P1-17-02: A Phase 1/2 Study of SAR245408 (S08) in Combination with Trastuzumab (T) or Paclitaxel (P) and T in Patients with HER2+ Metastatic Breast Cancer (MBC) Who Progressed on a Previous T-Based Regimen.
Authors: Tolaney S , Burris H , Gartner E , Mayer I , Saura C , Maurer M , DeCillis A , Ruiz-Soto R , Lager J , Winer E , Krop I 
Published: June 2012

Abstract
BACKGROUND: Most HER2+ MBC patients (pts) treated with a combination of T+P progress within 1 year. Activation of downstream pathways through either deficiency in PTEN or mutations in the PI3K pathway has been implicated in the development of resistance to T. S08 is a potent, orally bioavailable, pan-PI3K inhibitor that inhibits phosphorylation of multiple downstream components of the PI3K/PTEN signaling pathway and has demonstrated activity as a single agent and in combination with other anticancer agents (Edelman G, et al., ASCO 2010; Traynor AM, et al. ASCO 2010).
PATIENTS and METHODS: This ongoing, open-label multicenter phase 1/2 study (NCT01042925) was designed to assess safety and tolerability of S08 in combination with either T or T+P. Eligible female pts were ≥18 yrs, ECOG PS 0–2, with adequate organ and marrow function and had advanced or recurrent HER2+ MBC disease refractory to T. Pts have received, and progressed on at least 1 prior T-containing regimen for metastatic disease. Pts were allocated to Arm 1 or Arm 2 and received different dose levels of S08 (starting dose 200 mg PO, daily) in combination with either T 8/6 mg/kg IV on Day (D) 1 q3w (Arm 1) or T 8/6 mg/kg IV on D1 + P 80 mg/m2 on D 1, 8, and 15 q3w (Arm 2). In phase 1, a standard ascending 3 + 3 dose escalation design was used in each arm to evaluate safety/tolerability of the combinations. Following establishment of preliminary maximal tolerated doses (MTDs) for each combination, subsequent pts will be accrued to the phase 2 portion. Approximately 25 additional pts will be enrolled in each arm to further evaluate the safety and estimate the overall response rate (ORR) in each arm.
RESULTS: As of June 1st 2011, 33 pts median age 55 yrs were enrolled; 18 to Arm 1 and 15 to Arm 2. Based on preliminary data of the study, in Arm 1, the most common treatment emergent adverse events (TEAEs) regardless of relationship include rash, diarrhea, fatigue, nausea, vomiting; in Arm 2 were neutropenia, diarrhea, fatigue, nausea, hyporexia, hypokalemia, peripheral neuropathy, rash and hyperglycemia. SAEs reported in Arm 1 (3 subjects) included Gr3 dehydration (2 cases), Gr3 epigastric pain and Gr2 dyspnea; those SAEs in Arm 2 (4 subjects) included Gr4 neutropenia, Gr3 anorexia, Gr3 dehydration, Gr3 epigastric pain, Gr3 thromboembolism, Gr2 nausea, Gr2 pneumonitis and Gr2 headache. A total of 4 DLTs were reported; 2 in Arm 1 [Gr3 skin rash (S08; 400 mg dose)] and 2 in Arm 2 [Gr4 neutropenia (S08; 200mg dose)] (table 1). With phase I nearly complete, the MTD for arm 1 is S08 300 mg PO daily and T 8/6 mg/kg D1 q3w. The data for Arm 2 (current dose level ongoing at the maximum allowed per protocol) will be completed in August 2011. Preliminary PK data did not show interactions between S08 and either T or T+P.

DISCUSSION: S08 can be combined with either T or with T+P.
Additional safety, PK and efficacy data will be presented from phase 1.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-02.