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

Study Overview
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Brief Summary
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The trial is conducted in order to evaluate the efficacy, safety and pharmacokinetics of BI 2536 in the treatment of unresectable advanced pancreatic cancer as first line or second line therapy. A secondary aim is to identify the most suitable dosage regimen for the further phase II and III clinical programme of BI 2536. To achieve this objective, two dosage regimens are compared in patients receiving first line therapy.

Official Title
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An Open, Randomised, Clinical Phase II Trial in Patients With Unresectable Advanced Pancreatic Cancer Investigating the Efficacy, Safety, and Pharmacokinetics of BI 2536 Administered in Repeated 3-week Cycles as a Single i.v. Dose of 200 mg on Day 1 or as 60 mg Doses on Days 1, 2, and 3

Conditions
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Pancreatic Neoplasms

Intervention / Treatment
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* Drug: BI 2536


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male or female patient aged 18 years or older patient with confirmed diagnosis of unresectable, either locally advanced or metastatic, ductal adenocarcinoma of the pancreas patient who is either chemonaïve (for the first line cohorts), or who presents with progressive disease under first line chemotherapy with a gemcitabine based regimen (for the second line cohort) Karnofsky performance status of ¿ 70% for the first line cohorts, and Karnofsky performance status ¿ 50% for the second line cohort patient with at least one measurable tumour lesion that can accurately be measured by magnetic resonance imaging (MRI), or computed tomography (CT) in at least one dimension (longest diameter to be recorded) life expectancy of at least three months patient must have given written informed consent consistent with the guidelines of the international conference on harmonisation for good clinical practice (ICH-GCP) as well as with local legislation Exclusion Criteria: prior adjuvant chemotherapy (for first line cohorts only) ampullary carcinoma of the pancreas hypersensitivity to the trial drug or the excipients persistence of toxicities of prior anti cancer therapies which are deemed to be clinically relevant known second malignancy requiring therapy brain metastases which are symptomatic or require therapy absolute neutrophil count less than 1.500/mm3 platelet count less than 100.000/mm3 haemoglobin less than 9 mg/dl aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2.5 times the upper limit of normal, or AST or ALT greater than 5 times the upper limit of normal in case of known liver metastases bilirubin greater than 3.0 mg/dl (> 52 ¿mol/l, SI unit equivalent) under adequate drainaging measures (in case of obstructive jaundice) serum creatinine greater than 2.0 mg/dl concomitant intercurrent illnesses including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness or social situation that would limit compliance with trial requirement or which are considered relevant for the evaluation of the efficacy or safety of the trial drug radiotherapy within the past four weeks prior to treatment with the trial drug hormone- or immunotherapy or therapy with a biologic response modifier within the past four weeks treatment with any other investigational drug within the past four weeks men or women who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. abstinence, condom with spermicidal coating, diaphragm with spermicidal coating, oral contraceptive, progesterone implant, sterilisation) during the trial pregnancy or lactation patients unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 2536 High dose<br>Day 1 | Drug: BI 2536<br>* Intravenous Infusion<br>|
| Experimental: BI 2536 Low dose<br>Day 1 - 3 | Drug: BI 2536<br>* Intravenous Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Objective Response Evaluated According to the RECIST Criteria by Independent Review | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumour Control After the Fourth Treatment Course | 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. | 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. | 
| Duration of Overall Response | 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. | 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. | 
| Progression Free Survival (PFS) | 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. | 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. | 
| Overall Survival (OS) | 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. | From first treatment till the end of the trial or when a patient concluded the trial, up to 336 days. | 
| Best Objective Response Evaluated According to the RECIST Criteria by Investigator Assessment | 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. | 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. | 
| One-year Survival | 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. | 1 year, see description for detailed definition of the time frame. | 
| Number of Participants With Carbohydrate Antigen 19-9 (CA19-9) Response | 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. | Blood samples for CA19-9 analysis were collected on Days 1, 2, and 5 of each treatment period, up to 357 days. | 
| Number of Participants With Dose Limiting Toxicity (DLT) | 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. | 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. | 
| Quality of Life Assessment, Including Clinical Benefit Response: Overall Health | 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). | 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. | 
| Quality of Life Assessment, Including Clinical Benefit Response: Quality of Life | 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). | 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. | 
| Number of Participants With Incidence and Intensity of Adverse Events Graded According to Common Terminology Criteria for Adverse Events (CTCAE) | 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 | From first administration until 21 days after the day of last administration, up to 16 cycles, up to 357 days. |