Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 Test Product Study Sponsor: Clinical Trial Results Synopsis Bayer HealthCare Study Number: (307976) Study Phase: II Study Design Description NCT Official Study Title: Phase 2 study of ZK-Epothilone (ZK-Epo; ZK ) plus prednisone as first-line chemotherapy in subjects with metastatic androgen-independent prostate cancer Therapeutic Area: Oncology Name of Test Product: SName of Active Ingredient: Dose and Mode of Administration: Reference Therapy/Placebo Reference Therapy: None Dose and Mode of Administration: Sagopilone (ZK , BAY ) Prednisone Sagopilone Prednisone Dose: ZK : 16 mg/m 2 administered at 3-week intervals (maximum dose of 32 mg). Prednisone: 10 mg (5 mg tablet orally twice a day), self administered. Prednisone was started on Day 1 and continued through the duration of therapy (i.e., Day 21 of the last treatment course). Mode of Administration: ZK : 3-h intravenous (i.v.) infusion Prednisone: Oral Not applicable Duration of Treatment: Subjects were scheduled to receive 2-6 treatment courses at every 3- week intervals; in case of sustained clinical benefit, more than 6 treatment courses were allowed to be administered. Studied period: Date of first subjects first visit: 01 AUG 2006 Date of last subjects last visit: 21 DEC 2009 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: Not applicable Amendment No.1, dated 05 FEB 2007, described the following changes: Specification of the procedures in subjects who received more than 6 treatment courses, including an extra flow chart of the schedule of evaluations. Explanation of allowed alternative calculations of body surface area (BSA). Specification that the results had to be within 5% of the Du Bois and Du Bois formula. Page 1 of 9

3 The list of permitted concomitant medication was extended by luteinizing hormone-releasing hormone (LHRH)-analogues, because these drugs are expected in subjects without orchiectomy. Clarification that the tumor scans in subjects with measurable disease were to be performed with any computed tomography (CT), not only with spiral CT. Specification that confirmatory scans had to be done within 6 weeks of the first partial response (PR) or complete response (CR), if applicable. Specification that the data from additional courses (beyond Course 6) were to be analyzed separately. Amendment No. 2, dated 18 DEC 2007, described the following changes: Addition of information allowing subjects to have remote visits for Day 8 and Day 15. Amendment No. 3, dated 02 MAY 2008, described the following changes: The adaptation of Response Evaluation Criteria in Solid Tumors (RECIST) criteria in the protocol to published RECIST crieria. The RECIST criteria in the protocol required for best overall response stable disease (SD) two determinations of SD or better before progression. The published RECIST criteria state that for a best overall response status of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. Definition of algorithm for best overall response, PR and CR. Reconfirmation of these assessments had to be done within 4 weeks and not within 6 weeks as described in the protocol. Change of calculation basis of primary analysis set (PAS) from full analysis set (FAS) to per protocol set (PPS). As a result of the changed basis of the PAS, subjects with major protocol violations were now allowed to be replaced to ensure that sufficient subjects were to be included in the PAS both in Step 1 and Step 2. Specification of toxicity as reason for replacement. In the protocol, the term toxicity was not specified to be related to the study drug. It was specified that only subjects that terminated the study before the first PSA efficacy evaluation (Day 21 of Course 1) due to study drug-related toxicity were excluded from replacement. Introduction and definition of progression-free survival (PFS) and overall survival included as new secondary efficacy variable in this study. Introduction of an interim analysis after last subject last visit for availability of reliable study data at the earliest possible date. Extension of the safety follow-up for subjects with possibly drug-related toxicities CTCAE grade 2 from 3 to 6 months after last dose of ZK End-of-efficacy observation period limited to 12 months after "last subject last treatment." Page 2 of 9

