BI 6727 (Volasertib) in Combination With Cisplatin or Carboplatin in Patients With Advanced or Metastatic Solid Tumour

A Phase I Dose Escalation Trial of BI 6727 in Combination With Cisplatin or Carboplatin in Patients With Advanced or Metastatic Solid Tumors

The primary objective of this trial is to identify the maximum tolerated dose (MTD) of BI 6727 therapy in terms of drug-related adverse events when combined with a platinum therapy (cisplatin or carboplatin).

Secondary objectives are the collection of overall safety and antitumour efficacy data and the determination of the pharmacokinetic profile of BI 6727 combination treatment with cisplatin and carboplatin.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: BI 6727; Drug: BI-6727

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium
    • 1230.6.3201 Boehringer Ingelheim Investigational Site
  • Leuven, Belgium
    • 1230.6.3202 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Patients with confirmed diagnosis of advanced, non resectable and / or metastatic solid tumours, who have failed conventional treatment, or for whom no therapy of proven efficacy exists, or who are not amenable to established forms of treatment
2. Indication for a treatment with platinum therapy as judged by the investigator
3. Age 18 years or older
4. Written informed consent consistent with ICH-GCP and local legislation
5. ECOG performance score lower or equal 2
6. Recovery from CTCAE Grade 2 - 4 therapy-related toxicities from previous systemic anti-cancer therapies or radiotherapies (except alopecia grade 2)

Exclusion criteria:

1. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol
2. Pregnancy or breastfeeding
3. Active infectious disease or known chronic Hepatitis B/Hepatitis C infection and HIV I/II
4. Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the past 6 months
5. Second malignancy currently requiring another anti-cancer therapy
6. ANC less than 1500 / mm3
7. Platelet count less than 100 000 / mm3
8. Bilirubin greater than 1.5 mg / dl (> 26 micromol / L, SI unit equivalent) (except Gilbert's syndrome)
9. Aspartate amino transferase (AST) and / or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (if related to liver metastases greater than five times the upper limit of normal)
10. Serum creatinine greater than 1.5 mg / dl (> 132 micromol / L, SI unit equivalent) or creatinine clearance <70ml/min (as calculated according to Cockcroft-Gault formula for GFR estimate)
11. Known history of relevant QT-prolongation, e.g. long QT-syndrome
12. Pre-existing clinically relevant hearing loss
13. Women and men who are sexually active and unwilling to use a medically acceptable method of contraception
14. Treatment with other investigational drugs or participation in another clinical interventional trial within the past four weeks before start of therapy or concomitantly with this trial
15. Systemic anti-cancer therapy or radiotherapy within the past four weeks before start of therapy or concomitantly with this trial. This restriction does not apply to steroids and bisphosphonates.
16. Patients unable to comply with the protocol
17. Active alcohol or drug abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A. BI 6727-cisplatin; patient to receive 3-weekly infusion escalating dose of BI 6727 combined to cisplatin	Drug: BI 6727; low to high dose
Experimental: B. BI 6727-carboplatin; patient to receive 3-weekly infusion escalating dose of BI 6727 combined to carboplatin	Drug: BI-6727; Low to high dose (administered every 3 weeks). Depending on the toxicities observed, intermediary dose levels may be added

