P08.03 * 2B3-101, GLUTATHIONE PEGYLATED LIPOSOMAL DOXORUBICIN, IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS AND BREAST CANCER BRAIN METASTASES

Abstract

BACKGROUND: Without active delivery across the blood-brain barrier (BBB), efficacy of doxorubicin in intracranial tumors is limited. Glutathione pegylated liposomal doxorubicin (2B3-101) was developed as a brain-targeted chemotherapy. In rats treated with 2B3-101 doxorubicin brain delivery was 5-fold higher as compared to pegylated liposomal doxorubicin (Doxil®/Caelyx®). This resulted in a significant improvement in glioma growth inhibition. In a Phase I dose escalation study in 37 patients with advanced solid tumors and brain metastases (n = 24) or recurrent high grade gliomas (HGG; n = 13), 2B3-101 was well tolerated up to a dose intensity of 15 mg/m2/wk, both as single agent and in combination with trastuzumab. Preliminary evidence of anti-tumor activity was observed, including 1 intracranial partial response (PR) and 16 patients with stable disease (SD) after 2 cycles. These results warranted proceeding into a Phase IIa study. METHODS: The purpose of the ongoing Phase IIa study is to evaluate the safety, tolerability and intracranial anti-tumor activity of 2B3-101 in patients with recurrent HGG and the intracranial and extra-cranial anti-tumor activity of 2B3-101 in patients with breast cancer brain metastases (BCBM) (n = 14 per group). Patients with recurrent HGG are treated with 2B3-101 60 mg/m2 iv q28d while patients with BCBM are treated with 2B3-101 50 mg/m2 iv q21d, in HER2 positive patients combined with trastuzumab (iv, 6mg/kg, q21d). Results up to March 15th 2014 are described in this abstract; in October 2014 the complete data set will be presented. RESULTS: To date, 18 patients with HGG and 10 patients with BCBM have been enrolled in the Phase IIa part of the study and have received a total of 35 (range 1-4) and 34 (range 1-7) cycles of 2B3-101, respectively. At both dose regimes, the side effects were consistent with Doxil®/Caelyx® and with the earlier Phase I results of 2B3-101. The most common adverse events (AEs) grade ≥2 related to 2B3-101 were: neutropenia (28%), palmar-plantar erythrodysesthesia (PPE) (21%), infusion reactions (21%) and oral mucositis (17%). No CNS and/or cardiac toxicity were reported. 2B3-101 cycles were administered per protocol in 92% of the HGG patients and in 62% of the BCBM patients. The main reasons for dose delays/ reductions were neutropenia (19%) and PPE (69%). The anti-tumor activity was evaluable in 13 patients with HGG and in 9 patients with BCBM. In the HGG cohort, 31% of the patients had SD as best response (RANO), including 2 patients with a response of ≥30%. In the BCBM cohort, 11% had a PR and 56% had SD as best response (RECIST). The latter group, included 3 more patients with an intracranial response of ≥20%. CONCLUSIONS: This phase I/IIa trial shows that 2B3-101 has anti-tumor activity with a tolerable safety profile in recurrent HGG and in BCBM patients. These results warrant further randomized, controlled Phase IIb studies in both patient populations.