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01-02-2016 | Clinical trial

A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies

Authors: Amy Jo Chien, Alyson Cockerill, Craig Fancourt, Emmett Schmidt, Mark M. Moasser, Hope S. Rugo, Michelle E. Melisko, Andrew H. Ko, R. Katie Kelley, W. Michael Korn, Laura J. Esserman, Laura van‘t Veer, Christina Yau, Denise M. Wolf, Pamela N. Munster

Published in: Breast Cancer Research and Treatment | Issue 3/2016

Abstract

Purpose

Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies.

Methods

We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m² and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed.

Results

16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response.

Conclusions

MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.

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Title: A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies
Authors: Amy Jo Chien
Alyson Cockerill
Craig Fancourt
Emmett Schmidt
Mark M. Moasser
Hope S. Rugo
Michelle E. Melisko
Andrew H. Ko
R. Katie Kelley
W. Michael Korn
Laura J. Esserman
Laura van‘t Veer
Christina Yau
Denise M. Wolf
Pamela N. Munster
Publication date: 01-02-2016
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2016
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-016-3701-7

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