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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.

Current treatment of brain cancer is hampered by few effective treatment options and characterized by low survival rates. Some advanced drug delivery systems carrying small molecules are currently being developed and may have a major positive impact in the overall outcomes of the treatment regimens. We will discuss the benefits of liposomal formulations, the most commonly used nanoparticles for drug delivery. Liposomal formulation of chemotherapeutics can improve the efficacy and reduce the side effects of the chemotherapy by improving the drug release, pharmacokinetic and biodistribution profile. Uptake of these nanoparticles into the brain is however limited due to the presence of a blood–brain and blood–tumor barrier. By combining safe targeting ligands and receptors with well-known and safe nanocarrier technologies, brain-targeted liposomes may overcome these barriers and result in new and effective chemotherapeutic drugs for clinical use. Examples and practical issues involved in liposomal formulation of chemotherapeutics are discussed.

Methylprednisolone (MP) pulses are the mainstay for relapse therapy in multiple sclerosis (MS). To improve the efficacy of treatment and reduce the side effects of MP, a long circulating brain-targeted formulation was developed; glutathione polyethylene glycol (PEG)ylated liposomal MP (2B3-201). Here we investigate the efficacy of 2B3-201 in murine myelin oligodendrocyte induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of MS. After disease onset, mice were randomized to receive either saline, three injections of free MP (high dose MP, 100mg/kg i.v.), two injections of free MP (low dose MP, 10mg/kg; i.v.), or two injections of 2B3-201 (10mg/kg i.v.). Treatment with a low dose of 2B3-201 significantly reduced the severity of EAE as compared to saline control, similar to treatment with high dose free MP, while a low dose of free MP was not effective. In a histological analysis of the spinal cord, treatment with 2B3-201 significantly decreased T cell as well as macrophage/microglia infiltration in the CNS by about 50%. Moreover, application of a low dose of 2B3-201 or a high dose of free MP reduced the amount of astrocyte activation as well as the extent of axonal loss and also demyelination in spinal cord lesions as compared to low dose MP or sham treatment. In summary, in the murine MOG-EAE model of MS, a glutathione PEGylated liposomal formulation of MP (2B3-201) is clinically and histologically as effective as free MP at one tenth of the dosage as well as at a lower application frequency and clearly more effective than the same dosage of free MP. These positive proof-of-concept efficacy studies warrant further development of 2B3-201 for the treatment of neuroinflammatory conditions such as MS.

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

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.

Treatment options for brain cancer are limited and overall prognoses are poor. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is essentially based on the already marketed pegylated liposomal doxorubicin (Doxil), with an additional glutathione (GSH) coating to safely enhance delivery across the blood-brain barrier. In a GLP safety study 2B3-101 was administered by intravenous bolus injection on days 1, 15 and 29 to Wistar rats at 1.75, 3.5 and 7 mg/kg. Doxil (7 mg/kg), empty GSH-PEG-liposomes, and vehicle were included, resulting in 6 groups (10 animals/sex/group). Additional animals were allowed 4 weeks of recovery or were used for toxicokinetic analysis. From observations during the in-life part of the study, as well as after histopathological investigations, no major differences were noted between 2B3-101 and Doxil at 7 mg/kg q14dx3. No treatment-related changes in the brain were observed neither after repeated 2B3-101 exposure, nor after treatment with empty GSH-PEG liposomes. In addition, 2B3-101 did not result in doxorubicin-related toxicity in heart tissue. After 1st and 3rd administration of 7 mg/kg, plasma AUC values were 10-44% higher for Doxil when compared to 2B3-101, while C0 values were considered similar for both drug substances. Apparent half-lives for Doxil were 36.1 and 32.6 hours in males and females after the 3rd administration, respectively. For 2B3-101 these values were slightly shorter at 30.0 and 28.8 hours in males and females, respectively. The doxorubicin brain/plasma ratio showed retention of both 2B3-101 and Doxil after repeated doses, where 2B3-101 resulted in significantly higher doxorubicin retention in the brain 2 weeks after the 3rd administration (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5687. doi:1538-7445.AM2012-5687