Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
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.
Interventions
DRUGpemetrexed
500 mg/m\^2 i.v. on day 1 of 21 day cycle
DRUGBI 6727
BI 6727 i.v. on day 1 of a 21 day cycle
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologic or cytologic confirmed diagnosis of NSCLC 2. 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) 3. Patients who are eligible for pemetrexed as second line chemotherapy 4. Measurable disease by one or more techniques (CT, MRI) according to RECIST 5. Patients aged 18 years or older 6. Life expectancy of at least three (3) months 7. Eastern Cooperative Oncology Group (ECOG) performance Score 0-2 8. Written informed consent that is consistent with ICH-GCP guidelines and local legislation
Exclusion criteria
1. 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 2. 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 3. Any persisting toxicities which are deemed to be clinically significant from the previous therapy 4. 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. 5. Patients who are unwilling or unable to take folic acid and vitamin B12 supplementation 6. 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. 7. Other active malignancy diagnosed within the past 3 years (other than non melanomatous skin cancer and cervical intraepithelial neoplasia) 8. 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 9. 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 10. Patients who have received prior therapy with pemetrexed 11. Absolute neutrophil count (ANC) less than 1,500/mm3 12. Platelet count less than 100,000/mm3 13. Hemoglobin \<90g/L 14. Total bilirubin \>26µmol/L 15. 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 16. Serum creatinine level \>133µmol/L and/or creatinine clearance (measured or calculated) \<45 ml/min 17. Clinically relevant QTc prolongation 18. Women and men who are sexually active and unwilling to use a medically acceptable method of contraception 19. Pregnancy or breast feeding 20. Known or suspected active alcohol or drug abuse 21. Patients unable to comply with the protocol 22. Any known hypersensitivity to the trial drugs or their excipients 23. Patients with NSCLC of confirmed Squamous histology
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Time From the Date of Randomization to Date of Disease Progression or Death, Whichever Occurred First. | From randomization until disease progression or death | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | From first drug infusion until 21 days after last drug infusion, up to 1100 days | 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. |
| Overall Survival (OS) | From randomization until time of death | Overall survival (OS) was defined as the duration of time from randomization to time of death. |
| Duration of Overall Response | 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 | 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. |
| Occurrence and Intensity of AEs Graded According to CTCAE. | From first drug infusion until 21 days after last drug infusion, up to 1100 days | 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). |
| Occurence of DLT | Patients were treated for repeated 21-day treatment cycles until disease progression or intolerability of the trial drug, whichever occurred first. | 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. |
| Cmax 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 - maximum measured concentration of volasertib in plasma. |
| Total Clearance (CL) 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 | CL - total clearance of volasertib in plasma after IV administration |
| Vss 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 | Vss - apparent volume of distribution at steady state following IV administration of volasertib |
| Cmax 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 | Cmax - maximum measured concentration of pemetrexed in plasma |
| CL 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 | CL - total clearance of pemetrexed in plasma after IV administration |
| Vss 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 | Vss - apparent volume of distribution at steady state following IV administration of pemetrexed |
| Frequency of Patients With Possible Clinically Significant Abnormalities | From first drug infusion until 21 days after last drug infusion, up to 1100 days | Frequency of patients with possible clinically significant abnormalities |
Countries
Canada, The Bahamas
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Run-in Phase: Volasertib 250 mg + Pemetrexed 500 mg/m2 Patients received Volasertib 250 mg and pemetrexed 500 mg/m2 administered intravenously (i.v.) on day 1 of each 21 day cycle. | 6 |
| Run-in Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 Patients received Volasertib 300 mg and pemetrexed 500 mg/m2 administered intravenously (i.v.) on day 1 of each 21 day cycle | 6 |
