Abstract P6-17-04: A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases
Authors: Tang S-C , Bates S , Kesari S , Brenner AJ , Anders CK , Garcia A , Ibrahim NK , Tkaczuk KHR , Kumthekar P 
Published: May 2016

Abstract
Background: Treatment options for brain metastases are limited to local therapies due to the inability of most anti-cancer agents to cross the blood brain barrier (BBB). ANG1005 is a novel taxane derivative, being developed for targeted treatment of brain metastases. It consists of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the BBB and to penetrate malignant cells, regardless of location, via the low density lipoprotein (LDL) receptor related protein-1 (LRP-1) transport system.
Methods: Adult patients with measurable recurrent brain metastases from breast cancer with, or without, leptomeningeal disease are currently being enrolled in this multi-center, open-label study (planned n=56). ANG1005 is administered IV at 600 mg/m2 every three weeks (one cycle) until disease progression, unacceptable toxicity or consent withdrawal. HER2+ patients are allowed to continue HER2 targeted therapies. The primary endpoint is intracranial objective response rate, as assessed by MRI using CNS RECIST 1.1. Secondary endpoints include duration of intracranial response, median progression-free survival, 3/6/12-month progression-free survival rate, overall survival at 6 months, extracranial objective response rate, safety and tolerability. Extracranial response is also assessed by CT using RECIST 1.1. An imaging sub-study, evaluating the use of 18F-FLT-PET in comparison to MRI, is also ongoing in 10 patients with measurable brain metastases from breast cancer, receiving ANG1005 IV at 550 mg/m2.
Results: Accrual is ongoing and to date, 48 patients have been treated with a range of 1-18 cycles of ANG1005. Median age is 47 years (range: 26-65). Safety profile is similar to that of paclitaxel with myelosuppression as the predominating toxicity. Based on data from patients evaluated to date for intracranial response, 6/30 (20%) patients had a partial response (PR) and 17/30 (57%) had a stable disease (SD), as best response. A sub-analysis, based on breast cancer sub-type is presented below:
Intracranial Response by Breast Cancer SubsetOutcome by CNS RECISTHER2- (n=13)HER2+ (n=17)TNBC (n=6)LMD (n=11)PR, n (%)1 (8%)5 (29%)1 (17%)4 (36%)SD, n (%)6 (46%)10 (59%)2 (33%)5 (45%)PD, n (%)6 (46%)2 (12%)3 (50%)2 (18%)TNBC, triple-negative breast cancer, a sub-group of HER2-; LMD, leptomeningeal disease, including 3 HER2- and 8 HER2+ patients
The longest duration on treatment is for 18 cycles, seen in a patient with an intracranial PR that sustained for 10 cycles; the treatment is still ongoing.
Extracranial tumor evaluations were completed in 14 patients, all showing disease control including in those previously treated with paclitaxel. One (7%) patient had a PR and 13 (93%) patients had an SD.
Conclusions: CNS activity was observed in all subsets of breast cancer, suggesting that ANG1005 is a promising therapy for treatment of brain and leptomeningeal metastases from breast cancer. ANG1005 treatment also resulted in disease control in extracranial lesions, including patients previously treated with paclitaxel. The dose and treatment regimen were well tolerated with a safety profile similar to paclitaxel. Updated efficacy and safety data will be presented at the meeting.
Citation Format: Tang S-C, Bates S, Kesari S, Brenner AJ, Anders CK, Garcia A, Ibrahim NK, Tkaczuk KHR, Kumthekar P. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-17-04.