TY - JOUR
T1 - Phase i study of ceralasertib (AZD6738), a novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer
AU - Kim, Seung Tae
AU - Smith, Simon A.
AU - Mortimer, Peter
AU - Loembé, Arsene Bienvenu
AU - Cho, Heejin
AU - HKim, Kyoung Mee
AU - Smith, Claire
AU - Willis, Sophie
AU - Irurzun-Arana, Itziar
AU - Berges, Alienor
AU - Hong, Jung Yong
AU - Park, Se Hoon
AU - Park, Joon Oh
AU - Park, Young Suk
AU - Lim, Ho Yeong
AU - Kang, Won Ki
AU - Kozarewa, Iwanka
AU - Pierce, Andrew J.
AU - Dean, Emma
AU - Lee, Jeeyun
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3- related (ATR) protein. Patients and Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. Results: The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9). Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.
AB - Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3- related (ATR) protein. Patients and Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. Results: The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9). Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.
UR - http://www.scopus.com/inward/record.url?scp=85108946927&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-0251
DO - 10.1158/1078-0432.CCR-21-0251
M3 - Article
C2 - 33975862
AN - SCOPUS:85108946927
SN - 1078-0432
VL - 27
SP - 4700
EP - 4709
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -