Neoplasms
Conditions
Brief summary
The primary objective of the current study is to investigate the Maximum Tolerated Dose (MTD) in terms of safety and tolerability of BI 6727 in combination with fixed dose BIBF 1120, in patients with advanced or metastatic solid tumours.
Interventions
DRUGBI 6727
intravenous each 21 days
DRUGBIBF 1120
oral continuously
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with confirmed diagnosis of advanced, non resectable and/or metastatic solid tumours, who have failed conventional treatment, and for whom no therapy of proven efficacy exists, or who are not amenable to established forms of treatment 2. Age \> or = 18 years 3. European Cooperative Oncology Group performance status \< or = 2 4. Written informed consent in accordance with International Conference on Harmonization -Good Clinical Practice (ICH-GCP) and local legislation 5. Recovery from Common Terminology Criteria for Adverse Events grade 2-4 therapy-related toxicities from previous systemic anti-cancer therapies or radiotherapy (except alopecia)
Exclusion criteria
1. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the trial 2. Known hypersensitivity to the trial drugs or their excipients 3. Treatment with any other investigational drug or participation in any other interventional trial within 28 days before first administration of trial drug (BIBF 1120) or concomitantly with this trial 4. Systemic anti-cancer therapy or radiotherapy within 28 days before start of therapy or concomitantly with this trial. The restriction does not apply to steroids and bisphosphonates 5. Active infectious disease infection or HIV I/II 6. Other malignancy currently requiring another anti-cancer therapy 7. Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the past 6 months 8. Known inherited predisposition to bleeding or thrombosis 9. Radiographic evidence of cavitary or necrotic tumours 10. History of clinically significant haemoptysis within the past 3 months 11. Centrally located tumours with radiographic evidence (Computed Tomography or Magnetic Resonance Imaging) of local invasion of major blood vessels 12. Absolute Neutrophil Count (ANC) less than 1.5 x 1000000000/L 13. Platelets Count (PLT) less than 100 x 1000000000/L 14. Total bilirubin \> upper limit of normal (ULN) 15. Alaninaminotransferase (ALT) and/or Aspartateaminotransferase (AST) \>= 1.5 x ULN (in case of liver metastases: ALT and AST \>= 2.5 x ULN) 16. Serum creatinine \> 1.5 mg/dl 17. Major injuries and/or surgery or bone fracture within 28 days before first administration of trial drug (BIBF 1120), or planned surgical procedures during the trial period 18. Known history of clinically relevant QT prolongation (e.g. long QT syndrome) 19. History of severe haemorrhagic or thromboembolic event in the past 6 months (excluding central venous catheter thrombosis and peripheral deep vein thrombosis) 20. Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except for chronic low-dose therapy with acetylsalicylic acid \< or = 325mg per day) 21. Active alcohol or drug abuse 22. Women and men who are sexually active and unwilling to use a medically acceptable method of contraception during the trial 23. Pregnancy or breast-feeding 24. Patients unable to comply with the protocol 25. Uncontrolled hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD). | 28 days | DLT was defined as: 1. Drug-related CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or 4 non-haematological toxicity (except untreated vomiting, untreated nausea, or untreated diarrhoea) or 2. Drug-related CTCAE grade 4 neutropenia for 7 or more days and/or complicated by infection or 3. CTCAE grade 4 thrombocytopenia |
| Maximum Tolerated Dose (MTD) of Volasertib in Combination With Nintedanib | 28 days | The MTD was determined using a 3+3 design with de-escalation. The MTD was defined as the highest dose level at which maximal 1 out of 6 patients experienced DLT in the first course of the escalation nd de-escalation phase. However, all DLT's occurring in the trial were considered for selection of the recommended dose for further development. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Drug Related Adverse Events | From first study drug administration until 28 days after the last administration of any study medication, up to 485 days | Number of participants with investigator-defined drug related adverse events. |
| Number of Participants With Dose Limiting Toxicities | From first study drug administration until 28 days after the last administration of any study medication, up to 485 days | Number of participants with dose limiting toxicities (DLTs). DLT was defined as: 1. Drug-related CTCAE grade 3 or 4 non-haematological toxicity (except untreated vomiting, untreated nausea, or untreated diarrhoea) or 2. Drug-related CTCAE grade 4 neutropenia for 7 or more days and/or complicated by infection or 3. CTCAE grade 4 thrombocytopenia |
| Cmax of Volasertib | 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion | Maximum measured concentration (Cmax) in plasma of Volasertib in Cycle 1. |
| CL of Volasertib | 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion | Total plasma Clearance (CL) of Volasertib in Cycle 1. |
| Vss of Volasertib | 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion | Volume of distribution at steady state (Vss) of Volasertib in Cycle 1. |
| Cmax of Nintedanib | 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9 | Maximum measured concentration (Cmax) of Nintedanib in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient. |
| AUC(0-6h) of Nintedanib | 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9 | Area under the concentration-time curve (AUC) of Nintedanib over the time interval 0 to 6 hours in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient. |
| Tmax of Nintedanib | 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9 | Time from dosing to the maximum measured concentration, Cmax, of Nintedanib (tmax) in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient. |
| Number of Patients With Best Overall Response | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | Best overall response based on response evaluation criteria in solid tumors (RECIST) version 1.1. Best overall response is defined as the best overall response (complete response, partial response, stable disease, progressive disease or not evaluable) since the start of treatment. |
| Number of Patients With Objective Response (OR) | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.1. OR is defined as complete response (CR) or partial response (PR) as best response throughout the study. |
| Number of Patients With Disease Control | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Disease control is defined as complete response (CR), partial response (PR) or stable disease (SD) as best response throughout the study. |
| Duration of Disease Control | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Patients who had a best overall tumour response of complete response (CR), partial response (PR) or stable disease (SD) were assessed to show disease control. |
| Progression Free Survival (PFS) | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | PFS is defined as the time from start of treatment with study medication to tumour progression or death whichever occurs first. Tumour response was to be documented using appropriate techniques such as magnetic resonance imaging (MRI) or computer tomography (CT). |
Countries
Italy
Participant flow
Recruitment details
An uncontrolled, open-label, dose escalation study in cohorts of patients following the '3+3 design with de-escalation'. After entering the study, cohorts of patients were sequentially allocated to the dose levels.
Pre-assignment details
Beginning after the first cycle of treatment, intra-patient dose escalations were allowed and could be repeated after every cycle. Intra-patient dose escalation was not allowed after the maximum tolerated dose (MTD) was determined.
Participants by arm
| Arm | Count |
|---|---|
| 100 mg Volasertib + 200 mg Nintedanib Course 1 comprised of 28 days because of a 7-day run-in period for nintedanib (200 mg twice daily). The treatment with nintedanib started on Day 1 of Course 1 and continued until the end of the course. 100 mg volasertib was infused on Day 8 of Course 1; no nintedanib was to be taken on that day.
Course 2 and subsequent courses comprised 21 days. Volasertib was infused on Day 1 and continuous nintedanib administration re-started on Day 2. | 3 |
| 200 mg Volasertib + 200 mg Nintedanib Course 1 comprised of 28 days because of a 7-day run-in period for nintedanib (200 mg twice daily). The treatment with nintedanib started on Day 1 of Course 1 and continued until the end of the course. 200 mg volasertib was infused on Day 8 of Course 1; no nintedanib was to be taken on that day.
Course 2 and subsequent courses comprised 21 days. Volasertib was infused on Day 1 and continuous nintedanib administration re-started on Day 2. | 4 |
| 300 mg Volasertib + 200 mg Nintedanib Course 1 comprised of 28 days because of a 7-day run-in period for nintedanib (200 mg twice daily). The treatment with nintedanib started on Day 1 of Course 1 and continued until the end of the course. 300 mg volasertib was infused on Day 8 of Course 1; no nintedanib was to be taken on that day.
Course 2 and subsequent courses comprised 21 days. Volasertib was infused on Day 1 and continuous nintedanib administration re-started on Day 2. | 13 |
| 350 mg Volasertib + 200 mg Nintedanib Course 1 comprised of 28 days because of a 7-day run-in period for nintedanib (200 mg twice daily). The treatment with nintedanib started on Day 1 of Course 1 and continued until the end of the course. 350 mg volasertib was infused on Day 8 of Course 1; no nintedanib was to be taken on that day.
