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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.

BACKGROUND: Without active delivery across the blood-brain barrier, the efficacy of doxorubicin is limited in the treatment of brain tumors. 2B3-101 was 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 open-label study assessed the safety, tolerability, MTD, PK and anti-tumor activity of 2B3-101. For this analysis, 30 HGG and 25 BCBM patients were included who received a 2B3-101 starting dose of 40-70 mg/m2 q21d (n = 35) or 60 mg/m2 q28d (n = 20 all HGG). Treatment continued until disease progression or unacceptable toxicity. Anti-tumor activity was assessed by RANO in HGG or RECIST 1.1 in BCBM patients. RESULTS: As of 30-May-2014, 172 cycles (range 1-10) of 2B3-101 were administrated, 4 HGG and 2 BCBM patients are still on treatment. 2B3-101 was 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 (41%), palmar-plantar erythrodysesthesia (PPE) (39%), fatigue (36%), stomatitis (21%), and infusion-reaction (20%). Notable grade 3–4 AEs were neutropenia (26%) and PPE (14%). All were transient and manageable with standard medication or dose delays. Dose reductions were required in 25% of the patients. 2B3-101 showed no neuro-or cardiotoxicity. In 25 evaluable HGG patients, 52% had SD as best response and 3-months PFS rate of 40%. 3 patients had intracranial response of ≥ 20%. In 23 evaluable BCBM patients, 9% had PR and 48% SD as overall best response with 3-months PFS rate of 48%. 4 patients had intracranial response of ≥ 20%. CONCLUSIONS: 2B3-101 is safe, well tolerated and shows promise as a potential treatment option for progressive HGG and BCBM patients.

Without active delivery across the blood-brain barrier (BBB) the efficacy of doxorubicin in brain tumors is limited. 2B3-101, glutathione PEGylated liposomal doxorubicin, has been developed as brain-targeted chemotherapy. In preclinical studies, 2B3-101 showed a 5-fold enhanced doxorubicin brain-delivery versus pegylated liposomal doxorubicin (Doxil®). Patients with either solid tumor brain metastases or recurrent malignant gliomas were treated with 2B3-101 by a 90 min IV infusion q21d to assess (1) safety, tolerability and MTD (2) pharmacokinetics (PK) and (3) preliminary anti-tumor activity of 2B3-101, determined by brain MRIs and body CTs, according to RANO or RECIST criteria. Doses were escalated in cohorts of 3-6 patients. 28 patients received 2B3-101 at doses of 5-70 mg/m2, without DLTs. 15 patients had brain metastases from solid tumors, and 13 patients had recurrent malignant gliomas WHO grade III (3) or IV (10). Twenty-three patients (82%) received ≥ 3 prior therapies before 2B3-101. No cardiac or CNS toxicity was observed. At doses of ≥ 40 mg/m2, adverse events ≥ grade II (CTCAE v.4.0) were: neutropenia (21%), thrombocytopenia (4%), mucositis (4%), and PPE (18%). Grade I-II infusion reactions were observed in 4/28 patients, being transient and manageable with standard treatments. Pharmacokinetic data showed non-linear exposure of 2B3-101 without signs of accumulation with repeat dosing. Due to one case of thrombocytopenia grade IV at 60 mg/m2, this cohort was expanded to 6 patients. 2B3-101 demonstrates preliminary antitumor activity in the brain. At doses of ≥ 40 mg/m2, 12 of 16 patients demonstrated stable disease as best outcome (brain metastases (n=4), glioblastoma (n=5) and grade III glioma (n=3)). 2B3-101 also showed responses in extracranial disease. 2B3-201 is safe and well tolerated up to 70 mg/m2 q21d in both brain metastases from solid tumors and recurrent malignant gliomas. A dose intensity of 15 mg/m2/week was sustainable over at least 4 cycles. Based on this information, the phase IIa dose expansion study is currently ongoing with treatment regimens of 50 mg/m2 every 3 weeks for patients with brain metastases and 60 mg/m2 every 4 weeks for patients with recurrent malignant glioma. ClinicalTrials.gov NCT01386580, sponsored by to-BBB technologies BV. Citation Format: Pieter J. Gaillard, Bojana Milojkovic Kerklaan, Philippe Aftimos, Sevilay Altintas, Agnes Jager, Werner Gladdines, Fredrik Lonnqvist, Patricia Soetekouw, Henk Verheul, Ahmad Awada, Jan Schellens, Dieta Brandsma. Phase I dose escalating study of 2B3-101, glutathione PEGylated liposomal doxorubicin, in patients with solid tumors and brain metastases or recurrent malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT216. doi:10.1158/1538-7445.AM2014-CT216

The objective of the present investigation was to characterize the in vivo EEG effects of (synthetic) neuroactive steroids on the basis of a recently proposed mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model. After intravenous administration, the time course of the EEG effect of pregnanolone, 2beta-3alpha-5alpha-3-hydroxy-2-(2,2-dimethylmorpholin-4-yl)-pregnan-11,20-dione (ORG 21465), 2beta-3alpha-5alpha-21-chloro-3-hydroxy-2-(4-morpholinyl)-pregnan-20-one (ORG 20599), and alphaxalone was determined in conjunction with plasma concentrations in rats. For each neuroactive steroid the PK/PD correlation was described on the basis of a two-compartment pharmacokinetic model with an effect compartment to account for hysteresis. The observed concentration EEG effect relationships were biphasic and characterized with a mechanism-based pharmacodynamic model, which is based on a separation between the receptor activation process and the stimulus-response relationship. A single unique biphasic stimulus-response relationship could be identified for all neuroactive steroids, which was successfully described by a parabolic function. The receptor activation process was described by a hyperbolic function. Estimates for the maximum activation (e(PD)) were similar for the different neuroactive steroids but values of the potency estimate (K(PD)) ranged from 157 +/- 16 ng. ml(-1) for pregnanolone, 221 +/- 83 ng. ml(-1) for ORG 20599, and 483 +/- 42 ng. ml(-1) for alphaxalone to 1619 +/- 208 ng. ml(-1) for ORG 21465. A statistically significant correlation was observed between the in vivo potency and the IC(50) in an in vitro [(35)S]t-butylbicyclophosphorothionate binding assay (r = 0.91). It is concluded that the new PK/PD model constitutes a new mechanism-based approach to the quantification of the effects of (synthetic) neuroactive steroids in vivo effects. The results show that the neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA(A) receptor in vivo.

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.