ANG1005, a novel peptide-paclitaxel conjugate crosses the BBB and shows activity in patients with recurrent CNS metastasis from breast cancer, results from a phase II clinical study

Abstract

Background: ANG1005 is a novel taxane derivative, consisting of 3 paclitaxel molecules covalently linked to Angiopep-2, a peptide designed to utilize the LRP-1 transport system to cross the BBB/BCB and to penetrate malignant cells. We conducted an open label phase II clinical study to test its activity in metastatic breast cancer (BC) patients with recurrent brain metastasis (BM), including BCBM patients with newly diagnosed leptomeningeal carcinomatosis (LC). Methods: Adult patients with measurable recurrent BM from breast cancer, with or without LC, were enrolled in this multi-center, open-label study (n = 72 safety population; n = 58 efficacy population). ANG1005 was administered IV at 600 mg/m2 q3w. HER2+ patients were allowed to continue trastuzumab +/- pertuzumab. Intracranial (IC) response was assessed by Gd-MRI using CNS RECIST 1.1 and extracranial response was evaluated per RECIST 1.1. Results: Median age was 47.5 (26-76) years. Safety was similar to that of paclitaxel with myelosuppression as the predominant toxicity. Patients received a median of 6 (1-29) prior therapies for breast cancer, including 84% with prior taxane treatment. As prior therapy for BM, 87% patients had cranial surgery and/or radiation and 19% patients received systemic therapies. After ANG1005 treatment, best IC response in the efficacy population included 8/58 (14%) patients with PRs [3 (5%) confirmed PRs] and 33/58 (57%) with SD. Extracranial tumor responses of 1 (3%) CR, 2 (7%) PRs and 24 (80%) SDs were seen in 30 evaluable patients, including after prior taxane therapy (93%). The 6 month OS was 63.6 % (95% CI: 42.9, 78.5) for patients with LC. Importantly, Kaplan-Meier estimated median OS was 34.6 weeks (95% CI 24.1-40.9) from first ANG1005 treatment for LC patients. CNS clinical symptoms post-ANG1005 were improved, including in LC patients. Conclusions: ANG1005 is active against previously treated breast cancer metastasis both within and outside the CNS. The clinical benefit has resulted in an estimated median OS of ∼8 months for the patients with LC, exceeding the historical median of ∼4 months following therapy. A randomized study is planned.