Referring to Part of the Dossier. Protocol No.: DEP1501 EudraCT/IND No.:

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1 2. SYNOPSIS Name of Sponsor: Mundipharma Research Limited Name of Finished Product: epocyte Name of Active Ingredient: Cytarabine Liposome Injection INIVIUAL STUY TABLE Referring to Part of the ossier Volume: Page: Protocol No.: EP1501 EudraCT/IN No.: (For National Authority Use Only) Title of the Study: A phase I randomised multi-centre study to demonstrate the safety of Whole Brain Radiotherapy (WB) concomitant to intrathecal liposomal cytarabine (epocyte ) versus WB and sequential epocyte for the treatment of solid tumour neoplastic meningitis (STNM) with or without brain metastasis. Investigator(s): Univ. Prof. r. Meinhard Nevinny-Stickel, Medical University Innsbruck, Univ. Clinic for Radiation Therapy, Innsbruck, Austria et al. One site in Germany; 5 sites in Austria. A further 3 sites were initiated but did not enrol any subjects. Publication (Reference): None Study ates: 28-Jan-2011 to 30-Oct-2012 Study Status: Terminated Phase of evelopment: Phase 1 Objectives: The primary objective was to demonstrate the safety of WB concomitant to epocyte versus WB and sequential epocyte in terms of: extent of exposure, AEs, clinical laboratory evaluations, vital signs, Quality of Life Questionnaires (European Organisation for Research and of Cancer [EOC] Quality of Life Questionnaire [QLQ]-C30 and EOC QLQ-BN20). The secondary objective was to explore the efficacy of both treatment schedules in terms of: Overall Response Rate (ORR), Progression Free Survival (PFS), Time to Neurological Progression (TNP) and Overall Survival (OS). Methodology: Study EP1501 was a multi-site, multiple-dose, randomised, open-label, parallel-group study in subjects with solid tumour neoplastic meningitis conducted to assess the safety of WB concomitant to epocyte 50 mg (test treatment) versus WB with sequential epocyte 50 mg (reference treatment). Page 1 of 5

2 Study esign Graphic: Induction Phase Screening 21 days Induction Test R Reference Wk R = randomisation = radiotherapy. is for 5 days on, 2 days off each week. = epocyte Maintenance Phase Maintenance Phase Follow Up Test Reference Wk Page 2 of 5

3 Number of Subjects: It was planned to enrol 30 subjects with STNM, with or without brain metastasis. ue to the patient population being examined, recruitment was expected to be challenging, however, despite recruitment already being extended once, recruitment into the study was terminated on 23 AUG Unfortunately, many of the subjects only received study treatment for a short period of time before withdrawing prior to study completion, mainly due to progression of their underlying disease. This resulted in a lack of data being generated from the small number of successfully recruited patients making it difficult to draw any conclusions from the study. Actual subject numbers: enrolled population (19 subjects), randomised and safety populations (18 subjects; 10 in the concomitant WB group, 8 in the sequential WB group). One subject (subject no in the sequential WB group) completed the study according to the protocol (i.e. completed the induction and maintenance phase according to the dosing schedule). Indication and Criteria for Inclusion: Subjects were aged 18 years or older, male or female and had STNM as demonstrated by a positive lumbar Cerebrospinal Fluid (CSF) cytology (obtained within 21 days prior to treatment initiation), or characteristic signs and symptoms of neoplastic meningitis PLUS an Magnetic Resonance Imaging (MRI) indicating the presence of meningeal tumour (or Computerised Tomography (CT) scan if MRI was contra-indicated). Subjects were to be excluded if they had a CSF flow abnormality, had previously received WB or intrathecal (IT) treatment, or had brain metastases >3 cm diameter. Test, ose, and Mode of Administration: The treatments administered in the study were: epocyte sterile solution for IT injection: 10 mg of epocyte per ml (total study medication dose per administration = 50 mg) and WB. epocyte was supplied as a sterile solution for IT injection at a concentration of 10 mg/ml in 5 ml ready to use, single-use glass vials containing 50 mg of cytarabine. uring Week 1, WB with 3 Gy was administered on ays 1 and 2 and then with 1.8 Gy on the remaining 3 days of WB treatment. WB was given for 5 days out of 7 (i.e. no WB was to be given on a weekend). WB with 1.8 Gy was given for 5 days out of 7 during weeks 2, 3, and 4. Reference, ose, and Mode of Administration: The reference treatment was epocyte 50 mg IT given sequentially (starting in Week 5) after 4 doses of WB had been administered. Concomitant Medication Including Rescue: All other concomitant medications were allowed with the exception of other concurrent intrathecal drugs, including experimental drugs. uration of : Screening was performed within 21 days of first dose administration. The induction phase was 11 weeks for the reference treatment arm and 7 weeks for the test treatment arm. The maintenance phase was 20 weeks in both treatment groups. Follow-up lasted for up to 3 months for both treatment groups. Schedule: WB was administered for 5 days every week for 4 weeks commencing in Week 1. Induction Phase: Subjects in the Test arm received 4 doses of epocyte 50 mg IT given every 14 days commencing in Week 1. Subjects in the Reference arm received 4 doses of epocyte 50 mg IT given every 14 days commencing in Week 5 after completion of WB. Maintenance Phase: All subjects entered the maintenance phase of the treatment period and received a further 6 doses of epocyte 50 mg, one dose every 28 days (a total of 10 doses of epocyte 50 mg). Subjects commenced the maintenance phase of treatment in either Week 11 (Test ) or Week 15 (Reference ). At the end of treatment, subjects were followed up at monthly intervals to assess neurological status for a maximum of 3 months. Criteria for Evaluation: Efficacy Assessments: Efficacy was the secondary objective of this study and was assessed by ORR, PFS, TNP, and OS. Response assessments based on CSF cytology (if applicable) and neurological examination were performed at Week 5; response assessments based on CSF cytology (if applicable) MRI scan (or a CT scan performed only in case of contraindications for MRI), and neurological examination were performed at Week 11, Week 23, and Week 31. Response assessments based upon neurological examination, MRI, and CSF (only if available), were performed at early discontinuation/withdrawal. Safety: Safety was assessed by: Extent of exposure, AEs, clinical laboratory evaluations, vital signs, physical examination and Quality of Life questionnaires (EOC QLQ-C30 and EOC QLQ-BN20). Page 3 of 5