Course 2 and subsequent courses comprised 21 days. Volasertib was infused on Day 1 and continuous nintedanib administration re-started on Day 2. | 8 |
| 400 mg Volasertib + 200 mg Nintedanib Course 1 comprised of 28 days because of a 7-day run-in period for nintedanib (200 mg twice daily). The treatment with nintedanib started on Day 1 of Course 1 and continued until the end of the course. 400 mg volasertib was infused on Day 8 of Course 1; no nintedanib was to be taken on that day. | 2 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Dose-limiting toxicity | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other not stated above | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Progressive disease | 2 | 3 | 11 | 7 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | 100 mg Volasertib + 200 mg Nintedanib | 200 mg Volasertib + 200 mg Nintedanib | 300 mg Volasertib + 200 mg Nintedanib | 350 mg Volasertib + 200 mg Nintedanib | 400 mg Volasertib + 200 mg Nintedanib | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 9.2 | 60.0 years STANDARD_DEVIATION 7.1 | 57.5 years STANDARD_DEVIATION 8.8 | 53.1 years STANDARD_DEVIATION 12.9 | 59.0 years STANDARD_DEVIATION 5.7 | 56.3 years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 7 Participants | 2 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 6 Participants | 6 Participants | 1 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 13 / 13 | 8 / 8 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 | 5 / 13 | 2 / 8 | 1 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Volasertib in Combination With Nintedanib
The MTD was determined using a 3+3 design with de-escalation. The MTD was defined as the highest dose level at which maximal 1 out of 6 patients experienced DLT in the first course of the escalation nd de-escalation phase. However, all DLT's occurring in the trial were considered for selection of the recommended dose for further development.
Time frame: 28 days
Population: Treated Set. All patients who received \>= 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Maximum Tolerated Dose (MTD) of Volasertib in Combination With Nintedanib | 300 mg |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD).
DLT was defined as: 1. Drug-related CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or 4 non-haematological toxicity (except untreated vomiting, untreated nausea, or untreated diarrhoea) or 2. Drug-related CTCAE grade 4 neutropenia for 7 or more days and/or complicated by infection or 3. CTCAE grade 4 thrombocytopenia
Time frame: 28 days
Population: Treated set. All patients who received ≥1 dose of study medication were included in the treated set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD). | 0 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD). | 0 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD). | 3 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD). | 2 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD). | 2 participants |
Secondary
AUC(0-6h) of Nintedanib
Area under the concentration-time curve (AUC) of Nintedanib over the time interval 0 to 6 hours in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient.
Time frame: 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9
Population: PK analysis set.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | AUC(0-6h) of Nintedanib | 69.5 ng*h/mL | Geometric Coefficient of Variation 29.9 |
| 200 mg Volasertib + 200 mg Nintedanib | AUC(0-6h) of Nintedanib | 104.0 ng*h/mL | Geometric Coefficient of Variation 59.4 |
| 300 mg Volasertib + 200 mg Nintedanib | AUC(0-6h) of Nintedanib | 135.0 ng*h/mL | Geometric Coefficient of Variation 48.8 |
| 350 mg Volasertib + 200 mg Nintedanib | AUC(0-6h) of Nintedanib | 121.0 ng*h/mL | Geometric Coefficient of Variation 51 |
Secondary
CL of Volasertib
Total plasma Clearance (CL) of Volasertib in Cycle 1.
Time frame: 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion
Population: PK analysis set.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | CL of Volasertib | 720 mL/min | Geometric Coefficient of Variation 19.3 |
| 200 mg Volasertib + 200 mg Nintedanib | CL of Volasertib | 685 mL/min | Geometric Coefficient of Variation 4.22 |
| 300 mg Volasertib + 200 mg Nintedanib | CL of Volasertib | 792 mL/min | Geometric Coefficient of Variation 34.2 |
| 350 mg Volasertib + 200 mg Nintedanib | CL of Volasertib | 849 mL/min | Geometric Coefficient of Variation 29.3 |
| 400 mg Volasertib + 200 mg Nintedanib | CL of Volasertib | 589 mL/min | Geometric Coefficient of Variation 18.3 |
Secondary
Cmax of Nintedanib
Maximum measured concentration (Cmax) of Nintedanib in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient.
