Abstract
Background: The PI3K/protein kinase B (AKT) pathway Results: A total of 65 patients were enrolled; dose-limiting is commonly activated in several tumor types. Selective toxicities were hypophosphatemia and hypocalcemia. Adverse targeting of p110b could result in successful pathway inhibi-events included diarrhea (48%), nausea (40%), and vomiting tion while avoiding the on- and off-target effects of pan-PI3K (31%). Single- and repeat-dose exposure increased generally dose inhibitors. GSK2636771 is a potent, orally bioavailable, proportionally. GSK2636771 400 mg once daily was the RP2D. adenosine triphosphate-competitive, selective inhibitor of Phospho/total AKT ratio decreased with GSK2636771 in tumor PI3Kb. and surrogate tissue. A castrate-resistant prostate cancer (CRPC) Methods: We evaluated the safety, pharmacokinetics, phar-patient harboring PIK3CB amplification had a partial response for macodynamics and antitumor activity of GSK2636771 to over a year; an additional 10 patients derived durable (24 define the recommended phase II dose (RP2D). During the weeks) clinical benefit, including two other patients with CRPC dose-selection and dose-escalation stages (parts 1 and 2), with PIK3CB alterations (34 weeks). GSK2636771 400 mg patients with PTEN-deficient advanced solid tumors received once daily orally induced sufficient exposure and target inhibition escalating doses of GSK2636771 (25–500 mg once daily) using with a manageable safety profile. a modified 3þ3 design to determine the RP2D; tumor type-Conclusions: Genomic aberrations of PIK3CB may be associ-specific expansion cohorts (part 3) were implemented to fur-ated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); ther assess tumor responses at the RP2D. 5981–92. 2017 AACR.
| Original language | English |
|---|---|
| Pages (from-to) | 5981-5992 |
| Number of pages | 12 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 2017 Oct 1 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
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A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors. / Mateo, Joaquin; Ganji, Gopinath; Lemech, Charlotte; Burris, Howard A.; Han, Sae Won; Swales, Karen; Decordova, Shaun; DeYoung, M. Phillip; Smith, Deborah A.; Kalyana-Sundaram, Shanker; Wu, Jiuhua; Motwani, Monica; Kumar, Rakesh; Tolson, Jerry M.; Rha, SunYoung; Chung, Hyuncheol; Eder, Joseph P.; Sharma, Sunil; Bang, Yung Jue; Infante, Jeffrey R.; Yan, Li; De Bono, Johann S.; Arkenau, Hendrik Tobias.
In: Clinical Cancer Research, Vol. 23, No. 19, 01.10.2017, p. 5981-5992.Research output: Contribution to journal › Article
TY - JOUR
T1 - A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors
AU - Mateo, Joaquin
AU - Ganji, Gopinath
AU - Lemech, Charlotte
AU - Burris, Howard A.
AU - Han, Sae Won
AU - Swales, Karen
AU - Decordova, Shaun
AU - DeYoung, M. Phillip
AU - Smith, Deborah A.
AU - Kalyana-Sundaram, Shanker
AU - Wu, Jiuhua
AU - Motwani, Monica
AU - Kumar, Rakesh
AU - Tolson, Jerry M.
AU - Rha, SunYoung
AU - Chung, Hyuncheol
AU - Eder, Joseph P.
AU - Sharma, Sunil
AU - Bang, Yung Jue
AU - Infante, Jeffrey R.
AU - Yan, Li
AU - De Bono, Johann S.
AU - Arkenau, Hendrik Tobias
PY - 2017/10/1
Y1 - 2017/10/1
N2 - Background: The PI3K/protein kinase B (AKT) pathway Results: A total of 65 patients were enrolled; dose-limiting is commonly activated in several tumor types. Selective toxicities were hypophosphatemia and hypocalcemia. Adverse targeting of p110b could result in successful pathway inhibi-events included diarrhea (48%), nausea (40%), and vomiting tion while avoiding the on- and off-target effects of pan-PI3K (31%). Single- and repeat-dose exposure increased generally dose inhibitors. GSK2636771 is a potent, orally bioavailable, proportionally. GSK2636771 400 mg once daily was the RP2D. adenosine triphosphate-competitive, selective inhibitor of Phospho/total AKT ratio decreased with GSK2636771 in tumor PI3Kb. and surrogate tissue. A castrate-resistant prostate cancer (CRPC) Methods: We evaluated the safety, pharmacokinetics, phar-patient harboring PIK3CB amplification had a partial response for macodynamics and antitumor activity of GSK2636771 to over a year; an additional 10 patients derived durable (24 define the recommended phase II dose (RP2D). During the weeks) clinical benefit, including two other patients with CRPC dose-selection and dose-escalation stages (parts 1 and 2), with PIK3CB alterations (34 weeks). GSK2636771 400 mg patients with PTEN-deficient advanced solid tumors received once daily orally induced sufficient exposure and target inhibition escalating doses of GSK2636771 (25–500 mg once daily) using with a manageable safety profile. a modified 3þ3 design to determine the RP2D; tumor type-Conclusions: Genomic aberrations of PIK3CB may be associ-specific expansion cohorts (part 3) were implemented to fur-ated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); ther assess tumor responses at the RP2D. 5981–92. 2017 AACR.
AB - Background: The PI3K/protein kinase B (AKT) pathway Results: A total of 65 patients were enrolled; dose-limiting is commonly activated in several tumor types. Selective toxicities were hypophosphatemia and hypocalcemia. Adverse targeting of p110b could result in successful pathway inhibi-events included diarrhea (48%), nausea (40%), and vomiting tion while avoiding the on- and off-target effects of pan-PI3K (31%). Single- and repeat-dose exposure increased generally dose inhibitors. GSK2636771 is a potent, orally bioavailable, proportionally. GSK2636771 400 mg once daily was the RP2D. adenosine triphosphate-competitive, selective inhibitor of Phospho/total AKT ratio decreased with GSK2636771 in tumor PI3Kb. and surrogate tissue. A castrate-resistant prostate cancer (CRPC) Methods: We evaluated the safety, pharmacokinetics, phar-patient harboring PIK3CB amplification had a partial response for macodynamics and antitumor activity of GSK2636771 to over a year; an additional 10 patients derived durable (24 define the recommended phase II dose (RP2D). During the weeks) clinical benefit, including two other patients with CRPC dose-selection and dose-escalation stages (parts 1 and 2), with PIK3CB alterations (34 weeks). GSK2636771 400 mg patients with PTEN-deficient advanced solid tumors received once daily orally induced sufficient exposure and target inhibition escalating doses of GSK2636771 (25–500 mg once daily) using with a manageable safety profile. a modified 3þ3 design to determine the RP2D; tumor type-Conclusions: Genomic aberrations of PIK3CB may be associ-specific expansion cohorts (part 3) were implemented to fur-ated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); ther assess tumor responses at the RP2D. 5981–92. 2017 AACR.
UR - http://www.scopus.com/inward/record.url?scp=85032305458&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85032305458&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-0725
DO - 10.1158/1078-0432.CCR-17-0725
M3 - Article
C2 - 28645941
AN - SCOPUS:85032305458
VL - 23
SP - 5981
EP - 5992
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 19
ER -