4 Abnormal laboratory values were only considered as adverse events (AEs) if they met predefined criteria (e.g., causing the subject to withdraw from the study, requiring treatment or causing apparent clinical manifestations, or judged relevant by the investigator). Study Center(s): This study was conducted in 2 countries with 18 centers: 13 in USA and 5 in Argentina. Methodology: This was a prospective, single-arm, multi-center, Phase 2 study of ZK in combination with prednisone. The study was planned according to the Simon's two-step design. If results for the first 13 evaluable subjects met a pre-defined criterion (i.e., 3 prostate-specific antigen [PSA] responders), recruitment was to continue until 46 evaluable subjects were available. The outcome of the study was considered positive if PSA response was observed in at least 13 of the 46 subjects. During the main part of the study, 2-6 treatment courses were planned for each subject, with prolongation of the treatment, if indicated. The conduct of each course was similar, with 3 visits scheduled per course. Planned end-of-treatment (EOT) evaluations were conducted days after the last dose of the study drug. Additional follow-up evaluations were required for subjects who met any of the following criteria at the planned or additional EOT visits: Safety follow-up: Subjects with neurotoxicity grade 2 and subjects with possibly drug-related toxicity grade 2 (excluding alopecia) were followed-up. Follow-up Visit 1 (42 ± 3 days after last dose), follow-up Visit 2 (63 ± 3 days after last dose), follow-up Visit 3 (84 ± 3 days after last dose), and extended-safety follow-up was planned where applicable. For subjects with PD whose toxicities had resolved at an earlier follow-up visit, no further follow-up was required. For all the subjects whose toxicity had resolved at follow-up Visit 3, no further safety follow-up was required. For all the subjects with unresolved toxicity at follow-up Visit 3, at least 1 additional safety follow-up visit was required. This visit was not to occur later than 6 months after EOT assuming toxicity had not resolved to a grade of <2 prior to 6 months after EOT. Efficacy follow-up: Subjects with response or stable disease (subjects who had not had PSA progression or other evidence of disease progression) were followed up approximately every 3 months until PD, any new prostate cancer therapy, or 12 months after "last subject last treatment." Safety assessments: Safety was assessed by AEs, serious AEs (SAEs), standard laboratory tests (hematology, serum chemistry, urinalysis, coagulation), 12-lead electrocardiogram (ECG), vital signs (body temperature, heart rate, systolic blood pressure [SBP] and diastolic blood pressure [DBP]), neurological score (Scottish Gynaecological Cancer Trials Group [SGCTG] neurotoxicity score), and World Health Organization (WHO) performance status. Blood and urine samples for laboratory tests were collected at screening, weekly (Days 1, 8, and 15) during all courses, EOT visit, and at follow-up visits. ECGs were performed in all courses on pre-dose administration and at EOT visit. An ECG was only to be performed at Course 6 on Day 15 if Page 3 of 9

5 Indication/Main Inclusion Criteria: the subject continued on treatment after Course 6. Physical examination was done in all courses on pre-dose administration, and Course 6, Day 15 (only if the subject continued on treatment after Course 6), EOT visit, and at follow-up visits. SGCTG neurotoxicity score was assessed at screening, and pre-dose administration, Course 6, Day 15 (only if the subject continued on treatment after Course 6), EOT visit, and at follow-up visits. The questionnaire had 2 segments: in the "Patient Neurological Questionnaire" segment the subject provided details on potential tingling/numbness, burning/discomfort, and weakness for feet and/or fingers and in the "Structured Neurological Assessment" segment the investigator performed the assessments on two-point discrimination, "Romberg" test, tendon reflexes, and vibration test. WHO performance scores grade 0-5 (grade 0 = able to carry out all normal activity without restriction, grade 1 = restricted in physically strenuous activity but ambulatory and able to do light work, grade 2 = ambulatory and capable of all self-care but unable to carry out any work. Up and about more than 50% of waking hours, grade 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours, grade 4 = completely disabled. Cannot carry out any self-care. Totally confined to bed or chair, grade 5 = dead) were assessed on Day 1 of each course and Day 21 of Course 6 in subjects who continued after treatment after Course 6 andat EOT visit Efficacy assessments: Total PSA levels were assessed by a central laboratory at screening and on Day 21 of each treatment course during the main study and at each of the follow-up visits. Tumor response were assessed using CT scan or magnetic resonance imaging (MRI) as clinically appropriate. Evaluations were based on a modrecist. The scans were done at screening (within 4 weeks prior to first dose and if sufficient for modrecist evaluation) and, if the subject continued on study, then every 2 cycles until tumor progression. Overall response of CR or PR must be confirmed with a 2 nd radiological assessment 6 weeks after the 1 st assessment. Not repeated for subjects with progressive disease (PD) that has been confirmed by CT or MRI scan. Indication: Metastatic androgen-independent prostate cancer Main inclusion criteria: Males aged 18 years and older. Histological or cytological confirmed adenocarcinoma of the prostate. Metastatic disease (any T, any N, M1 stage). Serum testosterone <50 ng/ml (ongoing treatment with LHRH analogues or orchiectomy). Progression of disease despite adequate androgen-inhibiting hormone therapy, demonstrated by rising PSA on at least 2 consecutive measurements taken at least 7 days apart. The last measurement had to be 50% greater than the lowest PSA value achieved under the last previous treatment and 5 ng/ml. PSA value at screening (4-6 weeks after cessation of antiandrogen treatment) had to continue to be elevated. Page 4 of 9

