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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01023958

Enrollment

Registered

2009-12-02

Start date

2009-11-19

Completion date

2011-09-19

Last updated

2017-11-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms

Brief summary

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.

Interventions

DRUGBI 6727, IV infusion

phase II

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Histologically or cytologically confirmed urothelial cancer of the bladder, ureters or renal pelvis. 2. 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. 3. Male or female patient aged 18 years or older 4. Life expectancy of at least three (3) months 5. Eastern Co-operative Oncology Group performance score of 2 or less 6. 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 7. 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

1. More than one prior regimen of chemotherapy including prior adjuvant therapy 2. Brain metastases 3. Patients with bone metastasis as the only site of disease are excluded 4. 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. 5. QTc prolongation deemed clinically relevant by the investigator 6. Second malignancy currently requiring active therapy 7. Other active malignancy diagnosed within the past 3 years (other than non melanomatous skin cancer and cervical intraepithelial neoplasia) 8. Absolute neutrophil count (ANC) \<1,500/µl 9. Platelet count \<100,000/µl 10. Hemoglobin \<9 g/dl 11. Total bilirubin \>1.5 mg/dl 12. 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 13. Serum creatinine \>1.5 x ULN 14. Chemo-, Radio- or immunotherapy within the past 4 weeks. This does not apply to steroids and bisphosphonates. 15. Active infectious disease, or HIV, Hepatitis-B or -C infection 16. Active drug or alcohol abuse 17. 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 18. Pregnancy or breast feeding 19. 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. 20. Prior treatment with Polo-like kinase 1 (Plk1) inhibitor 21. Patient unable to comply with the protocol 22. Any known hypersensitivity to the trial drugs or their excipients

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Overall Survival	Time from first infusion to death, up to 2 years	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.
Duration of Overall Response	From the time of first response (CR or PR) to progression or death, up to 2 years	The duration of overall response is measured from the time of first response (CR or PR) to progression or death whichever occurs first.
Disease Control Rate	From first drug administration until end of study, up to 2 years	Disease control rate. Disease control is defined as having a best overall response of complete response (CR), partial response (PR) or stable disease (SD).
Duration of Disease Control	Time of first response to progression or death, up to 2 years	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.
AUC0-∞ of Volasertib	5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion	Area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of volasertib
Cmax of Volasertib	5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion	Maximum measured concentration in plasma (Cmax) of volasertib
t1/2 of Volasertib	5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion	Terminal half-life (t1/2) of volasertib
CL of Volasertib	5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion	Total plasma clearance after intravascular administration (CL) of volasertib
Vss of Volasertib	5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion	Apparent volume of distribution at steady state following intravascular administration (Vss) of volasertib
Tmax of Volasertib	5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion	Time from dosing to maximum measured concentration (Tmax) of volasertib
Occurrence and Intensity of AE's Graded According to CTCAE	From first drug administration until end of study, up to 2 years	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).
Progression-free Survival	Time from first treatment to the occurrence of tumor progression or death, up to 2 years	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.
Laboratory Investigation: Haemoglobin	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Haemoglobin
Laboratory Investigation: White Blood Cell Count	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter white blood cell count
Laboratory Investigation: Platelets	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Platelets
Laboratory Investigation: Neutrophils	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Neutrophils
Laboratory Investigation: Lymphocytes	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Lymphocytes
Laboratory Investigation: AST/GOT, SGOT	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Aspartate aminotransferase(AST)/GOT, SGOT
Laboratory Investigation: ALT/GPT, SGPT	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Alanine aminotransferase(ALT)/GPT, SGPT
Laboratory Investigation: Alkaline Phosphatase	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Alkaline phosphatase
Laboratory Investigation: Creatinine	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter Creatinine
Laboratory Investigation: Total Bilirubin	Baseline and last value on treatment (up to 2 years)	Difference from baseline in laboratory parameter total Bilirubin
Occurrence of Unacceptable Toxicity	From first drug administration up to 21 days after final administration, up to 2 years	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.

Countries

Taiwan, United States

Participant flow

Pre-assignment details

An open-label, single-arm, Phase II trial of intravenous volasertib (BI 6727) in patients with locally advanced, metastatic or recurrent urothelial cancer of the bladder, renal pelvis, or ureters after failure of prior chemotherapy.

Participants by arm

Arm	Count
Volasertib (BI 6727) Volasertib (BI 6727) was administered as intravenous infusion over 2 hours at Day 1 of each 21-day treatment course. Single dose, 300 mg as starting dose in first treatment course - possible dose escalation at the beginning of the 2nd course to 350 mg if well tolerated. Repeated administration in patients with clinical benefit until disease progression or intolerability of the study medication	50
Total	50

Arm

Count

Volasertib (BI 6727)

Volasertib (BI 6727) was administered as intravenous infusion over 2 hours at Day 1 of each 21-day treatment course. Single dose, 300 mg as starting dose in first treatment course - possible dose escalation at the beginning of the 2nd course to 350 mg if well tolerated. Repeated administration in patients with clinical benefit until disease progression or intolerability of the study medication

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Other adverse event	1
Overall Study	Progressive disease	48
Overall Study	Refused to continue medication	1

Baseline characteristics

Characteristic	Volasertib (BI 6727)
Age, Continuous	69.0 Years STANDARD_DEVIATION 7.4
Sex: Female, Male Female	10 Participants
Sex: Female, Male Male	40 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	49 / 50
serious Total, serious adverse events	13 / 50

Outcome results

Primary

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.

Time frame: From first drug administration until end of study, up to 2 years

Population: TS

Arm	Measure	Value (NUMBER)
Volasertib (BI 6727)	Objective Tumour Response According to RECIST Criteria	14.0 Percentage of participants

Secondary

AUC0-∞ of Volasertib

Area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of volasertib

Time frame: 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion

Population: Pharmacokinetic set (PKS) including patients with analyzable data for this endpoint.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Volasertib (BI 6727)	AUC0-∞ of Volasertib	5470 ng*h/mL	Geometric Coefficient of Variation 30.6

Secondary

CL of Volasertib

Total plasma clearance after intravascular administration (CL) of volasertib

Time frame: 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion

Population: PKS including patients with analyzable data for this endpoint.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Volasertib (BI 6727)	CL of Volasertib	914 mL/min	Geometric Coefficient of Variation 30.6

Secondary

Cmax of Volasertib

Maximum measured concentration in plasma (Cmax) of volasertib

Time frame: 5 mins before start of drug infusion and 2h, 3h, 6h, 24h, 168h and 336h after start of drug infusion

Population: PKS including patients with analyzable data for this endpoint.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Volasertib (BI 6727)	Cmax of Volasertib	253 ng/mL	Geometric Coefficient of Variation 51.9

Secondary

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).

Time frame: From first drug administration until end of study, up to 2 years

Population: TS

Arm	Measure	Value (NUMBER)
Volasertib (BI 6727)	Disease Control Rate	40.0 Percentage of participants

Secondary

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 frame: Time of first response to progression or death, up to 2 years

Population: Patients who achieved disease control in the TS.

Arm	Measure	Value (MEDIAN)
Volasertib (BI 6727)	Duration of Disease Control	27.0 Weeks

Secondary

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.

Time frame: From the time of first response (CR or PR) to progression or death, up to 2 years

Population: TS

Arm	Measure	Value (MEDIAN)
Volasertib (BI 6727)	Duration of Overall Response	41.0 Weeks

Secondary