Efficacy and Safety of BI 2536 in Advanced or Metastatic Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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The trial will be performed to evaluate whether BI 2536 may be effective in the treatment of advanced or metastatic NSCLC of stage IIIB or IV in patients who relapsed after or failed first-line therapy. A secondary aim is to identify the most suitable dosage schedule for the further Phase II and III clinical programme of BI 2536. To achieve this objective two dosage schedules are compared.

Official Title
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An Open, Randomised Clinical Phase II Trial to Investigate the Efficacy, Safety and Pharmacokinetics of a Single Dose of 200 mg of i.v. BI 2536 in Comparison to 50 mg of i.v. BI 2536 Administered on Days 1, 2 and 3 in Patients With Advanced or Metastatic Non Small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

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 patients aged 18 years or older with histologically or cytologically confirmed advanced or metastatic NSCLC of stage IIIB or IV, who relapsed or failed prior first-line chemotherapy for advanced or metastatic disease. At least one tumour lesion must be present that can accurately be measured by magnetic resonance imaging (MRI), or computed tomography (CT) in at least one dimension (longest diameter to be recorded) as 20 mm or greater with conventional techniques or as 10 mm or greater with spiral CT scan. Life expectancy of at least three months; Eastern co-operative oncology group (ECOG) performance score of 2 or less and written informed consent which must be consistent with international conference on harmonisation good clinical practice (ICH-GCP) and local legislation Exclusion Criteria: persistence of toxicities of prior anti cancer therapies which are deemed to be clinically relevant, known secondary 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 amino transferase (AST) or alanine amino transferase (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 1.5 mg/dl, serum creatinine greater than 2.0 mg/dl, concomitant intercurrent illnesses that would limit compliance with trial requirement or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, chemo-, hormone- or immunotherapy within the past four weeks or within less than four half-life times of the previous drug prior to treatment with the trial drug (whatever is the longest period), radiotherapy within the past four weeks prior to treatment with the trial drug, men or women who are sexually active and unwilling to use a medically acceptable method of contraception during the trial, pregnancy or lactation, treatment with any other investigational drug within the past four weeks or within less than four half-life times of the investigational drug before treatment with the trial drug (whatever is the longest period), patient unable to comply with the protocol, patients who are considered eligible by the investigator for other second-line chemotherapy, radiotherapy or immunotherapy, patients who have received more than two lines of prior anti-tumour therapy for advanced or metastatic non small cell lung cancer