6 WHO performance status 0-2. Only previous systemic treatment as endocrine therapy. Subjects with a previous cytotoxic chemotherapy for prostate cancer and subjects with an inadequate washout period for previous antiandrogen treatment were excluded. Study Objectives: Primary: To investigate the efficacy of ZK plus prednisone in subjects with androgen-independent prostate cancer (AIPC) who had not had previous chemotherapy. Secondary: Evaluation Criteria: To evaluate the safety and tolerability of ZK Efficacy (Primary) The proportion of subjects with PSA response, where PSA response was defined as a decrease of 50% in comparison with baseline (Day 1 of Course 1), with the response maintained for at least 28 days. If PSA response was established, a subject was referred to as a "PSA responder. Efficacy (Secondary) Time to progression: Defined as time from the assignment to treatment (date of enrollment to treatment phase) to the first evidence of objective disease progression, symptomatic deterioration, or death from tumor at any time point or PSA progression after a minimum of 2 courses of ZK Duration of PSA response: Defined as the time between the first date of PSA response and the first date of PSA progression. Progression-free survival: Defined as time from assignment to treatment (date of enrollment to study treatment phase) to first evidence of objective disease progression, symptomatic deterioration, or death or PSA progression after a minimum of 2 courses of ZK Time to PSA progression: Defined as time from assignment to treatment (date of enrollment to treatment phase) to first evidence of PSA progression. Overall survival: Defined as time between assignment to treatment (date of enrollment to treatment phase) and death. Proportion of subjects with objective response (defined as the "best overall response" of PR or CR from the start of study treatment through Day 21 of Course 6 [subjects who continued treatment beyond 6 courses] or the EOT visit [subjects who received no more than 6 courses]; if objective response was established, a subject was referred to as an "objective responder") and duration of objective response (defined as time from first date that confirmed CR or PR was established as "best overall response" [whichever status was recorded first] to first date that recurrence or overall response of PD was documented) were evaluated only in subjects with measurable disease. Safety: AEs according to the common terminology criteria for adverse events (CTCAE 3.0), neurological score (Scottish Gynaecological Cancer Trials Group [SGCTG] neurotoxicity score), WHO performance status, 12-lead electrocardiogram (ECG), vital signs (body temperature, heart Page 5 of 9

7 rate, SBP, DBP), and laboratory examinations (serum chemistry, hematology, coagulation, urinalysis) were evaluated. Statistical Methods: The statistical analysis sets are defined as follows: Full-analysis set: All subjects assigned to study treatment Safety set (SAF): All FAS subjects with at least 1 intake of study drug and was to be used for the analyses of the safety variables Per-protocol set: All FAS subjects without major protocol deviation Primary analysis set: Step 1-The first 13 PPS subjects for whom the primary efficacy variable was assessable Step 2-The next 33 PPS subjects for whom the primary efficacy variable was assessable The efficacy variables were analyzed in the FAS, in the PPS, and in the PAS. The analysis of the primary efficacy variable in the PAS was to be considered as the primary analysis, even if this choice led to a more optimistic conclusion than the corresponding analysis in the FAS or PPS. In general, all variables measured on a metric scale were presented by descriptive statistics; categorical and binary variables were displayed using frequency tables. Efficacy (Primary): The primary efficacy variable (proportion of subjects with a PSA response) was analyzed using the Simon's two-stage design. The primary efficacy analysis included testing a null hypothesis that the PSA response rate was 0.20 vs. an alternative hypothesis that the PSA response rate was >0.20 (one-sided type-one error rate of 0.10). The PSA response rate and its confidence interval (CI) were calculated. Frequency tables were given by time point for overall assessment of response. Efficacy (Secondary): For all time-to-event variables, Kaplan-Meier estimates for survival probabilities including 95% CI were calculated. Safety: Safety variables were summarized by means of descriptive statistics and/or frequency tables as appropriate. A complete list of all AEs listed by Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and coded using the MedDRA, Version The incidence rates of AEs and SAEs were summarized. CTCAE, Version 3.0, was used to grade AEs. Neurotoxicity was ordinally scaled from grade 0 (best grading) to grade 5 (worst grading/death) in 6 levels.changes in SGCTG neurotoxicity score were presented by descriptive statistics. A Kaplan-Meier analysis was to be performed for the time to first peripheral neuropathy (PNP). Time to first PNP was defined as the time between assignment to treatment and the first date of PNP. Patients who did not experience PNP were to be censored at the last infusion date +21 days or the last day on the study, whichever came first. Number of Subjects: Planned: 46 subjects Analysed: 53 subjects Page 6 of 9

