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 Drug Development
Central Nervous System Malignancies
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
  • 1Neurology Department, Medical Oncology Departement, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, 1066CX - Amsterdam/NL
  • 2Clinical Pharmacology, Medical Oncology Departement, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, 1066CX - Amsterdam/NL
  • 3Department Of Medical Oncology, Clinical Trial Unit, Institut Curie, 75005 - Paris/FR
  • 4Department Of Medical Oncology, Antwerp University Hospital, Antwerp/BE
  • 5Division Of Hematology Oncology, University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center Chapel Hill, Chapel Hill/US
  • 6Department Of Medicine; Breast Unit, Institut Gustave Roussy, FR-94805 - Villejuif/FR
  • 7Medical Oncology, Leiden University Medical Center (LUMC), 2333ZA - Leiden/NL
  • 8Medical Oncology Dept., Academisch Ziekenhuis Maastricht (AZM), NL-6229 HX - Maastricht/NL
  • 9To-bbb Technologies B.v., Medical Department, to-BBB technologies B.V., leiden/NL
  • 10To-bbb Technologies B.v., Medical Department, to-BBB technologies B.V., Leiden/NL
  • 11Medical Oncology, Erasmus MCDaniel den Hoed Cancer Center, NL-3075 EA - Rotterdam/NL
  • 12Medical Oncology, Vrije University Medical Centre (VUMC), NL-1081 HV - Amsterdam/NL
  • 13Clinical Pharmacology & Medical Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 14Oncology, Institut Jules Bordet, Brussels/BE

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.