Abstract P6-15-02: A Phase Ib Study Evaluating Safety, Tolerability, Pharmacokinetics (PK), and Activity of the Phosphoinositide-3 Kinase (PI3K) Inhibitor GDC-0941 in Combination with Trastuzumab-MCC-DM1 (T-DM1) in Patients with Advanced HER2-Positive Breast Cancer
Authors: Krop IE , Wolff AC , Winer EP , Miller KD , Park BH , Ware J , Holden S , Levy GG , Derynck M , Storniolo AM. 
Published: April 2011

Abstract
Background: Aberrant activation of the PI3K pathway has been hypothesized to reduce the efficacy of trastuzumab-based therapy in patients with HER2-positive breast cancer. Inhibition of the PI3K pathway in combination with continued suppression of HER2 signaling is one strategy that may enhance sensitivity to HER2-directed therapy. GDC-0941 is a potent and selective oral pan-inhibitor of class I PI3K (in vitro IC50 for the p110-alpha subunit is 3 nM) and demonstrates single-agent activity in preclinical xenograft models. T-DM1 is a novel antibody-drug conjugate that combines the biological properties of trastuzumab with the highly potent anti-microtubule agent DM1 and has shown promising activity in two Phase II studies in heavily pretreated patients with advanced HER2- positive breast cancer. In vivo studies of GDC-0941 dosed in combination with T-DM1 have shown increased anti-tumor activity relative to either T-DM1 or GDC-0941 alone in trastuzumab-resistant and PI3K mutant breast cancer xenograft models.
Material and Methods: Patients with histologically confirmed advanced HER2-positive breast cancer who have progressed on prior trastuzumab therapy were enrolled in a Phase Ib study (GDC4627g) of GDC-0941 and T-DM1 using a 3+3 dose escalation design. Treatment consists of T-DM1 IV on a 21-day schedule (q3wks) and GDC-0941 orally given daily for 14 of 21 days. Objectives include an evaluation of the safety, tolerability and PK of GDC-0941 administered with T-DM1, as well as determining the maximum tolerated dose of this combination.
Results: Thirteen patients have been enrolled in three successive cohorts. Starting doses of T-DM1 and GDC-0941 were 3.6 mg/kg and 80 mg, respectively (T-DM1 administered one day after GDC-0941, cycle 1 only). A dose-limiting toxicity (DLT) of Grade 4 thrombocytopenia was seen in the first cohort. The cohort was expanded without any additional DLTs. Two DLTs were observed in the second cohort (T-DM1 3.6 mg/kg and GDC-0941 115 mg): Grade 4 thrombocytopenia in one patient and Grade 3 fatigue in a second patient in the setting of newly diagnosed brain metastases. A third cohort was enrolled with a reduced dose of T-DM1 of 3.0 mg/kg and GDC-0941 at 100 mg (both starting the same day on cycle 1). No DLTs were observed and dose escalation continues. Preliminary PK for GDC-0941, T-DM1 and free DM1 were similar to historical profiles from previous studies of these molecules. Evidence of clinical activity has been reported in a number of participants.
Conclusions: This trial represents the first report of a regimen combining a HER2-targeted agent with a PI3K inhibitor. DLTs observed with this combination to date have been Grade 4 thrombocytopenia and Grade 3 fatigue. Encouraging evidence of clinical activity has been observed. Dose-escalation continues and updated PK/PD, safety and efficacy data will be presented. Data from this study will inform plans for a subsequent Translational Breast Cancer Research Consortium clinical trial.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-02.