A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer

被引：8

作者：

van der Biessen, Diane A. J. ^{[1
]}

Gietema, Jourik A. ^{[2
]}

de Jonge, Maja J. A. ^{[1
]}

Desar, Ingrid M. E. ^{[3
]}

den Hollander, Martha W. ^{[2
]}

Dudley, Matthew ^{[4
]}

Dunbar, Martin ^{[4
]}

Hetman, Robert ^{[4
]}

Serpenti, Camille ^{[5
]}

Xiong, Hao ^{[4
]}

Mittapalli, Rajendar K. ^{[4
]}

Timms, Kirsten M. ^{[6
]}

Ansell, Peter ^{[4
]}

Ratajczak, Christine K. ^{[4
]}

Shepherd, Stacie Peacock ^{[4
]}

van Herpen, Carla M. L. ^{[3
]}

机构：

[1] Erasmus Univ, Med Ctr, Erasmus MC Canc Inst, Rotterdam, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands

[3] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands

[4] AbbVie Inc, N Chicago, IL USA

[5] AbbVie BV Hoofddorp, Hoofddorp, Netherlands

[6] Myriad Genet Inc, Salt Lake City, UT USA

来源：

INVESTIGATIONAL NEW DRUGS | 2018年 / 36卷 / 05期

关键词：

PARP inhibitor; BRCA; Solid tumor; Ovarian cancer; Homologous recombination deficiency; POLY(ADP-RIBOSE) POLYMERASE; EPITHELIAL OVARIAN;

D O I：

10.1007/s10637-017-0551-z

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20mg once daily to 500mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500mg BID and half-life of 2h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7months) versus HRD negative patients (1.8months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767.

引用

页码：828 / 835

页数：8

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