Antiangiogenic (AG) Synergy with Ixabepilone (IXA): Translation of Preclinical Studies to the Clinical Setting.
Authors: Lee F. , Lewin A. , Wen M. , Ryseck R. , Fargnoli J. , Poruchynsky M. , Fojo T. , Mudenda B. , Rugo H. 
Published: December 2010

Background: Optimal benefit from AG therapy generally requires combination with cytotoxic agents, including taxane (TAX) microtubule stabilizing agents (MTSA), e.g. paclitaxel (PTX). IXA, is a new MTSA approved for the treatment of metastatic breast cancer (MBC). We evaluated the antitumor activity of IXA combined with several AG agents, relative to TAX based MTSAs and showed that IXA+BEV demonstrates advantages over PTX. Studies were conducted to determine parameters that might limit TAX effectiveness, while retaining IXA activity. A Phase II clinical trial provides preliminary support for the benefits of IXA+BEV in MBC.Methods: Three IXA+AG agent combinations were explored: BEV, sunitinib (SUN) or brivanib (BRV), a dual VEGF/FGF inhibitor in phase III clinical trial. Therapeutic synergy (TS) was evaluated in several human tumor xenografts (Table 1).Synergy of IXA with three diverse AG agents Antitumor activity (log cell kill, LCK)TumorIXAAG agentsIXA+AG agentsPat-21 (basal breast)1.60.3 (BEV)2.3 (+BEV)151b (renal)0.60.5 (SUN)1.3 (+SUN)L2987 (NSCLC)1.31.4 (BRV)2.4 (+BRV) In vitro AG activity was determined in endothelial cells (ECs) of bovine (ABAE) or human (HUVEC) origin, which express known TAX resistance factors, (βIII tubulin (βIII) and/or MDR1 P-glycoprotein (Pgp)). In vivo AG activity was determined using the Matrigel™ plug and tumoral microvessel density assays. Pgp and βIII expression was determined by Western blot or IHC. Effects of BEV on IXA tumor access was evaluated by determining acetylated α-tubulin (AαT), a post-translational marker of stabilized MTs. Phase II trial: women with locally advanced or MBC, randomized to Arm A (IXA 16 mg/m2 IV on days 1, 8 & 15 q28 days/ BEV 10 mg/kg IV q 2 wks), Arm B (IXA 40 mg/m2 IV q3 wks/BEV 15 mg/kg IV q 3 wks) or Arm C (PAC 90 mg/m2 IV, schedule/BEV as in Arm A).Results: IXA showed marked TS when combined with BEV, SUN or BRV and a 5X &gt;LCK in the GEO colon model when combined with BEV than PAC+BEV. BEV did not enhance IXA induced AαT levels, a marker of tumor drug access. IXA was 3-fold more cytotoxic to ECs than PTX. Tumor associated ECs expressed high βIII and Pgp levels. IXA was more active than PTX in inhibiting EC infiltration and proliferation in Matrigel™ plugs in vivo (P&lt;0.0001). In GEO, BEV+IXA produced synergistic reduction of tumoral vascular density compared to BEV (P&lt;0.0001) or IXA (P=0.035). In contrast, BEV+PTX was not better than PTX alone (P=0.373). In a phase II trial, IXA+BEV showed an efficacy and safety profile similar to PTX+BEV (%ORR Arms A, B, C: 50, 71, 56%).Discussion: IXA has potent AG activity as a single agent and robust TS in combination with AG agents. Mechanism studies suggest that resistance factors found in ECs, like βIII and Pgp, have little impact on IXA, while limiting the activity of TAX. Initial clinical studies demonstrate that IXA+BEV is safe and effective for the 1st line treatment of patients with MBC, with a profile similar to that of PAC+BEV.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 206.