Trial of BI 6727 (Volasertib) Monotherapy and BI 6727 in Combination With Pemetrexed Compared to Pemetrexed Monotherapy in Advanced NSCLC

Study Overview
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Brief Summary
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The trial objective will be to evaluate whether BI 6727 monotherapy or in combination with pemetrexed may be effective in the treatment of advanced or metastatic NSCLC in patients who relapsed after or failed first-line platinum based therapy. The secondary objectives are to identify the acceptable dose of BI 6727 in combination with pemetrexed and to characterize the pharmacokinetic profiles of BI 6727 alone. Arm A, BI6727 monotherapy arm is closed to further recruitment.

Official Title
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A Randomised Open-label Phase II Trial of BI 6727 Monotherapy and BI 6727 in Combination With Standard Dose Pemetrexed Compared to Pemetrexed Monotherapy in Second Line Non-small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: pemetrexed
* Drug: pemetrexed
* Drug: BI 6727


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologic or cytologic confirmed diagnosis of NSCLC Recurrent, advanced or metastatic NSCLC that has progressed following one prior platinum based chemotherapy regimen (not counting adjuvant or neoadjuvant chemotherapy if completed more than 12 months prior to platinum based therapy) Patients who are eligible for pemetrexed as second line chemotherapy Measurable disease by one or more techniques (CT, MRI) according to RECIST Patients aged 18 years or older Life expectancy of at least three (3) months Eastern Cooperative Oncology Group (ECOG) performance Score 0-2 Written informed consent that is consistent with ICH-GCP guidelines and local legislation Exclusion criteria: Treatment with an investigational drug in another clinical study within the past 28 days prior to the start of therapy or concomitantly with this study Anti-cancer therapy for NSCLC (except radiotherapy for palliative reasons) within the past 28 days prior to Treatment Day 1 of Cycle 1 of this trial Any persisting toxicities which are deemed to be clinically significant from the previous therapy Patients who have received more than one prior chemotherapy regimen for advanced disease (not including prior adjuvant therapy). Patients may have received prior epidermal growth factor receptor tyrosine kinase inhibitors. Patients who are unwilling or unable to take folic acid and vitamin B12 supplementation Active brain metastases (stable for <28 days, symptomatic, or requiring concurrent steroids). Patients who have received prior whole brain irradiation and whose brain metastases are stable according to the criteria above will not be excluded. Other active malignancy diagnosed within the past 3 years (other than non melanomatous skin cancer and cervical intraepithelial neoplasia) 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 Patients unable or unwilling to interrupt concomitant administration of NSAIDS 5 days prior to, the day of and 2 days after the administration of pemetrexed, with the exception of lose dose aspirin 81mg daily Patients who have received prior therapy with pemetrexed Absolute neutrophil count (ANC) less than 1,500/mm3 Platelet count less than 100,000/mm3 Hemoglobin <90g/L Total bilirubin >26µmol/L Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) less than 2.5 X ULN, except in case of known liver metastasis where maximum 5 X ULN is acceptable Serum creatinine level >133µmol/L and/or creatinine clearance (measured or calculated) <45 ml/min Clinically relevant QTc prolongation Women and men who are sexually active and unwilling to use a medically acceptable method of contraception Pregnancy or breast feeding Known or suspected active alcohol or drug abuse Patients unable to comply with the protocol Any known hypersensitivity to the trial drugs or their excipients Patients with NSCLC of confirmed Squamous histology

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 6727 +pemetrexed<br>BI 6727 plus 500 mg/^m2 pemetrexed i.v. on day 1 of 21 day cycle | Drug: pemetrexed<br>* 500 mg/m^2 i.v. on day 1 of 21 day cycle<br>Drug: BI 6727<br>* BI 6727 i.v. on day 1 of a 21 day cycle<br>|
| Active Comparator: pemetrexed<br>500 mg/m^2 i.v. on day 1 of a 21 day cycle | Drug: pemetrexed<br>* 500 mg/m^2 i.v. on day 1 of 21 day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Time From the Date of Randomization to Date of Disease Progression or Death, Whichever Occurred First. | Disease progression was defined according to the Response Evaluation Criteria in Solid Tumours (RECIST)) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occured first. For patients with known date of progression (or death): PFS [days] = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS [days, censored] = date of last imaging showing no progression - date randomization + 1 day. The number of participants analysed displays the number of patients with an event (progression). | From randomization until disease progression or death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Objective tumor response, defined as complete response (CR), and partial response (PR), evaluated according to RECIST criteria. Evaluation of target lesions: Complete Response (CR): disappearance of all target lesions. Partial Response (PR): ≥30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Evaluation of nontarget lesions: Complete Response (CR): disappearance of all nontarget lesions. | From first drug infusion until 21 days after last drug infusion, up to 1100 days | 
| Overall Survival (OS) | Overall survival (OS) was defined as the duration of time from randomization to time of death. | From randomization until time of death | 
| Duration of Overall Response | The duration of overall response was measured from the time 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 treatment began). The duration of overall CR was measured from the time measurement criteria were first met for CR until the first date that recurrent disease was objectively documented. Duration of disease control is presented here. | From the time measurement criteria were met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented | 
| Occurrence and Intensity of AEs Graded According to CTCAE. | All patients were carefully monitored during and after each treatment cycle. Adverse events (AEs) were recorded and were graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE). | From first drug infusion until 21 days after last drug infusion, up to 1100 days | 
| Occurence of DLT | Occurence of Dose-limiting toxicity (DLT). A DLT was defined as one or more of the following: treatment-related CTCAE Grade 3 or 4 nonhematological toxicity (except emesis or diarrhea responding to supportive treatment). treatment-related CTCAE Grade 4 neutropenia for ≥7 days and/or complicated by infection. CTCAE Grade 4 thrombocytopenia. | Patients were treated for repeated 21-day treatment cycles until disease progression or intolerability of the trial drug, whichever occurred first. | 
| Frequency of Patients With Possible Clinically Significant Abnormalities | Frequency of patients with possible clinically significant abnormalities | From first drug infusion until 21 days after last drug infusion, up to 1100 days | 
| Cmax of Volasertib | Cmax - maximum measured concentration of volasertib in plasma. | 5 minutes (min) before the start of Volasertib infusion and 1 hour (h), 2h, 4h, 24h, 168h and 336h after the start of Volasertib infusion | 
| Total Clearance (CL) of Volasertib | CL - total clearance of volasertib in plasma after IV administration | 5 minutes (min) before the start of Volasertib infusion and 1 hour (h), 2h, 4h, 24h, 168h and 336h after the start of Volasertib infusion | 
| Vss of Volasertib | Vss - apparent volume of distribution at steady state following IV administration of volasertib | 5 minutes (min) before the start of Volasertib infusion and 1 hour (h), 2h, 4h, 24h, 168h and 336h after the start of Volasertib infusion | 
| Cmax of Pemetrexed | Cmax - maximum measured concentration of pemetrexed in plasma | 5 minutes before pemetrexed infusion, at the end of the infusion and 1.5 hours (h), 2.5h, 4.5h and 25.5h after the end of pemetrexed infusion | 
| CL of Pemetrexed | CL - total clearance of pemetrexed in plasma after IV administration | 5 minutes before pemetrexed infusion, at the end of the infusion and 1.5 hours (h), 2.5h, 4.5h and 25.5h after the end of pemetrexed infusion | 
| Vss of Pemetrexed | Vss - apparent volume of distribution at steady state following IV administration of pemetrexed | 5 minutes before pemetrexed infusion, at the end of the infusion and 1.5 hours (h), 2.5h, 4.5h and 25.5h after the end of pemetrexed infusion |