4 Statistical Methods: Analysis Populations: The enrolled population included all subjects who signed informed consent [19 subjects]. The safety population included all randomised subjects who received at least one dose of study drug or one dose of radiotherapy [18 subjects]. This population was used for the analysis of all data. The population was based on the actual treatment received (as treated). Efficacy Analyses: This study was prematurely terminated after 18 subjects had been randomised, therefore the statistical analysis of efficacy data was not carried out and efficacy data were listed only. Safety Analyses: Safety data were summarised descriptively by treatment group and overall for subjects in the safety population. In addition, all safety data were listed. Sample Size Rationale: The sample size was not determined on the basis of a formal sample size calculation but was based on the number of patients that could realistically be recruited from the target patient population. Results: Efficacy: ue to the early termination of this study, the sample size was not considered as sufficient for the analysis of efficacy endpoints. For that reason the statistical analysis of efficacy data was not carried out and no inferences regarding treatment differences in the efficacy data have been made. Safety: All 18 subjects included in the safety population reported at least one AE during the study. In this study, the most commonly occurring Preferred Term (PT) was headache (50% in both treatment groups). Other commonly occurring AEs were nausea (33.3%), alopecia (33.3%), increased C-reactive protein (27.8%), fatigue (27.8%), vomiting (27.8%) and vertigo (27.8%). A total of 230 AEs were reported during the study, of which approximately half (111) were considered by the Investigator to be related (unlikely, probably, possibly or definitely) to study medication. Four subjects overall (3 in the concomitant WB group; one in the sequential WB group) reported at least one AE which was categorised as Grade 4 at its worst severity and 5 subjects overall (2 in the concomitant WB group; 3 in the sequential WB group) reported at least one AE which was categorised as Grade 3 at its worst severity. However, most of these AEs were isolated cases reported by individual subjects and no overall difference between the treatment groups was observed. Only 3 PTs (leukopenia, general physical health deterioration and pulmonary embolism) were reported by 2 or more subjects at Grade 3 and/or 4. A pre-specified AE of special interest was arachnoiditis. Two subjects in the concomitant WB treatment group reported arachnoiditis. In both cases, arachnoiditis was considered probably related to study medication by the Investigator. Additional AEs of special interest, which were not pre-defined, were symptoms of systemic exposure to epocyte. One subject (no.1001/100103) reported AEs that may be characteristic of systemic exposure to epocyte (e.g. Hypokalaemia,leucopenia, and anaemia). Four deaths occurred during the study; 3 in the sequential WB group and one in the concomitant WB group. All deaths were considered to be not related or unlikely related to study treatment. The most common reason for discontinuing the study was progression of systemic disease (5 subjects; 3 in the concomitant WB group and 2 in the sequential WB group). The second most common reason for discontinuing the study was the subject s own choice (4 subjects; 2 in each group). Similar numbers of subjects in both treatment groups reported AEs that led to their discontinuation from the study (4 subjects in the concomitant WB group; 3 subjects in the sequential WB group). The majority of the AEs that led to discontinuation were in the nervous system disorders System Organ Class (SOC) (3 subjects overall) and general disorders and administration site conditions SOC (3 subjects overall). None of the PTs leading to discontinuation were reported by more than one subject in either treatment group. To conclude, numbers of subjects with AEs, related AEs, SAEs and related SAEs were comparable between the 2 treatment groups. The numbers of subjects with abnormal laboratory values and abnormal vital sign values were sporadic and there was no discernable trend related to treatment. Page 4 of 5

5 Conclusions: The nature and incidence of deaths, SAEs and discontinuations due to AEs reflect the general poor state of health and underlying disease of the subjects entered into this study. Subjects were required to have SSTM in addition to their primary tumour, and the majority of subjects had stage IV neoplastic meningitis at diagnosis. The early termination of this study resulted in limited data being collected, however, one subject completed the study according to the protocol (subject no. 1001/100103), who had a progression-free survival time of 331 days. This subject had been diagnosed with breast cancer 6 years prior to entering this study and was randomised to receive sequential WB and epocyte IT 50 mg. In this randomised, open-label study, the intrathecal administration of epocyte at the investigated dose level concomitant to WB treatment had a similar overall safety profile to sequential epocyte administration after WB treatment. Overall, the safety evaluation of the 2 dosing regimens did not demonstrate any unexpected toxicity, as the safety data collected from this study were similar to that of previous studies used to register epocyte as a marketed product. ate of the Report: 27-Nov-2013 Page 5 of 5