Time frame: 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9
Population: PK analysis set.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Cmax of Nintedanib | 22.5 ng/mL | Geometric Coefficient of Variation 58 |
| 200 mg Volasertib + 200 mg Nintedanib | Cmax of Nintedanib | 30.2 ng/mL | Geometric Coefficient of Variation 66.2 |
| 300 mg Volasertib + 200 mg Nintedanib | Cmax of Nintedanib | 36.7 ng/mL | Geometric Coefficient of Variation 53.3 |
| 350 mg Volasertib + 200 mg Nintedanib | Cmax of Nintedanib | 34.2 ng/mL | Geometric Coefficient of Variation 53.8 |
Secondary
Cmax of Volasertib
Maximum measured concentration (Cmax) in plasma of Volasertib in Cycle 1.
Time frame: 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion
Population: Pharmacokinetic (PK) analysis set. The PK analysis set included all patients who took at least 1 dose of study medication and provided at least 1 blood sample following drug administration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Cmax of Volasertib | 164 ng/mL | Geometric Coefficient of Variation 77.6 |
| 200 mg Volasertib + 200 mg Nintedanib | Cmax of Volasertib | 409 ng/mL | Geometric Coefficient of Variation 23.3 |
| 300 mg Volasertib + 200 mg Nintedanib | Cmax of Volasertib | 532 ng/mL | Geometric Coefficient of Variation 33.3 |
| 350 mg Volasertib + 200 mg Nintedanib | Cmax of Volasertib | 534 ng/mL | Geometric Coefficient of Variation 25.5 |
| 400 mg Volasertib + 200 mg Nintedanib | Cmax of Volasertib | 1210 ng/mL | Geometric Coefficient of Variation 54.1 |
Secondary
Duration of Disease Control
Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Patients who had a best overall tumour response of complete response (CR), partial response (PR) or stable disease (SD) were assessed to show disease control.
Time frame: Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment.
Population: All patients of the treated set that were assessed to show disease control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Duration of Disease Control | 163.0 days |
| 200 mg Volasertib + 200 mg Nintedanib | Duration of Disease Control | 348.0 days |
| 300 mg Volasertib + 200 mg Nintedanib | Duration of Disease Control | 141.0 days |
| 350 mg Volasertib + 200 mg Nintedanib | Duration of Disease Control | 215.0 days |
| 400 mg Volasertib + 200 mg Nintedanib | Duration of Disease Control | 56.0 days |
| Total Patients | Duration of Disease Control | 161.5 days |
Secondary
Number of Participants With Dose Limiting Toxicities
Number of participants with dose limiting toxicities (DLTs). DLT was defined as: 1. Drug-related CTCAE grade 3 or 4 non-haematological toxicity (except untreated vomiting, untreated nausea, or untreated diarrhoea) or 2. Drug-related CTCAE grade 4 neutropenia for 7 or more days and/or complicated by infection or 3. CTCAE grade 4 thrombocytopenia
Time frame: From first study drug administration until 28 days after the last administration of any study medication, up to 485 days
Population: Treated Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities | 0 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities | 1 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities | 6 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities | 2 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Participants With Dose Limiting Toxicities | 2 participants |
Secondary
Number of Participants With Drug Related Adverse Events
Number of participants with investigator-defined drug related adverse events.
Time frame: From first study drug administration until 28 days after the last administration of any study medication, up to 485 days
Population: Treated Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Number of Participants With Drug Related Adverse Events | 3 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Participants With Drug Related Adverse Events | 3 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Participants With Drug Related Adverse Events | 12 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Participants With Drug Related Adverse Events | 7 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Participants With Drug Related Adverse Events | 2 participants |
Secondary
Number of Patients With Best Overall Response
Best overall response based on response evaluation criteria in solid tumors (RECIST) version 1.1. Best overall response is defined as the best overall response (complete response, partial response, stable disease, progressive disease or not evaluable) since the start of treatment.
Time frame: Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment.
