The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma

Andrew Spencer, Sung-Soo Yoon, Simon Harrison, Shannon R Morris, Deborah A Smith, Richard A Brigandi, Jennifer Lynn Shannon Gauvin, Rakesh Kumar, Joanna B Opalinska, Christine Chen

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib-an oral AKT inhibitor-in patients with advanced hematologic malignancies. Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6 ), diarrhea (32.9 ), and dyspepsia (24.7 ). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at >75-mg doses; the mediantime to peak plasma concentrationswas1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan s cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma. This trial was registered at www.clinicaltrials.gov as NCT00881946. (Blood. 2014;124(14):2190-2195).
Original languageEnglish
Pages (from-to)2190 - 2195
Number of pages6
JournalBlood
Volume124
Issue number14
DOIs
Publication statusPublished - 2014

Cite this

Spencer, A., Yoon, S-S., Harrison, S., Morris, S. R., Smith, D. A., Brigandi, R. A., ... Chen, C. (2014). The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood, 124(14), 2190 - 2195. https://doi.org/10.1182/blood-2014-03-559963
Spencer, Andrew ; Yoon, Sung-Soo ; Harrison, Simon ; Morris, Shannon R ; Smith, Deborah A ; Brigandi, Richard A ; Gauvin, Jennifer Lynn Shannon ; Kumar, Rakesh ; Opalinska, Joanna B ; Chen, Christine. / The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. In: Blood. 2014 ; Vol. 124, No. 14. pp. 2190 - 2195.
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abstract = "The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib-an oral AKT inhibitor-in patients with advanced hematologic malignancies. Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6 ), diarrhea (32.9 ), and dyspepsia (24.7 ). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at >75-mg doses; the mediantime to peak plasma concentrationswas1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan s cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma. This trial was registered at www.clinicaltrials.gov as NCT00881946. (Blood. 2014;124(14):2190-2195).",
author = "Andrew Spencer and Sung-Soo Yoon and Simon Harrison and Morris, {Shannon R} and Smith, {Deborah A} and Brigandi, {Richard A} and Gauvin, {Jennifer Lynn Shannon} and Rakesh Kumar and Opalinska, {Joanna B} and Christine Chen",
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Spencer, A, Yoon, S-S, Harrison, S, Morris, SR, Smith, DA, Brigandi, RA, Gauvin, JLS, Kumar, R, Opalinska, JB & Chen, C 2014, 'The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma' Blood, vol. 124, no. 14, pp. 2190 - 2195. https://doi.org/10.1182/blood-2014-03-559963

The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. / Spencer, Andrew; Yoon, Sung-Soo; Harrison, Simon; Morris, Shannon R; Smith, Deborah A; Brigandi, Richard A; Gauvin, Jennifer Lynn Shannon; Kumar, Rakesh; Opalinska, Joanna B; Chen, Christine.

In: Blood, Vol. 124, No. 14, 2014, p. 2190 - 2195.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Spencer, Andrew

AU - Yoon, Sung-Soo

AU - Harrison, Simon

AU - Morris, Shannon R

AU - Smith, Deborah A

AU - Brigandi, Richard A

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AU - Kumar, Rakesh

AU - Opalinska, Joanna B

AU - Chen, Christine

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N2 - The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib-an oral AKT inhibitor-in patients with advanced hematologic malignancies. Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6 ), diarrhea (32.9 ), and dyspepsia (24.7 ). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at >75-mg doses; the mediantime to peak plasma concentrationswas1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan s cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma. This trial was registered at www.clinicaltrials.gov as NCT00881946. (Blood. 2014;124(14):2190-2195).

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