8 Results Summary Subject Disposition and Baseline Study Results Of the 70 screened subjects, 53 were assigned to treatment and received at least 1 treatment course. All of the treated subjects were included in the SAF and the FAS. These 53 treated subjects constitute both the FAS and SAF. Five subjects had major protocol violations. Thus, the PPS consisted of 48 subjects. Based on the PPS, the first 46 evaluable subjects were included in the PAS. The study population (FAS) consisted of 41 Caucasian and 6 Black and 6 Hispanic men aged between 48 and 86 years (median: 66.0 years). All of them had a confirmed diagnosis of adenocarcinoma of the prostate. At treatment start, the median disease duration was 3.9 years and ranged from 0.4 to 18.1 years. About 60% of the subjects had T2 or T3 disease at first diagnosis; the maximum number of affected lymph nodules was 2; and nearly 30% of the subjects were free of metastases. At study entry, all of the subjects had developed metastatic disease (M1) as required per protocol. The subjects WHO performance status was 0 or 1 in about 90% of the cases. Fifteen of the 53 treated subjects (28.3%) discontinued treatment before Course 6, 13 (24.5%) due to AEs and most (11 subjects) due to neuropathy. One subject withdrew his consent and another was discontinued from treatment because of non-compliance. A total of 303 treatment courses were administered to the subjects, with a median number of 5 courses per subject. The mean value of the individual mean dose during the first 6 cycles was 15.1±1.4 mg/m 2. The mean dose intensity was 94 ± 9%. Thus, the treatment compliance was high. Dose postponements and/or dose reductions occurred in about 30% of the study population and were mostly due to AEs. Results Summary Efficacy The primary efficacy variable, the proportion of PSA responders, was analyzed in 46 subjects in the PAS. PSA response was defined as 50% reduction in PSA levels compared to baseline (Day 1 of Course 1) value, from the start of the study treatment through Day 21 of Course 6 or the EOT visit in the event of premature discontinuation. There were 3 responders among the 13 subjects in the PAS for Stage 1. Hence the study was continued into Stage 2. Fourteen more responders were observed in the next 33 evaluable subjects leading to a total of 17 responders (37.0%) in the PAS (Table 1). To conclude success, a total of at least 13 responders were required according to Simon s two-stage design. Therefore, it can be concluded that the response rate was significantly higher than p0=20%. The response probability was estimated to be , with an 80% CI ranging between and (Blyth-Still-Casella method). Table 1: Number of subjects with PSA response (primary analysis set) In addition to the 17 PSA responders in the PAS, 2 further subjects in the FAS and PPS met the criteria for PSA response, which resulted in PSA response rates of 35.8% and 39.6%, respectively. One subject fulfilled the criteria for PSA response about 2 months after EOT visit and was, therefore, not considered as a responder in the primary analysis. The proportion of subjects who had a decrease in PSA levels by at least 30% within 3 months of starting the study was evaluated in a further analysis. The results showed that 63.0% of subjects in the Page 7 of 9

9 PAS, 64.6% of subjects in the PPS, and 67.9% of subjects in the FAS met this criterion. Analysis of the secondary efficacy variables was based on the PPS and on the FAS; only the rate of objective responders was additionally analyzed in the PAS. The rate of objective tumor response was 33.3% (12/36 subjects) in the PPS, 32.5% (13/40 subjects) in the FAS, and 32.4% (11/34 subjects) in the PAS. One of the subjects achieved CR, the others PR. Table 2 shows a summary of the results for the time-to-event variables as obtained with the Kaplan-Meier product limit method. The median duration of objective response and the corresponding CI could not be calculated, because only 3 of the 12 responders experienced a relapse or disease progression during study observation. The same applied to the parameter overall survival, as only 4 subjects died. Table 2: Kaplan-Meier analysis of time-to-event variables (per-protocol set) Results Summary Safety An overview on the numbers of subjects with specific