Population: Treated Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Complete Response | 0 participants |
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Partial Response | 0 participants |
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Progressive Disease | 1 participants |
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Not Evaluable | 0 participants |
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Missing | 0 participants |
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Stable Disease | 2 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Not Evaluable | 0 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Partial Response | 0 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Stable Disease | 2 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Progressive Disease | 2 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Missing | 0 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Complete Response | 0 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Missing | 1 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Not Evaluable | 0 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Complete Response | 1 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Partial Response | 1 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Stable Disease | 7 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Progressive Disease | 3 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Partial Response | 0 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Stable Disease | 4 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Not Evaluable | 0 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Progressive Disease | 3 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Complete Response | 0 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Missing | 1 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Partial Response | 0 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Progressive Disease | 0 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Missing | 1 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Stable Disease | 1 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Not Evaluable | 0 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Best Overall Response | Complete Response | 0 participants |
Secondary
Number of Patients With Disease Control
Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Disease control is defined as complete response (CR), partial response (PR) or stable disease (SD) as best response throughout the study.
Time frame: Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment.
Population: Treated Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Disease Control | 2 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Disease Control | 2 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Disease Control | 9 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Disease Control | 4 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Disease Control | 1 participants |
Secondary
Number of Patients With Objective Response (OR)
Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.1. OR is defined as complete response (CR) or partial response (PR) as best response throughout the study.
Time frame: Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment.
Population: Treated Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Missing | 0 participants |
| 100 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Objective Response (OR) | 0 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Missing | 0 participants |
| 200 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Objective Response (OR) | 0 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Objective Response (OR) | 2 participants |
| 300 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Missing | 1 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Objective Response (OR) | 0 participants |
| 350 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Missing | 1 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Missing | 1 participants |
| 400 mg Volasertib + 200 mg Nintedanib | Number of Patients With Objective Response (OR) | Objective Response (OR) | 0 participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from start of treatment with study medication to tumour progression or death whichever occurs first. Tumour response was to be documented using appropriate techniques such as magnetic resonance imaging (MRI) or computer tomography (CT).
Time frame: Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment.
Population: Treated Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Progression Free Survival (PFS) | 114.0 days |
| 200 mg Volasertib + 200 mg Nintedanib | Progression Free Survival (PFS) | 116.0 days |
| 300 mg Volasertib + 200 mg Nintedanib | Progression Free Survival (PFS) | 99.0 days |
| 350 mg Volasertib + 200 mg Nintedanib | Progression Free Survival (PFS) | 72.5 days |
| 400 mg Volasertib + 200 mg Nintedanib | Progression Free Survival (PFS) | 83.0 days |
| Total Patients | Progression Free Survival (PFS) | 96.5 days |
Secondary
Tmax of Nintedanib
Time from dosing to the maximum measured concentration, Cmax, of Nintedanib (tmax) in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient.
Time frame: 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9
Population: PK analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Tmax of Nintedanib | 3.00 h |
| 200 mg Volasertib + 200 mg Nintedanib | Tmax of Nintedanib | 1.88 h |
| 300 mg Volasertib + 200 mg Nintedanib | Tmax of Nintedanib | 2.42 h |
| 350 mg Volasertib + 200 mg Nintedanib | Tmax of Nintedanib | 2.00 h |
Secondary
Vss of Volasertib
Volume of distribution at steady state (Vss) of Volasertib in Cycle 1.
Time frame: 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion
Population: PK analysis set.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg Volasertib + 200 mg Nintedanib | Vss of Volasertib | 5710 L | Geometric Coefficient of Variation 39.9 |
| 200 mg Volasertib + 200 mg Nintedanib | Vss of Volasertib | 5590 L | Geometric Coefficient of Variation 6.53 |
| 300 mg Volasertib + 200 mg Nintedanib | Vss of Volasertib | 5010 L | Geometric Coefficient of Variation 34.7 |
| 350 mg Volasertib + 200 mg Nintedanib | Vss of Volasertib | 6080 L | Geometric Coefficient of Variation 21.2 |
| 400 mg Volasertib + 200 mg Nintedanib | Vss of Volasertib | 2710 L | Geometric Coefficient of Variation 87.3 |