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: 200 milligram (mg) of BI 2536<br>Day 1 | Drug: BI 2536<br>* Intravenous Infusion<br>|
| Experimental: 50 milligram (mg) of BI 2536<br>Day 1, 2, and 3 | Drug: BI 2536<br>* Intravenous Infusion<br>|
| Experimental: 60 milligram (mg) of BI 2536<br>Day 1, 2, and 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 |
| --- | --- | --- |
| Objective Tumour Response Evaluated According to the Response Evaluation Criteria in Solid Tumours (RECIST 1.0) by Central Review of the Tumour Images | The best overall response was the best response recorded from start of treatment until the participant progressed, received any other anti-tumour therapy, died or until the individual participant's end of trial. Number of participants with 'Objective tumour response evaluated according to RECIST 1.0 by central review of the tumour images = Yes' are reported. Objective response is complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter). Changes in tumour measurements were confirmed by repeat assessments that had to be performed 6 weeks after the criteria for response had been first met. | assessed at baseline, then every 6 weeks (every second treatment course) until disease progression or start of any other anti-tumour therapy or death or individual participant's end of trial, up to 533 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression-free survival defined as time from date of randomisation until date of imaging indicating progressive disease (PD) as assessed by the independent central imaging review (according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0) or date of investigator assessment of clinical progression or date of progressive disease recorded during the follow-up period or death date, whatever comes first. Participants without documented progression at the time of analysis were censored at the date of the last visit. Per RECIST version 1.0 for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started or the appearance of one or more new lesions. | every 6 weeks (every second treatment course), up to 419 days | 
| Overall Survival | Overall survival defined as time from date of randomisation until date of death from any cause. Participants alive at the time of analysis were censored at the date of the last trial visit or last date of follow-up, whatever came last. | every 6 weeks (every second treatment course), up to 599 days | 
| Duration of Overall Response | For participants who showed an overall tumour response of complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter), 'duration of overall response' was defined as the time from the first date where measurement criteria were met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease (PD) was objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started). Tumour response was evaluated based on local radiological images according to RECIST version 1.0 (agreed upon by independent review). The number of participants with an CR or PR who experienced the event 'recurrent or PD' is reported instead of the time-to-event data with unit of time as the number analyzed was too small to perform a Kaplan-Meier analysis. | assessed at baseline, then every 6 weeks (every second treatment course) until disease progression or start of any other anti-tumour therapy or death or individual participant's end of trial, up to 533 days | 
| Objective Tumour Response Evaluated According to the Response Evaluation Criteria in Solid Tumours (RECIST 1.0) by Investigator | The best overall response was the best response recorded from start of treatment until the participant progressed, received any other anti-tumour therapy, died or until the individual participant's end of trial. 'Objective tumour response evaluated according to RECIST 1.0 by investigator' is 'Yes' if the best overall response is either complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter). Otherwise it is 'No'. To be assigned a status of 'partial response' or 'complete response', changes in tumour measurements were confirmed by repeat assessments that had to be performed six weeks after the criteria for response had been first met. Number of participants with 'Objective tumour response evaluated according to RECIST 1.0 by investigator = Yes' are reported. | assessed at baseline, then every 6 weeks (every second treatment course) until disease progression or start of any other anti-tumour therapy or death or individual participant's end of trial, up to 533 days | 
| Time-to-deterioration for Symptom Score 'Cough' Assessed on Question 1 on the Lung Cancer Module QLQ LC13 of the European Organization for Research and Treatment Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 Version 3.0 | Time to deterioration for cough [days] was defined as the time from randomization to deterioration in score for the symptom 'cough'. Participants were considered to have deteriorated if a 10-point increase from the baseline score at any time point after baseline was observed. Participants who died before deteriorating were analyzed as having deteriorated at the time of death. Participants with disease progression without deterioration in score were censored at the time of the last scale measurement. Participants with no QoL assessments were censored at day 1. The score for symptom 'cough' was based on Question 1 on the lung cancer module QLQ LC13 of the EORTC QLQ C30 Version 3.0. A linear transformation was used to standardize the raw scores, so that scores range from 0 to 100. A high score represents a higher (worse) level of the symptom 'cough'. | baseline and every 3 weeks (prior to the first administration of BI 2536 in a treatment course comprising 3 weeks), up to 539 days | 
| Time-to-deterioration for Symptom Score 'Dyspnoea' Assessed on the Composite of Questions 3-5 on the Lung Cancer Module QLQ LC13 of the European Organization for Research and Treatment Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 Version 3.0 | Time to deterioration for dyspnoea [days] was defined as the time from randomization to deterioration in score for the symptom 'dyspnoea'. Participants were considered to have deteriorated if a 10-point increase from the baseline score at any time point after baseline was observed. Participants who died before deteriorating were analyzed as having deteriorated at the time of death. Participants with disease progression without deterioration in score were censored at the time of the last scale measurement. Participants with no QoL assessments were censored at day 1. The score for symptom 'dyspnoea' was based on the composite of Questions 3-5 on the lung cancer module QLQ LC13 of the EORTC QLQ C30 Version 3.0. A linear transformation was used to standardize the raw scores, so that scores range from 0 to 100. A high score represents a higher (worse) level of the symptom 'dyspnoea'. | baseline and every 3 weeks (prior to the first administration of BI 2536 in a treatment course comprising 3 weeks), up to 539 days | 
| Time-to-deterioration for Symptom Score 'Pain' Assessed on the Composite of Questions 9 and 19 of the European Organization for Research and Treatment Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 Version 3.0 | Time to deterioration for pain [days] was defined as the time from randomization to deterioration in score for the symptom 'pain'. Participants were considered to have deteriorated if a 10-point increase from the baseline score at any time point after baseline was observed. Participants who died before deteriorating were analyzed as having deteriorated at the time of death. Participants with disease progression without deterioration in score were censored at the time of the last scale measurement. Participants with no QoL assessments will be censored at day 1. The score for symptom 'pain' was based on the composite of Questions 9 and 19 of the EORTC QLQ C30 Version 3.0. A linear transformation was used to standardize the raw scores, so that scores range from 0 to 100. A high score represents a higher (worse) level of the symptom 'pain'. | baseline and every 3 weeks (prior to the first administration of BI 2536 in a treatment course comprising 3 weeks), up to 539 days | 
| BI 2536 Plasma Concentrations After Intravenous Infusion of 200 Milligram BI 2536 on Day 1 in Treatment Course 1 | BI 2536 plasma concentrations after intravenous infusion of 200 milligram BI 2536 on day 1 in treatment course 1. Geometric Coefficient of Variation reported in percentage [%]. | on day 1 in treatment course 1: 0.5 hour (h) , 1 h, 2 h, 4 h, 120 h post-dose (planned times) | 
| BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 | BI 2536 plasma concentrations after intravenous infusion of 50 / 60 milligram BI 2536 on day 1 in treatment course 1. Geometric Coefficient of Variation reported in percentage [%]. | on day 1 in treatment course 1: 1 hour (h), 2 h, 23.92 h, 25 h, 47.92 h, 48.5 h, 49 h, 50 h, 52 h, 120 h post-dose (planned times) | 
| Incidence of Adverse Events Categorized by Common Terminology Criteria for Adverse Events (CTCAE) Grades | Number of participants with adverse events categorized by common terminology criteria for adverse events (CTCAE) grades (version 3.0) are reported. | On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days | 
| Incidence of Dose Limiting Toxicity (DLT) | Dose limiting toxicity was defined as drug related common terminology criteria for adverse events (CTCAE) grade 3 or greater non haematological toxicity (excluding untreated nausea, vomiting or diarrhoea) or drug related CTCAE grade 4 neutropenia for seven or more days and / or complicated by infection or CTCAE grade 4 thrombocytopenia. Number of participants with DLT is reported. | On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days | 
| Number of Participants With Neutropenia of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 | Number of participants with neutropenia of common terminology criteria for adverse events (CTCAE) grade 3 or 4. | On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days | 
| Number of Participants With Thrombocytopenia of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 | Number of participants with thrombocytopenia of common terminology criteria for adverse events (CTCAE) grade 3 or 4. | On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days | 
| Change From Baseline in Systolic/Diastolic Blood Pressure at Individual Participant's End-of-trial Visit | Change from baseline in systolic/diastolic blood pressure at individual participant's end-of-trial visit. | baseline, date of individual participant's end of trial visit which was 533 days after start of treatment at the latest | 
| Change From Baseline in Pulse Rate at Individual Participant's End-of-trial Visit | Change from baseline in pulse rate at individual participant's end-of-trial visit. | baseline, date of individual participant's end of trial visit which was 533 days after start of treatment at the latest |