Open, Randomized Phase II Trial to Investigate the Efficacy and Safety of the PLK-1 Inhibitor BI 2536 in Patients With Advanced, Unresectable Pancreatic Cancer

Best objective response: Tumour assessment by independent review of tumour imaging by an external contract research organization (CRO) according to Response Evaluation Criteria In Solid Tumours (RECIST) after every second treatment course, including imaging (e.g. Computed tomography (CT), Magnetic resonance imaging (MRI)) and submission of image(s) to central imaging unit. Complete remission (CR): Disappearance of all target lesions for at least 4 weeks from the documentation of CR. Partial remission (PR): At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum Longest Diameter (LD). Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as references the smallest sum LD since the treatment started. No best response: includes all RECIST categories which are considered as failing to respond to therapy, e.g. progressive disease, death or unknown.

Time frame: Tumour measurements performed at screening (day -21 to -1), at the end of every other treatment period (2x 3 weeks), and at the end of the trial or when a patient concluded the trial, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 and who had an evaluation after baseline.

Best objective response: Tumour assessment by investigator assessment of tumour imaging according to Response Evaluation Criteria In Solid Tumours (RECIST) after every second treatment course, including imaging (e.g. Computed tomography (CT), Magnetic resonance imaging (MRI)) and submission of image(s) to central imaging unit. Complete remission (CR): Disappearance of all target lesions for at least 4 weeks from the documentation of CR. Partial remission (PR): At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum Longest Diameter (LD). Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest sum LD since the treatment started. No best response: includes all RECIST categories which are considered as failing to respond to therapy, e.g. progressive disease, death or unknown.

Time frame: Tumour measurements performed at screening (day -21 to -1), at the end of every other treatment period (2x 3 weeks), and at the end of the trial or when a patient concluded the trial, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 were considered, including patients who had been replaced for any reason. 4 patients did not have any evaluations after baseline.

The duration of overall response was measured from the time measurement criteria were met for complete remission (CR) or partial remission (PR) (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented, taking as reference for progressive disease the smallest measurements recorded since the treatment started. Tumour assessment by independent review of tumour imaging by an external CRO according to RECIST after every second treatment course, including imaging (e.g. CT, MRI) and submission of image(s) to central imaging unit.

Time frame: Tumour measurements performed at screening (day -21 to -1), at the end of every other treatment period (2x 3 weeks), and at the end of the trial or when a patient concluded the trial, up to 357 days.

Population: All patients who received at least 1 single dose of BI 2536, who had an evaluation after baseline and who had an unconfirmed best overall response by independent review.

Number of participants with carbohydrate antigen 19-9 (CA19-9) response rate was defined as the proportion of patients with a decrease in CA19-9 serum levels of ≥25% from baseline in 2 consecutive measurements performed ≥4 weeks apart. Additionally, the proportion of patients with an improved response was assessed, i.e. a decrease in CA19-9 of ≥75% at 2 consecutive measurements ≥4 weeks apart. By definition, a positive CA19-9 response could not occur in patients with normal baseline CA19-9 levels.

Time frame: Blood samples for CA19-9 analysis were collected on Days 1, 2, and 5 of each treatment period, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 were considered, including patients who had been replaced for any reason. 19 patients did not have elevated CA19-9 levels at baseline and could not be included.

Dose limiting toxicity (DLT) was defined as drug-related CTCAE (Common Terminology Criteria for Adverse Events, version 3.0) grade ≥3 non-haematological toxicity (excluding untreated nausea, vomiting or diarrhoea), drug related CTCAE grade 4 neutropenia for ≥7 days and / or complicated by infection of CTCAE grade 4, or drug related CTCAE grade 4 haematological toxicity other than neutropenia.

Time frame: Tumour measurements performed at screening (day -21 to -1), at the end of every other treatment period (2x 3 weeks), and at the end of the trial or when a patient concluded the trial, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 were considered, including patients who had been replaced for any reason. 1 participants did not experience any adverse event and was not included in the analysis.

