Abstract B43: ANG1005, a novel brain-penetrant drug conjugate, in CNS metastases from breast cancer: FLT-PET imaging as a predictor of response
Authors: O'Sullivan Ciara C. , Lindenberg Maria , Bryla Christine , Davarpanah Nicole , Peer Cody , Patronas Nicholas , Amiri-Kordestani Laleh , Balasubramaniam Sanjeeve , Fojo Tito , Figg William D. , Choyke Peter 
Published: May 2016

Background:

The novel drug conjugate ANG1005 consists of 3 molecules of paclitaxel covalently linked to Angiopep-2. After binding to the low-density lipoprotein receptor-related protein, ANG1005 crosses the blood brain barrier (BBB) by endocytosis. A multi-center Phase II study, with the primary endpoint of intracranial response in patients with breast cancer brain metastases is in progress. At the NCI, a biomarker substudy is evaluating 18F-FLT (3'-Fluoro-3' deoxythymidine)-PET for response assessment.

Methods:

Patients with measurable brain metastases from breast cancer received ANG1005 at a dose of 550mg/m2 IV once every 21 days. Before and after cycle 1, all patients on study underwent imaging with 18F-FLT, a thymidine analog and novel imaging agent; retention of 18F-FLT correlating with DNA synthesis. In order to detect brain metastases and assess response to treatment, we compared FLT PET images with MRI-gadolinium contrast scans, obtaining both dynamic and static images. We determined the percentage (%) change after treatment with ANG1005; a decrease in ≥20% was considered significant.

Results:

Ten patients were enrolled on study. A total of 32 target and 20 non target CNS lesions in 10 patients were imaged and analyzed by MRI and FLT-PET.

At 30 minutes, SUVmax ranged from 0.8 to 6.3 at baseline (mean 2.64), and the SUV80%, (mean of top 20% SUV units) ranged from 0.7 to 5.12. The median% change from baseline to post one cycle of ANG1005 was -19.9% for SUVmax (range +85.4 to -67.7, and was median -20.2% for SUV80% (range 95.7 to -69%). Two patients had confirmed partial responses lasting 6 and 18 cycles, respectively. Six patients had stable disease and received a median of 6 cycles. Tumor reductions, as determined by MRI per CNS RECIST version 1.1 ranged from -5% to -60% in lesion size, compared to baseline. Both FLT-PET parameters correlated with the% change in MRI measurements in the target lesions (R2 = 0.64, P = 0.0002).

Conclusion:

The development of CNS-directed therapies designed to cross the BBB, such as the paclitaxel conjugate ANG1005, is a research priority. As contrast-enhanced MRI detection of brain metastases is representative of gadolinium leakage through the BBB, as opposed to actual tumor volume, better approaches are needed to evaluate drug efficacy. Pilot evaluations of FLT-PET imaging in this setting suggest that it is a promising tool that may serve as a complementary assessment method for breast cancer brain metastases going forward.

Citation Format: Ciara C. O'Sullivan, Maria Lindenberg, Christine Bryla, Nicole Davarpanah, Cody Peer, Nicholas Patronas, Laleh Amiri-Kordestani, Sanjeeve Balasubramaniam, Tito Fojo, William D. Figg, Peter Choyke. ANG1005, a novel brain-penetrant drug conjugate, in CNS metastases from breast cancer: FLT-PET imaging as a predictor of response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B43.