| Randomization Phase: Volasertib 300 mg Patients received Volasertib 300 mg administered intravenously (i.v.) on day 1 of each 21 day cycle | 37 |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 Patients received Volasertib 300 mg and Pemetrexed 500 mg/m2 intravenously (i.v.) on day 1 of each 21 day cycle | 47 |
| Randomization Phase: Pemetrexed 500 mg/m2 Patients received Pemetrexed 500 mg/m2 administered intravenously (i.v.) on day 1 of each 21 day cycle | 47 |
| Total | 143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Randomized Phase | Adverse Event | 0 | 0 | 4 | 5 | 5 |
| Randomized Phase | Not treated | 0 | 0 | 1 | 1 | 1 |
| Randomized Phase | Other reason not defined above | 0 | 0 | 4 | 2 | 4 |
| Randomized Phase | Progressive disease | 0 | 0 | 25 | 36 | 34 |
| Randomized Phase | Refused to continue medication | 0 | 0 | 2 | 2 | 2 |
| Run-in Phase | Adverse Event | 1 | 1 | 0 | 0 | 0 |
| Run-in Phase | Other reason not defined above | 0 | 1 | 0 | 0 | 0 |
| Run-in Phase | Progressive disease | 4 | 4 | 0 | 0 | 0 |
| Run-in Phase | Refused to continue medication | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Run-in Phase: Volasertib 250 mg + Pemetrexed 500 mg/m2 | Run-in Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Randomization Phase: Volasertib 300 mg | Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Randomization Phase: Pemetrexed 500 mg/m2 |
|---|---|---|---|---|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 9.12 | 66.2 years STANDARD_DEVIATION 8.3 | 62.3 years STANDARD_DEVIATION 6.83 | 62.9 years STANDARD_DEVIATION 8.6 | 63.5 years STANDARD_DEVIATION 10.26 | 62.5 years STANDARD_DEVIATION 8.89 |
| Sex: Female, Male Female | 73 Participants | 5 Participants | 4 Participants | 16 Participants | 23 Participants | 25 Participants |
| Sex: Female, Male Male | 70 Participants | 1 Participants | 2 Participants | 21 Participants | 24 Participants | 22 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 | 6 / 6 | 6 / 6 | 35 / 36 | 46 / 46 | 44 / 46 |
| serious Total, serious adverse events | 2 / 6 | 0 / 6 | 8 / 36 | 10 / 46 | 12 / 46 |
Outcome results
Primary
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).
Time frame: From randomization until disease progression or death
Population: Randomized phase II set, which included all patients who were randomized as part of phase II of the study (not the run in phase)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: Volasertib 300 mg | Progression Free Survival (PFS) Time From the Date of Randomization to Date of Disease Progression or Death, Whichever Occurred First. | 1.4 months |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Progression Free Survival (PFS) Time From the Date of Randomization to Date of Disease Progression or Death, Whichever Occurred First. | 3.3 months |
| Randomization Phase: Pemetrexed 500 mg/m2 | Progression Free Survival (PFS) Time From the Date of Randomization to Date of Disease Progression or Death, Whichever Occurred First. | 5.3 months |
Comparison: Hazard ratio and 95% confidence interval (CI) from Cox proportional-hazards regression model, stratified by histology (Nonsquamous vs. NOS). P-value from log-rank test stratified by histology (one-sided for volasertib 300 mg + pemetrexed 500 mg/m2 vs. pemetrexed 500 mg; two-sided for volasertib 300 mg vs. pemetrexed 500 mg/m2).p-value: 0.00395% CI: [1.271, 3.292]Log Rank
Comparison: Hazard ratio and 95% CI from Cox proportional-hazards regression model, stratified by histology (Nonsquamous vs. NOS). P-value from log-rank test stratified by histology (one-sided for volasertib 300 mg + pemetrexed 500 mg/m2 vs. pemetrexed 500 mg/m2; two-sided for volasertib 300 mg vs. pemetrexed 500 mg/m2).p-value: 0.280495% CI: [0.735, 1.771]Log Rank
Secondary
CL of Pemetrexed
CL - total clearance of pemetrexed in plasma after IV administration
Time frame: 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
Population: PK set including patients with evaluable data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | CL of Pemetrexed | 54.4 mL/min | Geometric Coefficient of Variation 17.4 |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | CL of Pemetrexed | 69.1 mL/min | Geometric Coefficient of Variation 30 |
Secondary
Cmax of Pemetrexed
Cmax - maximum measured concentration of pemetrexed in plasma
Time frame: 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
Population: PK set including patients with evaluable data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Cmax of Pemetrexed | 131000 ng/mL | Geometric Coefficient of Variation 24.7 |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Cmax of Pemetrexed | 115000 ng/mL | Geometric Coefficient of Variation 32.1 |
Secondary
Cmax of Volasertib
Cmax - maximum measured concentration of volasertib in plasma.
