Intravenous BI 6727 (Volasertib) in 2nd Line Treatment of Urothelial Cancer

Study Overview
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Brief Summary
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The primary objective of this trial is to evaluate the efficacy and safety of BI 6727 in patients with locally advanced, metastatic or recurrent urothelial cancer after failure of first line or adjuvant/neoadjuvant chemotherapy.

Official Title
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An Open-label, Single-arm, Phase II Trial of Intravenous BI 6727 in Patients With Locally Advanced, Metastatic or Recurrent Urothelial Cancer of the Bladder, Renal Pelvis, or Ureters After Failure of Prior Chemotherapy

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BI 6727, IV infusion


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically or cytologically confirmed urothelial cancer of the bladder, ureters or renal pelvis. Patients with stage III, IV or recurrent urothelial cancer of the bladder, ureter or renal pelvis after failure or recurrence after first line or adjuvant/neoadjuvant chemotherapy. Recurrence is defined as relapse within 2 years after cessation of prior first-line chemotherapy. Male or female patient aged 18 years or older Life expectancy of at least three (3) months Eastern Co-operative Oncology Group performance score of 2 or less At least one target tumor lesion that has not been irradiated within the past three months and 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 with conventional techniques or as >10 mm with spiral CT The patient must have given written informed consent prior to inclusion into the trial which must be consistent with the International Conference on Harmonization, Good Clinical Practice (ICH-GCP) and local legislation Exclusion criteria: More than one prior regimen of chemotherapy including prior adjuvant therapy Brain metastases Patients with bone metastasis as the only site of disease are excluded Serious illness or organ system dysfunction, which in the opinion of the investigator, would either compromise patient safety, interfere with the evaluation of the safety of the test drug or limit compliance with trial requirements. QTc prolongation deemed clinically relevant by the investigator Second malignancy currently requiring active therapy Other active malignancy diagnosed within the past 3 years (other than non melanomatous skin cancer and cervical intraepithelial neoplasia) Absolute neutrophil count (ANC) <1,500/µl Platelet count <100,000/µl Hemoglobin <9 g/dl Total bilirubin >1.5 mg/dl Aspartate amino transferase (AST) and/or alanine amino transferase (ALT) >2.5 x ULN, or aspartate amino transferase (AST) and/or alanine amino transferase (ALT) >5 x ULN in case of known liver metastases Serum creatinine >1.5 x ULN Chemo-, Radio- or immunotherapy within the past 4 weeks. This does not apply to steroids and bisphosphonates. Active infectious disease, or HIV, Hepatitis-B or -C infection Active drug or alcohol abuse Women and men who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial Pregnancy or breast feeding Treatment with any investigational drug within the past 4 weeks or within less than four half-life times of the investigational drug before treatment with the trial drug and/or persistence of toxicities of prior anticancer therapies which are deemed to be clinically relevant. Prior treatment with Polo-like kinase 1 (Plk1) inhibitor Patient unable to comply with the protocol Any known hypersensitivity to the trial drugs or their excipients

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm<br>open label | Drug: BI 6727, IV infusion<br>* phase II<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumour Response According to RECIST Criteria | Objective tumor response, defined as complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. | From first drug administration until end of study, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival (PFS) is the time from first treatment to the occurrence of tumor progression or death, whichever occurs first. Disease progression is defined according to the RECIST guideline but also includes the investigators' assessment which may, in some cases, include only clinical progression (deterioration of general health status per investigator). PFS was analyzed with the Kaplan-Meier curve. Greenwood's variance estimate was used to form confidence intervals. Patients without evidence of disease progression were to be censored at the last image date. | Time from first treatment to the occurrence of tumor progression or death, up to 2 years | 
| Overall Survival | Overall survival (OS) is the time from first infusion to death. Patients who were alive at the time of analysis or lost to follow-up were censored at the last follow-up date when they were known to be alive. Overall survival was analyzed with the Kaplan-Meier curve. Greenwood's variance estimate was used to form confidence intervals. | Time from first infusion to death, up to 2 years | 
| Duration of Overall Response | The duration of overall response is measured from the time of first response (CR or PR) to progression or death whichever occurs first. | From the time of first response (CR or PR) to progression or death, up to 2 years | 
| Disease Control Rate | Disease control rate. Disease control is defined as having a best overall response of complete response (CR), partial response (PR) or stable disease (SD). | From first drug administration until end of study, up to 2 years | 
| Duration of Disease Control | Disease control is defined as having a best overall response of CR, PR, or SD. The duration of disease control is measured from the time of first response to progression or death whichever occurs first. | Time of first response to progression or death, up to 2 years | 
| AUC0-∞ of Volasertib | Area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of volasertib | 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion | 
| Cmax of Volasertib | Maximum measured concentration in plasma (Cmax) of volasertib | 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion | 
| t1/2 of Volasertib | Terminal half-life (t1/2) of volasertib | 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion | 
| CL of Volasertib | Total plasma clearance after intravascular administration (CL) of volasertib | 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion | 
| Vss of Volasertib | Apparent volume of distribution at steady state following intravascular administration (Vss) of volasertib | 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion | 
| Tmax of Volasertib | Time from dosing to maximum measured concentration (Tmax) of volasertib | 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion | 
| Occurrence and Intensity of AE's Graded According to CTCAE | Occurrence and intensity of adverse events (AEs) graded according to Common Toxicity Criteria of Adverse Events (CTCAE). The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE). | From first drug administration until end of study, up to 2 years | 
| Occurrence of Unacceptable Toxicity | Occurrence of unacceptable toxicity is defined by CTCAE as as drug related CTCAE Grade 3 or greater non-hematological toxicity (except emesis or diarrhea responding to supportive treatment); drug-related CTCAE Grade 4 neutropenia for seven or more days and / or complicated by infection; or drug-related CTCAE Grade 4 thrombocytopenia. | From first drug administration up to 21 days after final administration, up to 2 years | 
| Laboratory Investigation: Haemoglobin | Difference from baseline in laboratory parameter Haemoglobin | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: White Blood Cell Count | Difference from baseline in laboratory parameter white blood cell count | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: Platelets | Difference from baseline in laboratory parameter Platelets | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: Neutrophils | Difference from baseline in laboratory parameter Neutrophils | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: Lymphocytes | Difference from baseline in laboratory parameter Lymphocytes | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: AST/GOT, SGOT | Difference from baseline in laboratory parameter Aspartate aminotransferase(AST)/GOT, SGOT | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: ALT/GPT, SGPT | Difference from baseline in laboratory parameter Alanine aminotransferase(ALT)/GPT, SGPT | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: Alkaline Phosphatase | Difference from baseline in laboratory parameter Alkaline phosphatase | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: Creatinine | Difference from baseline in laboratory parameter Creatinine | Baseline and last value on treatment (up to 2 years) | 
| Laboratory Investigation: Total Bilirubin | Difference from baseline in laboratory parameter total Bilirubin | Baseline and last value on treatment (up to 2 years) |