Abstract B76: A phase II study of ANG1005, a novel, brain-penetrant taxane derivative, in breast cancer patients with brain metastases.
Authors: Lin Nancy U. , Schwartzberg Lee , Kesari Santosh , Elias Anthony , Anders Carey , Raizer Jeffrey , Kozloff Mark , Amiri-Kordestani Laleh 
Published: August 2014

Abstract
Background: Treatment for brain metastases is an unmet medical need. ANG1005 consists of 3 paclitaxels covalently linked to a proprietary 19-AA peptide that targets LRP1, a receptor highly expressed on the surface of the BBB and on tumor cells. Preclinically, ANG1005 achieves significantly higher concentrations in the brain relative to free paclitaxel. Preliminary evidence of efficacy in humans was observed in the phase I studies.
Methods: ANG1005 was evaluated for activity to treat brain metastases from breast cancer patients (pts) with HER2- and HER2+ disease. The primary objective was to determine intracranial response. Secondary objectives included safety and tolerability, progression-free survival (PFS), duration of PFS and overall survival (OS).
A phase II, multi-center, open label, single-arm study with ANG1005 IV once every 3 weeks. The initial starting dose was 650 mg/m2 (13 pts) but decreased to 550 mg/m2(67 pts) due to poor tolerance. An interim analysis on 30 pts by Geron Corp. (sponsor at that time) concluded that the futility point was reached. Recruitment was halted and ANG1005 returned to Angiochem Inc. (Cancer Res 2012; 72: Abstract P3-12-04). As a consequence, some pts were withdrawn from study. Nevertheless, several investigators continued treatment due to patient benefit. Here, we present the results from the complete intent-to-treat (ITT) data analyses including pts withdrawn prematurely.
Results: At both dose levels, side effects were consistent with a taxane profile. At 650 mg/m2, the most common adverse events (AEs) included neutropenia (69%), no febrile neutropenia, fatigue (31%), peripheral (sensory) neuropathy (15%), mucosal inflammation (8%), and leucopenia (8%). At 550 mg/m2, the most common AEs included neutropenia (27%) with 2 (3%) cases of febrile neutropenia, peripheral (sensory) neuropathy (9%), anemia (6%), leucopenia (6%) and fatigue (5%). Percentages are given for incidences of AEs grade≥3.
At 650 mg/m2, none of the pts with HER2- disease had intracranial partial response (PR). However, 3/5 (60%) pts had stable disease (SD). PFS rate at three months (PFS3) was 75%, median PFS was 7.9 months and OS at 6 months was 75% for this cohort. Clinical activity in the 650 mg/m2 HER2+ cohort included 4/8 (50%) pts with PRs, 1/8 (13%) pt with SD, PFS3 of 71%, median PFS of 5.6 months and OS at 6 months of 86%.
At 550 mg/m2, in the HER2- cohort, 5/39 (13%) pts had PRs and 14/39 (36%) pts had SD. PFS3 was 35%, median PFS was 2.8 and OS at 6 months was 60% in this cohort. Results for HER2+ cohort at 550 mg/m2 included 5/28 (18%) pts with PRs, 17/28 (61%) pts with SD, PFS3 of 71%, median PFS of 4.2 months and OS at 6 months of 82%. One patient with HER2+ disease has received 14 cycles of ANG1005 at 550 mg/m2 and is still on treatment.
Conclusion: ANG1005 has shown evidence of clinical activity for the treatment of brain metastases in breast cancer patients and warrants further development.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B76.
Citation Format: Nancy U. Lin, Lee Schwartzberg, Santosh Kesari, Anthony Elias, Carey Anders, Jeffrey Raizer, Mark Kozloff, Laleh Amiri-Kordestani. A phase II study of ANG1005, a novel, brain-penetrant taxane derivative, in breast cancer patients with brain metastases. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B76.