Number of participants with incidence and intensity of Adverse Events (AE) graded according to CTCAE. Intensity of AEs was scaled according to US-NCI CTCAE, version 3.0. Severity grades 1 to 5 were based on the following general guidelines, with unique clinical descriptions of severity for each AE: * Grade 1 Mild * Grade 2 Moderate * Grade 3 Severe * Grade 4 Life-threatening or disabling * Grade 5 Death

Time frame: From first administration until 21 days after the day of last administration, up to 16 cycles, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 were considered, including patients who had been replaced for any reason. 1 patient did not experience any AE and was not included in the endpoint.

One-year survival was defined as survival at 1 year after randomisation. For the cohort of first line patients, this time point coincided with the beginning of treatment with the Trial drug. For second line patients, 1 year survival was defined as 1 year after the start of the previous first line treatment for pancreatic cancer.

Time frame: 1 year, see description for detailed definition of the time frame.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 were considered, including patients who had been replaced for any reason.

Overall survival (OS) was the time from first treatment until death. If there was no occurrence of death or progression until the last follow-up of the trial, the time was to be censored at the date of last trial visit. OS was analysed with the Kaplan-Meier method for each of the treatment arms. Kaplan-Meier estimates and confidence intervals were tabulated at specific points in time. Greenwood's variance estimate was used to form confidence intervals. The secondary endpoint One-year survival was integrated into the secondary endpoint overall survival.

Time frame: From first treatment till the end of the trial or when a patient concluded the trial, up to 336 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 were considered, including patients who had been replaced for any reason.

Progression free survival (PFS) was defined as the duration of time from randomisation to time of progression or death. For patients without documented progression at the time of analysis, PFS was censored as the total observation time without new anti-cancer therapy. PFS was analysed with the Kaplan-Meier method for each of the treatment arms. Kaplan-Meier estimates and confidence intervals were tabulated at specific points in time. Greenwood's variance estimate was used to form confidence intervals. Progressive disease: At least a 20% increase in the sum of Longest Diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions.

Time frame: Tumour measurements performed at screening (day -21 to -1), at the end of every other treatment period (2x 3 weeks), and at the end of the trial or when a patient concluded the trial, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 were considered, including patients who had been replaced for any reason.

Quality of life (QOL) was measured using the widely used and validated measure the European Organization for Research and Treatment - Quality of Life Questionnaire (EORTC QLQ-C30), based on questions 29 How would you rate your overall health during the past week? and 30 How would you rate your overall quality of life during the past week?, scored between 1 (very poor) to 7 (Excellent).

Time frame: Data from the last available questionnaire for each patient. Questionnaires were taken at screening (day -21 to -1), at the beginning (Day 1) and end (Day 22 ± 3) of every treatment period (3 weeks), and at the end of the trial, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 and who had an evaluation after baseline.

Quality of life (QOL) was measured using the widely used and validated measure the European Organization for Research and Treatment - Quality of Life Questionnaire (EORTC QLQ-C30), based on questions 29 How would you rate your overall health during the past week? and 30 How would you rate your overall quality of life during the past week?, scored between 1 (very poor) to 7 (Excellent).

Time frame: Data from the last available questionnaire for each patient. Questionnaires were taken at screening (day -21 to -1), at the beginning (Day 1) and end (Day 22 ± 3) of every treatment period (3 weeks), and at the end of the trial, up to 357 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 and who had an evaluation after baseline.

Tumour control rate was defined as the number of patients in a treatment arm who had completed 4 courses of treatment and presented with Stable Disease (SD), Partial Response (PR), or Complete Remission (CR). Tumour assessment by independent review of tumour imaging according to RECIST after every second treatment course, including imaging (e.g. CT, MRI) and submission of image(s) to central imaging unit. Complete remission (CR): Disappearance of all target lesions for at least 4 weeks from the documentation of CR. Partial remission (PR): At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum Longest Diameter (LD). Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest sum LD since the treatment started. The secondary endpoint duration of overall response was integrated into and displayed with tumour control endpoints.

Time frame: Tumour measurements performed at screening (day -21 to -1) and at the end of of the fourth 3-week treatment cycle, up to 105 days.

Population: Treated Set (TS): all patients who received at least 1 single dose of BI 2536 and who had an evaluation after baseline.