Time frame: 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
Population: Pharmacokinetic (PK) set, which included all patients in the treated set with volasertib monotherapy or combined with pemetrexed and provided at least 1 blood sample for measurement of volasertib (BI 6727) or pemetrexed. Including patients with evaluable data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Cmax of Volasertib | 554 ng/mL | Geometric Coefficient of Variation 35.9 |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Cmax of Volasertib | 635 ng/mL | Geometric Coefficient of Variation 51.8 |
| Randomization Phase: Pemetrexed 500 mg/m2 | Cmax of Volasertib | 565 ng/mL | Geometric Coefficient of Variation 39 |
Secondary
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.
Time frame: 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
Population: Randomized phase II set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: Volasertib 300 mg | Duration of Overall Response | 23.0 weeks |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Duration of Overall Response | 19.6 weeks |
| Randomization Phase: Pemetrexed 500 mg/m2 | Duration of Overall Response | 23.4 weeks |
Secondary
Frequency of Patients With Possible Clinically Significant Abnormalities
Frequency of patients with possible clinically significant abnormalities
Time frame: From first drug infusion until 21 days after last drug infusion, up to 1100 days
Population: On-treatment for lab
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | AST/GOT, SGOT - High | 0 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Creatinine - High | 0 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Haemoglobin - Low | 1 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - Low | 0 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Neutrophils - Low | 4 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Bilirubin, total - High | 1 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Alkaline phosphatase - High | 0 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - High | 0 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - High | 0 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | Lymphocytes - Low | 4 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - Low | 4 participants |
| Randomization Phase: Volasertib 300 mg | Frequency of Patients With Possible Clinically Significant Abnormalities | ALT/GPT, SGPT - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Bilirubin, total - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Neutrophils - Low | 2 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - Low | 2 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Lymphocytes - Low | 4 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Haemoglobin - Low | 2 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Creatinine - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | AST/GOT, SGOT - High | 1 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Alkaline phosphatase - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - Low | 1 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | ALT/GPT, SGPT - High | 1 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - High | 1 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Creatinine - High | 0 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Haemoglobin - Low | 16 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - Low | 15 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - High | 1 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - Low | 8 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - High | 3 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Neutrophils - Low | 13 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Lymphocytes - Low | 16 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | AST/GOT, SGOT - High | 0 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | ALT/GPT, SGPT - High | 0 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Alkaline phosphatase - High | 0 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Bilirubin, total - High | 1 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Neutrophils - Low | 23 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Haemoglobin - Low | 21 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | AST/GOT, SGOT - High | 6 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | ALT/GPT, SGPT - High | 10 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - Low | 3 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Bilirubin, total - High | 1 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Alkaline phosphatase - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - High | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - Low | 25 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Creatinine - High | 3 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Lymphocytes - Low | 22 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Neutrophils - Low | 12 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Alkaline phosphatase - High | 5 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Haemoglobin - Low | 14 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | AST/GOT, SGOT - High | 3 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - Low | 12 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - Low | 2 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Bilirubin, total - High | 1 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Platelets - High | 3 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | ALT/GPT, SGPT - High | 6 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Lymphocytes - Low | 22 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | White blood cell ct. - High | 1 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Frequency of Patients With Possible Clinically Significant Abnormalities | Creatinine - High | 0 participants |
Secondary
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.
