472P - Phase 1/2a study of glutathione PEGylated liposomal doxorubicin (2B3-101) in patients with brain metastases (BM) from solid tumors or recurrent hig...
Date | 27 September 2014 |
Event | ESMO 2014 |
Session | Poster Display session |
Topics | Clinical Research Central Nervous System Malignancies Basic Scientific Principles |
Presenter | Dieta Brandsma |
Citation | Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331 |
Authors |
D. Brandsma1, B. Milojkovic Kerklaan2, V. Dieras3, S. Altintas4, C.K. Anders5, M. Arnedos Ballester6, H. Gelderblom7, P.M.M.B. Soetekouw8, W. Gladdines9, F. Lonnqvist10, A. Jager11, M.E. van Linde12, J. Schellens13, P. Aftimos14
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Abstract
Aim
Background: Without active delivery across the blood-brain barrier, the efficacy of doxorubicin is limited in the treatment of brain tumors. Therefore, 2B3-101 has been developed as a brain-targeted doxorubicin product. In preclinical studies, 2B3-101 showed a 5-fold increased delivery of doxorubicin to the brain and improved survival of mice with HGG, compared to Caelyx®.
Methods
This study assessed the safety, tolerability, MTD, PK, and anti-tumor activity of 2B3-101 in pts with advanced solid tumors and BM or HGG. In phase 1, pts with BM or HGG received 2B3-101 (5-70 mg/m2 q21d) and breast cancer (BC) BM pts received 2B3-101 (40-50 mg/m2 q21d) with trastuzumab. In phase 2a, BCBM pts received 2B3-101 (50 mg/m2 q21d) alone or with trastuzumab, HGG pts received 2B3-101 (60 mg/m2 q28d); melanoma and SCLC pts received 2B3-101 (50 mg/m2 q21d) in exploratory arms.
Results
Results up to March 2014 from pts treated with ≥40 mg/m2 are described. PK data showed non-linear exposure of 2B3-101 without signs of accumulation upon repeat dosing, a half-life of 69h (range 43-120h) independent of trastuzumab co-treatment. 203 cycles (range 1-10) of 2B3-101 alone or with trastuzumab were given to 68 pts. 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 doses were selected based upon tolerability after repeated dosing. Most frequent reported treatment emergent AEs ≥ grade 2 were: neutropenia (36%), PPE (34%), fatigue (32%), stomatitis (19%), and infusion reaction (18%). All were transient and manageable with standard treatment. 2B3-101 showed no CNS- or cardiotoxicity. In evaluable BCBM pts (n = 19), 11% had PR and 53% SD as overall best response, including 4 pts with intracranial (IC) response of ≥ 20% with 3-months PFS rate of 58%. In evaluable HGG pts (n = 24), 54% had SD as best response, including 3 pts with IC response of ≥ 20% and a 3-months PFS rate of 33%.
Conclusions
2B3-101 is safe and well tolerated and shows activity in advanced BCBM and HGG pts, diseases with limited treatment options. Results warrant further randomized, controlled Phase 2b studies, with initial focus on (HER2+) BCBM. ClinicalTrials.gov NCT01386580, sponsored by to-BBB technologies BV.
Disclosure
B. Milojkovic Kerklaan: research grant; W. Gladdines: employee; F. Lonnqvist: employee. All other authors have declared no conflicts of interest.