Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer

Sarah P Blagden; Anne L Hamilton; Linda Mileshkin; Shirley Wong; Agnieszka Michael; Marcia Hall; Jeffrey C Goh; Alla S Lisyanskaya; Michelle DeSilvio; Eleni Frangou; Euan A Stronach; Prashanth Gopalakrishna; Tarek M Meniawy; Hani Gabra

doi:10.1158/1078-0432.CCR-18-2277

Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer

Sarah P Blagden, Anne L Hamilton, Linda Mileshkin, Shirley Wong, Agnieszka Michael, Marcia Hall, Jeffrey C Goh, Alla S Lisyanskaya, Michelle DeSilvio, Eleni Frangou, Euan A Stronach, Prashanth Gopalakrishna, Tarek M Meniawy, Hani Gabra

UWA Medical School

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Abstract

PURPOSE: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors.Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum refractory ovarian cancer (PPROC).

EXPERIMENTAL DESIGN: Part I was a combination 3+3 dose-escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with three-weekly intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) for 6 cycles followed by maintenance afuresertib at 125mg/day until progression or toxicity. Part II was a single arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the maximum tolerated dose (MTD) defined in Part I in combination with PC for 6 cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose-escalation), and investigator-assessed overall response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Part II).

RESULTS: Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities (DLTs) of grade 3 rash were observed, one at 125mg and two at 150mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. (etc -see manuscript for full version).

Original language	English
Pages (from-to)	1472-1478
Number of pages	7
Journal	Clinical Cancer Research
Volume	25
Issue number	5
Early online date	18 Dec 2018
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-2277
Publication status	Published - 1 Mar 2019

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Blagden et al., 2018 Phase IB Dose-Escalationi and Expansion study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian CancerAccepted author manuscript, 859 KB

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Blagden, S. P., Hamilton, A. L., Mileshkin, L., Wong, S., Michael, A., Hall, M., Goh, J. C., Lisyanskaya, A. S., DeSilvio, M., Frangou, E., Stronach, E. A., Gopalakrishna, P., Meniawy, T. M., & Gabra, H. (2019). Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer. Clinical Cancer Research, 25(5), 1472-1478. https://doi.org/10.1158/1078-0432.CCR-18-2277

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title = "Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer",

abstract = "PURPOSE: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors.Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum refractory ovarian cancer (PPROC).EXPERIMENTAL DESIGN: Part I was a combination 3+3 dose-escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with three-weekly intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) for 6 cycles followed by maintenance afuresertib at 125mg/day until progression or toxicity. Part II was a single arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the maximum tolerated dose (MTD) defined in Part I in combination with PC for 6 cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose-escalation), and investigator-assessed overall response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Part II).RESULTS: Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities (DLTs) of grade 3 rash were observed, one at 125mg and two at 150mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. (etc -see manuscript for full version).",

author = "Blagden, {Sarah P} and Hamilton, {Anne L} and Linda Mileshkin and Shirley Wong and Agnieszka Michael and Marcia Hall and Goh, {Jeffrey C} and Lisyanskaya, {Alla S} and Michelle DeSilvio and Eleni Frangou and Stronach, {Euan A} and Prashanth Gopalakrishna and Meniawy, {Tarek M} and Hani Gabra",

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Blagden, SP, Hamilton, AL, Mileshkin, L, Wong, S, Michael, A, Hall, M, Goh, JC, Lisyanskaya, AS, DeSilvio, M, Frangou, E, Stronach, EA, Gopalakrishna, P, Meniawy, TM & Gabra, H 2019, 'Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer', Clinical Cancer Research, vol. 25, no. 5, pp. 1472-1478. https://doi.org/10.1158/1078-0432.CCR-18-2277

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T1 - Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer

AU - Blagden, Sarah P

AU - Hamilton, Anne L

AU - Mileshkin, Linda

AU - Wong, Shirley

AU - Michael, Agnieszka

AU - Hall, Marcia

AU - Goh, Jeffrey C

AU - Lisyanskaya, Alla S

AU - DeSilvio, Michelle

AU - Frangou, Eleni

AU - Stronach, Euan A

AU - Gopalakrishna, Prashanth

AU - Meniawy, Tarek M

AU - Gabra, Hani

PY - 2019/3/1

Y1 - 2019/3/1

N2 - PURPOSE: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors.Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum refractory ovarian cancer (PPROC).EXPERIMENTAL DESIGN: Part I was a combination 3+3 dose-escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with three-weekly intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) for 6 cycles followed by maintenance afuresertib at 125mg/day until progression or toxicity. Part II was a single arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the maximum tolerated dose (MTD) defined in Part I in combination with PC for 6 cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose-escalation), and investigator-assessed overall response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Part II).RESULTS: Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities (DLTs) of grade 3 rash were observed, one at 125mg and two at 150mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. (etc -see manuscript for full version).

AB - PURPOSE: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors.Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum refractory ovarian cancer (PPROC).EXPERIMENTAL DESIGN: Part I was a combination 3+3 dose-escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with three-weekly intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) for 6 cycles followed by maintenance afuresertib at 125mg/day until progression or toxicity. Part II was a single arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the maximum tolerated dose (MTD) defined in Part I in combination with PC for 6 cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose-escalation), and investigator-assessed overall response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Part II).RESULTS: Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities (DLTs) of grade 3 rash were observed, one at 125mg and two at 150mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. (etc -see manuscript for full version).

U2 - 10.1158/1078-0432.CCR-18-2277

DO - 10.1158/1078-0432.CCR-18-2277

M3 - Article

C2 - 30563934

SN - 1078-0432

VL - 25

SP - 1472

EP - 1478

JO - Clinical Cancer Reserach

JF - Clinical Cancer Reserach

IS - 5

ER -

Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer

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