Abstract P1-12-01: A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant peptide-drug conjugate, in breast cancer patients with recurrent CNS metastases
Authors: Ibrahim NK , Tang S-C , Brenner AJ , Kesari S , Piccioni DE , Anders CK , Carillo JA , Chalasani P , Kabos P , Puhalla S , Garcia AA , Tkaczuk KH , Ahluwalia MS , Lakhani NJ , Kumthekar P 
Published: March 2017

Abstract
Background: The incidence of CNS metastatic disease in breast cancer patients (pts) seems to have increased in recent years with the improvement of systemic therapy. However, treatment options for CNS metastases have remained limited due to the inability of most agents to cross the BBB. ANG1005 is a novel peptide drug-conjugate, 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.
Methods: We conducted an open label phase II clinical study to test its activity in metastatic breast cancer (BC) pts with recurrent brain metastasis (BM), including BCBM pts with newly diagnosed leptomeningeal carcinomatosis (LC). Adult pts with measurable, recurrent BM from breast cancer, with or without LC (n=72 safety population; n=58 efficacy population) were enrolled in the study. 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 (EC) 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 (WBC: 83%, RBC: 71%, PLT: 69%). Pts received a median of 6 (1-29) prior therapies for BC, including 84% with taxanes. As prior therapy for BM, 87% pts had cranial surgery and/or radiation and 19% pts received systemic therapies. Intracranial tumor response is presented for all pts as well as the various patient subsets as shown below:
Table 1: Intracranial Response by Breast Cancer SubsetOutcome by CNS RECISTAllHER2+HER2-TNBCLCSample size, n5828301223PR (best response), n (%)8 (14%)4 (14%)4 (13%)2 (17%)5 (22%)Confirmed PR, n (%)3 (5%)2 (7%)1 (3%)02 (9%)SD, n (%)33 (57%)19 (68%)14 (47%)5 (42%)12 (52%))PD, n (%)17 (29%)5 (18%)12 (40%)5 (42%)6 (26%)Clinical benefit (SD+PR), %71%82%60%59%74%Abbreviations: TNBC, triple-negative breast cancer, a sub-group of HER2-; LC, leptomeningeal carcinomatosis
Table 1 definitions: data based on evaluable pts with clinical or radiological evaluation ≥ 4 weeks from C1D1; LC pts included 15 HER2+ and 8 HER2-; best response is the best response recorded from the start of the study treatment until the disease progression; confirmed PR requires a ≥28-day confirmation of response.
Extracranial tumor responses of 1 (3%) CR, 2 (7%) PRs and 24 (80%) SDs were seen in 30 evaluable pts, including after prior taxanes (93%). The 6 month OS in all pts was 50.2% (95% CI: 37.4, 61.6).
In general, CNS clinical symptoms post-ANG1005 were improved, including in LC pts.
Conclusions: ANG1005 is active against previously treated BC metastasis both within and outside the CNS. A randomized study is planned. Updated efficacy and safety data will be presented at the meeting.
Citation Format: Ibrahim NK, Tang S-C, Brenner AJ, Kesari S, Piccioni DE, Anders CK, Carillo JA, Chalasani P, Kabos P, Puhalla S, Garcia AA, Tkaczuk KH, Ahluwalia MS, Lakhani NJ, Kumthekar P. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant peptide-drug conjugate, in breast cancer patients with recurrent CNS metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-01.