types of AEs during the treatment period is shown in Table 3. Table 3: Number of subjects with AEs during the treatment period (safety set) All of the 53 subjects (100.0%) reported at least 1 AE during the treatment period of the study. In 33 of the 34 subjects (97.1%) in follow-up, the AEs occurred or were still present during the follow-up. In most of the subjects (84.9%) at least 1 AE had not resolved by the end of the study. Overall, 4 subjects died: 3 from PD (which was not to be reported as an SAE) and 1 from gastrointestinal hemorrhage (which was unrelated to ZK administration). The highest incidences of AEs were observed for peripheral neuropathy (94.3%), fatigue (54.7%), pain in extremity (47.2%), constipation (24.5%), nausea (24.5%), and muscular weakness (20.8%). Drug-related AEs occurred in 52 subjects (98.1%). As with all AEs, the highest incidences of drug-related AEs were seen for peripheral neuropathy (92.5%), fatigue (50.9%), and pain in extremity (43.4%). More than half of the subjects (58.5%) experienced at least 1 AE of CTCAE grade 3, and in all of them at least 1 of these AEs was rated as drug-related. AEs of CTCAE grade 4 occurred in 6 subjects (11.3%) and of CTCAE grade 5 in 1 subject (gastrointestinal hemorrhage, see above). The highest incidences of AEs of CTCAE grade 3 were reported for peripheral neuropathy (22.6%), pain in extremity (7.5%), fatigue (5.7%), back pain (5.7%), and syncope (5.7%). Page 8 of 9

10 Events indicating neurotoxicity (pooled under term peripheral neuropathy) were expected to be the most clinically relevant events in the study. AEs indicating neurotoxicity were frequent and occurred in 94.3% of the subjects during the treatment period. In 88.2% of the 34 subjects in follow-up, the AEs occurred or were still present during the follow-up. The maximum intensity of such AEs was CTCAE grade 1 or 2 in the majority of subjects (71.7%). The remaining subjects (22.6%) experienced at least 1 AE indicating neurotoxicity of CTCAE grade 3. In all but 1 subject, these events were classified by the investigators as drug-related. The median time to first AE indicating neurotoxicity was estimated to be 8 days (95% CI: 7-21 days). Twenty subjects (37.7%) prematurely discontinued study medication due to AEs, 16 of them due to peripheral neuropathy, which was serious in 1 subject. The other AEs leading to treatment termination were ejection fraction decreased (SAE), postural hypotension (non-serious AE), fatigue (non-serious AE), and humerus fracture and syncope (both SAEs in 1 subject). Overall, 10 subjects (18.9%) experienced a total of 19 SAEs during the treatment period and/or follow-up. The only SAE that occurred in more than 1 subject was pulmonary embolism (n=2; 1.9%). In 4 of the 10 subjects concerned, at least 1 SAE was classified by the investigators as drug-related (1 case each of pulmonary embolism, ejection fraction decreased, dizziness, and paresthesia). Most changes in laboratory values were from common toxicity criteria (CTC) grade 0 to CTC grade 1 or 2. Changes to CTC grade 4 were seen on 15 occasions, and all of these changes were from CTC grade 0. The highest incidence rate of change to CTC grade 4 was observed with creatinine and low calcium levels (3 subjects each). All other changes to CTC grade 4 occurred in a maximum of 2 subjects. Mean and median values for vital signs (heart rate and systolic and diastolic blood pressure) were inconspicuous at all time points measured, and no systematic trends were observed. Overall, 1 out of 53 subjects (1.9%) was reported with an AE of grade 1 "body temperature increased" at the end of study. Abnormal findings according to the overall ECG interpretation were already present in about half of the subjects at screening, and this proportion remained constant throughout the study. None of the abnormalities observed on the ECG was assessed as clinically relevant. Analysis of the SGCTG neurological questionnaire showed that the total mean scores increased over the course of the study by approximately 6 score points, from 1.3 ± 1.5 at screening to 7.1 ± 3.4 at end of the study, indicating worsening of neurological symptoms. A trend toward a worsening of the subjects general condition was also reflected in the course of the frequency distributions of the grades of the WHO performance status. At the screening visit, only 4 subjects (7.5%) had a WHO performance status of grade 2, all others (92.5%) of grade 0 or 1. By the end of the study, the proportion of subjects with a WHO performance status of grade 0 or 1 had decreased to 35.8%. However, none of the subjects deteriorated to grade 3, and only 1 subject to grade 4. Conclusion(s) This study demonstrated proof of concept of ZK plus prednisone as first-line chemotherapy in men with metastatic androgen-independent prostate cancer. The regimen is feasible and the toxicities were manageable. Publication(s): None at the time of report creation Date Created or Date Last Updated: 14 OCT 2014 Date of Clinical Study Report: 28 JUN 2010 Page 9 of 9