1 - Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792).

AU - Plummer, ER

AU - Dean, Emma

AU - Evans, J

AU - Greystoke, A

AU - Herbschleb, K

AU - Ranson, M

AU - Brown, J

AU - Zhang, Y

AU - Karan, S

AU - Pollard, J

AU - Penney, MS

AU - Asmal, M

AU - Middleton, MR

PY - 2016

Y1 - 2016

N2 - ackground: ATR is a regulator of the cellular response to replication stress, where it signals DNA damage repair through the homologous recombination pathway.Many cancer cells depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with marked preclinical anticancer activity in combination with DNA-damaging chemotherapy in preclinical models. A multicenter phase I study of VX-970 in combination with Gem was performed. Methods: Patients (pts) with advanced solid tumors measurable by RECIST 1.1 received IV VX-970 in combination with Gem in a 3+3 dose-escalation design. Gem was administered on days 1 and 8 and VX-970 on days 2, 9 and 16 of each 21-day cycle. Results: 50 pts were treated (28 M/22 F), median age 62 yrs (range 28-79 yrs), ECOG PS 0/1: 15/35. Primary tumors were colorectal (n=15), NSCLC (n=6), breast (n=4), pancreatic (n=2) and other (n=23). Gr 3/4 treatment-related AEs occurred in 25 pts. Maximum tolerated dose was not reached. VX-970 exposure was approximately linear based on Cmax and AUC0-∞ ; terminal T1/2 was ≈16 h. Best response was PR in 4 pts (breast, NPC, NSCLC, and CUP). Two pts with cancers not typically responsive to chemotherapy had prolonged SD: PFS was 415 days (papillary ca) and >191 days (GIST). Exposures achieved at ≈90mg/m2 correlated to those showing maximum preclinical activity. In a parallel phase I study this dose blocked ATR activity by ≈75% in patient tumor biopsies. Preliminary data from a non-randomized comparison of cohorts 1-4 (VX-970 < 90mg/m2 with Gem 875 mg/m2) and 5-7 (VX-970 ≥ 90mg/m2 with Gem 500mg/m2) showed median PFS of 8.3 and 29.3 weeks, respectively. Conclusions: The recommended phase II dose is VX-970 210 mg/m2 and Gem 1000 mg/m2. Preliminary evidence of activity was observed. Studies in biomarker-defined NSCLC and SCLC are ongoing, as are additional studies with VX-970 and platinum in TNBC. Clinical trial information: NCT02157792

AB - ackground: ATR is a regulator of the cellular response to replication stress, where it signals DNA damage repair through the homologous recombination pathway.Many cancer cells depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with marked preclinical anticancer activity in combination with DNA-damaging chemotherapy in preclinical models. A multicenter phase I study of VX-970 in combination with Gem was performed. Methods: Patients (pts) with advanced solid tumors measurable by RECIST 1.1 received IV VX-970 in combination with Gem in a 3+3 dose-escalation design. Gem was administered on days 1 and 8 and VX-970 on days 2, 9 and 16 of each 21-day cycle. Results: 50 pts were treated (28 M/22 F), median age 62 yrs (range 28-79 yrs), ECOG PS 0/1: 15/35. Primary tumors were colorectal (n=15), NSCLC (n=6), breast (n=4), pancreatic (n=2) and other (n=23). Gr 3/4 treatment-related AEs occurred in 25 pts. Maximum tolerated dose was not reached. VX-970 exposure was approximately linear based on Cmax and AUC0-∞ ; terminal T1/2 was ≈16 h. Best response was PR in 4 pts (breast, NPC, NSCLC, and CUP). Two pts with cancers not typically responsive to chemotherapy had prolonged SD: PFS was 415 days (papillary ca) and >191 days (GIST). Exposures achieved at ≈90mg/m2 correlated to those showing maximum preclinical activity. In a parallel phase I study this dose blocked ATR activity by ≈75% in patient tumor biopsies. Preliminary data from a non-randomized comparison of cohorts 1-4 (VX-970 < 90mg/m2 with Gem 875 mg/m2) and 5-7 (VX-970 ≥ 90mg/m2 with Gem 500mg/m2) showed median PFS of 8.3 and 29.3 weeks, respectively. Conclusions: The recommended phase II dose is VX-970 210 mg/m2 and Gem 1000 mg/m2. Preliminary evidence of activity was observed. Studies in biomarker-defined NSCLC and SCLC are ongoing, as are additional studies with VX-970 and platinum in TNBC. Clinical trial information: NCT02157792

UR - http://meeting.ascopubs.org/

M3 - Conference contribution

VL - 34

BT - Journal of Clinical Oncology

T2 - ASCO annual conference 2016

Y2 - 3 June 2016 through 7 June 2016

ER -

Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792).

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