Abstract P6-16-04: Phase 1/2a study of glutathione PEGylated liposomal doxorubicin (2B3-101) in breast cancer patients with brain metastases
Authors: Aftimos Philippe G , Milojkovic-Kerklaan Bojana , Diéras Véronique , Altintas Sevilay , Anders Carey , Arnedos Monica , Gelderblom Hans , Soetekouw Patricia , Gladdines Werner , Gaillard Pieter , de Sousa Carlos , Jager Agnes , van Linde Myra , Awada Ahmad , Schellens Jan , Brandsma Dieta 
Published: May 2015

Abstract
Background:
The incidence of brain metastases (BM) in breast cancer (BC) patients (pts) has increased over the past decade. The brain is regarded as a sanctuary site for metastatic cells which are partially protected from drugs by the blood-brain barrier (BBB).
2B3-101 is a doxorubicin (DOX) liposomal formulation that uses glutathione transporters on the BBB to penetrate the brain. Non-clinical studies have shown a 5-fold enhanced delivery of DOX to the brain after IV administration of 2B3-101 compared to liposomal DOX, without signs of cardio- or neurotoxicity.
Methods:
This phase 1/2a open label study assessed the safety, tolerability, MTD, PK, and anti-tumor activity of single agent 2B3-101 in pts with BM of solid tumors, or high-grade gliomas.
For this analyses BCBM pts (n=25) were included. These pts received 2B3-101 at a starting dose of either 40 (n=3) or 50 (n=22) mg/m2 IV every 3 weeks, until disease progression or unacceptable toxicity. Anti-tumor activity was assessed by RECIST 1.1. Patients with HER2-positive BCBM were treated with concurrent trastuzumab.
Results:
As of May 30, 2014, 88 cycles (median 2, range 1-10) of 2B3-101 alone or with trastuzumab were administered to 25 heavily pretreated BC pts, 3 pts are still on treatment. Median age was 47 (33–61) years and 18 (72%) pts had HER2+ disease. Pts had received a median of 7 (4–15) prior regimens; 18 (72%) had received prior radiation therapy to the brain.
In phase 1, 2B3-101 alone or with trastuzumab was well tolerated up to a dose intensity of 15 mg/m2/wk. Cycle 1 MTD was not reached. Phase 2a dose of 50 mg/m2 was selected based upon tolerability after repeated dosing. The most frequent reported treatment emergent AEs are qualitatively consistent with conventional PEGylated liposomal DOX and were (≥ grade 2): neutropenia (59%), palmar plantar erythrodysesthesia (PPE) (50%), fatigue (45%), stomatitis (22%), and infusion reaction (18%). Notable Grade 3–4 AEs were neutropenia (35%) and PPE (13%). All AEs were transient and manageable with dose delays, reductions and standard medication. 57% of pts had 2B3-101 dose delays and 39% of pts required dose reductions. 2B3-101 showed no neuro- or cardiotoxicity. PK data showed non-linear exposure of 2B3-101 without signs of accumulation upon repeat dosing, a mean half-life of 69h (range 43-120h) and independent of trastuzumab co-treatment.
Best overall and intracranial tumor responses of 2B3-101 in 23 evaluable BCBM pts (92% of total) are summarized in Table 1.
Table 1: Anti-tumor activity results of 2B3-101 in BCBM patientsPopulationNumber of evaluable ptsOverall partial responseOverall stable diseaseIntracranial tumor response of ≥ 20%.12-weeks overall PFS rateOverall232 (9%)11 (48%)4 (17%)48%"Luminal"40 (0%)2 (50%)1 (25%)50%HER2 positive162 (13%)9 (56%)3 (19%)56%TNBC30 (0%)0 (0%)0 (0%)0%
Conclusions:
2B3-101 alone or with trastuzumab is safe and well tolerated and shows intra- and extracranial anti-tumor activity in heavily pretreated BC pts. A 12-week PFS rate of 56% in HER2+ BCBM was observed, which warrants further clinical studies. An international, multicenter, randomized, controlled phase IIb study in HER2+ BCBM is being planned.
NCT01386580, sponsored by to-BBB technologies BV.
Citation Format: Philippe G Aftimos, Bojana Milojkovic-Kerklaan, Véronique Diéras, Sevilay Altintas, Carey Anders, Monica Arnedos, Hans Gelderblom, Patricia Soetekouw, Werner Gladdines, Pieter Gaillard, Carlos de Sousa, Agnes Jager, Myra van Linde, Ahmad Awada, Jan Schellens, Dieta Brandsma. Phase 1/2a study of glutathione PEGylated liposomal doxorubicin (2B3-101) in breast cancer patients with brain metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-04.