Abstract LB-231: Phase Ib dose escalation and biomarker study of MK2206 in combination with standard doses of weekly paclitaxel in patients with locally advanced or metastatic solid tumors with expansion in advanced breast cancer
Authors: Gonzalez-Angulo Ana M. , Krop Ian , Piha-Paul Sarina , Li Yisheng , Culotta Kirk S. , Moulder-Thompson Stacy , Tsimberidou Apostolia , Velez-Bravo Vivianne M. , Madden Timothy L. , Norberg Lisa M. , Doyle Austin , Winder Eric P. , Mills Gordon B. , Meric-Bernstam Funda , Kurzrock Razelle 
Published: August 2012

Abstract
Background: AKT protein kinase is activated in a large proportion of human solid tumors. Increased levels of AKT phosphorylation and PTEN loss predict poor outcome. Synergistic or additive inhibitory effects have been observed on proliferation/viability of breast cancer cell lines when MK2206, allosteric inhibitor of AKT, is given in combination with taxanes. Primary goals: determine the maximum tolerated dose (MTD) of the combination of MK2206 and weekly paclitaxel and to determine safety and activity of the combination in metastatic breast cancer. Secondary objectives included pharmacokinetics (PK), pharmacodynamic (PD) studies in tissue and blood, and toxicity. Methods: Phase Ib 3+3 dose escalation study. Patients were treated using continuous weekly dosing. A fixed dose of paclitaxel was given at 80mg/m2 weekly on day 1, followed by MK2206 PO on day 2. During dose escalation: MK2206 was escalated using 3 levels: 90mg, 135mg, 200mg. For expansion: MK2206 was given at the MTD of 200mg po. Treatment was continued until tumor progression, excessive toxicity, or patient (pt) request. Blood was collected for PK and PD markers as scheduled. Sequential tumor biopsies were completed in most patients. A cycle consisted of 3 weeks of therapy and DLT was defined as unacceptable toxicity occurring during the first cycle. Results: 23 patients were treated, 9 in the dose escalation and 14 in the dose expansion. Four patients were replaced at dose expansion due to lack of compliance, early progression or intolerance at first dose (2 of these pts were included in the toxicity analysis). Median age was 55 years, 4 male and 19 female. Dose escalation was completed with no DLT. CTCAE Grade ≥3 adverse events were G3 fatigue (2/9 pts), and G3 rash (1/9 pts), and G3 nail infection (1/9 pts). CTCAE in expansion phase will be reported and included G3/4 rash in at least 4 patients requiring MK2206 dose reduction to 135mg weekly. Based on this, phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK2206 135mg weekly on day 2. Observed clinical activity in the dose escalation included: objective responses in pts with a metastatic breast and a metastatic colon cancers, and stable disease over 15 weeks in 2 pts with ocular melanomas, 1 squamous cell carcinoma of the head and neck and 1 ovarian cancer. Expansion cohort clinical activity will be reported. Baseline molecular testing revealed PTEN low/loss in a pt with colon cancer (best and longest response), and a pt with head and neck cancer (on therapy for 25 weeks). Conclusion: Combined paclitaxel and MK2206 were well tolerated. There was clinical activity in the dose escalation, with PTEN low/loss noted in some patients with prolonged SD or PR. Complete report on dose expansion, molecular correlates will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-231. doi:1538-7445.AM2012-LB-231