Background: Annually, more than 4,000 patients are diagnosed with leptomeningeal carcinomatosis (LC) from breast cancer in the U.S. Since most therapies cannot cross the Blood-CSF-Barrier (BCB) and the Blood-Brain-Barrier (BBB), treatment options for LC are limited to local radiation and few chemotherapy agents, none of which have provided durable clinical benefit, leading to short overall survival (OS) of 3-4 months. ANG1005 is a novel peptide-drug conjugate, consisting of 3 paclitaxel molecules covalently linked to a peptide that targets the LRP-1 receptor to cross both BCB and BBB, and enter the tumor cells, where the paclitaxel is cleaved off to exert its anti-tumor activity. ANG1005 has previously shown in a phase 2 study to prolong OS in LC patients from breast cancer with brain metastases (BM) to 8 months.

Trial Design: This is an open-label, multi-center phase 3 randomized study to evaluate the efficacy of ANG1005 in HER2-negative breast cancer patients with newly diagnosed LC and documented history of previously treated BM when compared to Physician Best Choice (PBC). Hundred and fifty (150) patients will be randomized 1:1 to receive either ANG1005 experimental treatment or an Investigator assigned PBC control treatment. ANG1005 will be administered by intravenous (IV) infusion at a starting dose of 600 mg/m2 every 3 weeks. Allowed PBC therapies include capecitabine, eribulin, or high-dose IV methotrexate. CNS disease (LC and BM) will be evaluated at screening and every 6 weeks by MRI, CSF cytology and neurological assessments according to LANO and RANO-BM criteria. Extracranial disease will be evaluated by CT scans according to RECIST at screening and every 6-12 weeks. All patients will be followed for survival every 6-8 weeks from the date of the last dose until death, lost to follow-up or consent withdrawal.

Eligibility Criteria: Eligible patients are adults (≥ 18 years old) with HER2-negative breast cancer, newly diagnosed LC and documented history of previously treated BM. Patients must be neurologically stable and have adequate blood counts, organ and bone marrow function with an ECOG status grade ≤2. Patients previously treated with ANG1005 or with known allergy to paclitaxel or its components are excluded.

Specific aims: The primary endpoint is OS. Secondary endpoints include CNS (LC and BM) progression-free survival and clinical benefit rate, 6- and 12-month OS rates, LC response rate and duration of response, OS for triple negative patients and safety.

Statistical Methods: This study is sized for testing the hypothesis of improved OS for ANG1005 versus PBC in all patients (HR=0.58, two-sided test, overall type 1 error of 5%). Interim analysis for OS (using O'Brien Fleming boundaries for efficacy and a fixed HR=1 for futility) will be performed when a total of 55 death events are reached across both arms.

Study Accrual: Target accrual is 150 patients. The study is currently planned to start in the fall of 2018.

Citation Format: Kumthekar P, Lawrence B, Iordanova V, Ibrahim N, Mazanet R. ANG1005 in leptomeningeal disease (ANGLeD) trial: A randomized, open-label, phase 3 study of ANG1005 compared with Physician's Best Choice in HER2-negative breast cancer patients with newly diagnosed leptomeningeal carcinomatosis and previously treated brain metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-06-01.