Time frame: From first drug infusion until 21 days after last drug infusion, up to 1100 days
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Complete response (CR) | 0.0 percentage of participants |
| Randomization Phase: Volasertib 300 mg | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Partial response (PR) | 16.7 percentage of participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Complete response (CR) | 0.0 percentage of participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Partial response (PR) | 50.0 percentage of participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Partial response (PR) | 8.1 percentage of participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Complete response (CR) | 0.0 percentage of participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Complete response (CR) | 0.0 percentage of participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Partial response (PR) | 21.3 percentage of participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Partial response (PR) | 10.6 percentage of participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. | Complete response (CR) | 0.0 percentage of participants |
p-value: >0.9999Fisher Exact
p-value: 0.2596Fisher Exact
Secondary
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.
Time frame: Patients were treated for repeated 21-day treatment cycles until disease progression or intolerability of the trial drug, whichever occurred first.
Population: Treated set, run-in phase, first course only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomization Phase: Volasertib 300 mg | Occurence of DLT | 1 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurence of DLT | 1 participants |
Secondary
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).
Time frame: From first drug infusion until 21 days after last drug infusion, up to 1100 days
Population: Treated set, which included all patients who were dispensed and were documented to have taken at least one dose of investigational treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 5 | 0 participants |
| Randomization Phase: Volasertib 300 mg | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 2 | 0 participants |
| Randomization Phase: Volasertib 300 mg | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 4 | 3 participants |
| Randomization Phase: Volasertib 300 mg | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 3 | 3 participants |
| Randomization Phase: Volasertib 300 mg | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 1 | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 2 | 2 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 4 | 1 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 1 | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 5 | 0 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 3 | 3 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 3 | 8 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 4 | 6 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 5 | 3 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 2 | 12 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 1 | 6 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 4 | 5 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 1 | 2 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 2 | 18 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 3 | 19 participants |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 5 | 2 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 3 | 15 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 2 | 18 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 1 | 6 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 5 | 0 participants |
| Randomization Phase: Pemetrexed 500 mg/m2 | Occurrence and Intensity of AEs Graded According to CTCAE. | CTCAE Grade 4 | 5 participants |
Secondary
Overall Survival (OS)
Overall survival (OS) was defined as the duration of time from randomization to time of death.
Time frame: From randomization until time of death
Population: Randomized phase II set, including only patients who died.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: Volasertib 300 mg | Overall Survival (OS) | 22.9 months |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Overall Survival (OS) | 17.1 months |
| Randomization Phase: Pemetrexed 500 mg/m2 | Overall Survival (OS) | 17.4 months |
p-value: 0.840695% CI: [0.538, 2.14]Log Rank
p-value: 0.39695% CI: [0.599, 1.949]Log Rank
Secondary
Total Clearance (CL) of Volasertib
CL - total clearance of volasertib in plasma after IV administration
Time frame: 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
Population: PK set including patients with evaluable data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Total Clearance (CL) of Volasertib | 782 mL/min | Geometric Coefficient of Variation 24.8 |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Total Clearance (CL) of Volasertib | 882 mL/min | Geometric Coefficient of Variation 30.4 |
| Randomization Phase: Pemetrexed 500 mg/m2 | Total Clearance (CL) of Volasertib | 867 mL/min | Geometric Coefficient of Variation 31.6 |
Secondary
Vss of Pemetrexed
Vss - apparent volume of distribution at steady state following IV administration of pemetrexed
Time frame: 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
Population: PK set including patients with evaluable data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Vss of Pemetrexed | 9.40 Litres | Geometric Coefficient of Variation 20.5 |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Vss of Pemetrexed | 13.1 Litres | Geometric Coefficient of Variation 45.8 |
Secondary
Vss of Volasertib
Vss - apparent volume of distribution at steady state following IV administration of volasertib
Time frame: 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
Population: PK set including patients with evaluable data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Randomization Phase: Volasertib 300 mg | Vss of Volasertib | 6730 Litres | Geometric Coefficient of Variation 42.1 |
| Randomization Phase: Volasertib 300 mg + Pemetrexed 500 mg/m2 | Vss of Volasertib | 6750 Litres | Geometric Coefficient of Variation 39.7 |
| Randomization Phase: Pemetrexed 500 mg/m2 | Vss of Volasertib | 6230 Litres | Geometric Coefficient of Variation 34.5 |