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose	The maximum tolerated dose (MTD) was defined as the highest dose studied for which the incidence of DLT was less than 33% (i.e. 1/6 patients) during the first cycle, for Volasertib in combination with cisplatin or carboplatin. 0=not maximum tolerated dose, 1=was maximum tolerated dose.	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Dose Limiting Toxicities	Percentage of participants with dose limiting toxicities (DLTs) during the first treatment cycle.	3 weeks
Objective Response Rate	Objective response was defined as the proportion of participants having at least a best response of complete response (CR) or partial response (PR) determined based on RECIST criteria, version 1.0 (V1.0). Tumour response was documented using appropriate techniques	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Duration of Objective Response	Duration of objective response was defined as the time from first documented confirmed complete response (CR) or partial response (PR) to first evidence of progressive disease (PD) or death from any cause, whichever occurred first, determined based on RECIST V1.0 criteria. Tumour response was documented using appropriate techniques	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Best Overall Response	Best overall response was defined as the best response obtained since the start of study treatment until disease progression, determined based on RECIST V1.0 criteria.	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Disease Control Rate	Percentage of participants with confirmed disease control, defined as the proportion of patients with a best overall response of at least stable disease (SD), determined based on RECIST V1.0 criteria.	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Duration of Disease Control	Duration of Disease control was defined as the time from the start of study treatment to the time of disease progression or death, whichever occurred first.	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Progression-free Survival	Progression-free survival based on RECIST V1.0 criteria was defined as the time from start of treatment to the date of evidence of progressive disease (PD) or death from any cause, whichever occurred first.	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Incidence and Intensity of Adverse Events According to CTCAE Version 3.0	Incidence and intensity of adverse events according to common terminology criteria for adverse events (CTCAE) version 3.0	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Percentage of Participants With Serious Adverse Events	Percentage of participants with serious adverse events (AEs)	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Percentage of Participants With Significant Adverse Events	Percentage of participants with significant adverse events (AEs): dose limiting toxicity (DLT) was defined as significant AE. DLTs (i.e. significant AEs) per protocol were: drug related CTCAE grade 3 or 4 non haematological toxicity (except vomiting or diarrhoea responding to supportive treatment and ototoxicity); drug related CTCAE grade 4 neutropenia for seven or more days and / or complicated by infection; drug related CTCAE Grade 4 thrombocytopenia; drug related febrile neutropenia grade 3 (ANC<1000/mm³ and fever≥ 38.5°C)	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Total Plasma Clearance After Intravascular Administration (CL)	Total plasma clearance after intravascular administration (CL) of Volasertib in combination with cisplatin or carboplatin during treatment cycle 1.	1 hour (h) 35 minutes (min) before start of volasertib infusion and 1h, 2h, 8h, 24h, 48h, 168h and 336h after start of volasertib infusion
Apparent Volume of Distribution at Steady State Following Intravascular Administration (Vss)	Apparent volume of distribution at steady state following intravascular administration (Vss) of Volasertib in combination with cisplatin or carboplatin during treatment cycle 1.	1 hour (h) 35 minutes (min) before start of volasertib infusion and 1h, 2h, 8h, 24h, 48h, 168h and 336h after start of volasertib infusion
Change From Baseline in Pulse Rate	Change from baseline in pulse rate at last value on treatment	Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Change From Baseline in Neutrophils	Change from baseline in neutrophils with the maximum value on treatment	Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Change From Baseline in Platelets	Change from baseline in platelets with the maximum value on treatment	Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Frequency of Participants (%) With Possible Clinically Significant Abnormalities for Neutrophils	Frequency of participants (%) with possible clinically significant abnormalities for neutrophils: : defined as neutrophils >=CTCAE grade 2 (CTCAE v3.0), with worsening from baseline. The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE).	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Frequency of Participants (%) With Possible Clinically Significant Abnormalities for Platelets	Frequency of participants (%) with possible clinically significant abnormalities for platelets : defined as platelets >=CTCAE grade 2 (based on CTCAE v3.0), with worsening from baseline. The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE).	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Platelets Based on Last Value on Treatment	Percentage of participants with transitions relative to the baseline CTC grade (version 3) for platelets based on last value on treatment. Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE).	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Neutrophils Based on Last Value on Treatment	Percentage of participants with transitions relative to the baseline CTC grade (version 3) for neutrophils based on last value on treatment. Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE)	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Platelets Based on Worst Value on Treatment	Percentage of participants with transitions relative to the baseline CTC grade (version 3) for platelets based on worst value on treatment. Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE).	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Neutrophils Based on Worst Value on Treatment	Percentage of participants with transitions relative to the baseline CTC grade (version 3) for neutrophils based on worst value on treatment. Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE)	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Worst CTCAE Grade on Treatment for Platelets	Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE).	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days
Worst CTCAE Grade on Treatment for Neutrophils	Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE).	From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Awada A, Dumez H, Aftimos PG, Costermans J, Bartholomeus S, Forceville K, Berghmans T, Meeus MA, Cescutti J, Munzert G, Pilz K, Liu D, Schoffski P. Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity. Invest New Drugs. 2015 Jun;33(3):611-20. doi: 10.1007/s10637-015-0223-9. Epub 2015 Mar 22.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: August 31, 2009
• First Submitted That Met QC Criteria: August 31, 2009
• First Posted (Estimate): September 1, 2009

Study Record Updates

• Last Update Posted (Actual): January 31, 2019
• Last Update Submitted That Met QC Criteria: August 21, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Other Study ID Numbers: 1230.6; 2008-003926-40 (EudraCT Number: EudraCT)