Leukemia, Myeloid, Acute
Conditions
Brief summary
The trial will be performed in two parts, a phase I part and a phase IIa part. In the phase I part of the trial, BI 6727 will be investigated as monotherapy and in combination with low dose cytarabine (LD-Ara-C) in patients with relapsed/refractory AML that are not eligible for intensive treatment. The dose of BI 6727 will be escalated to determine the maximum tolerated dose (MTD) of BI 6727 monotherapy and BI 6727 in combination with LD-Ara-C in AML patients. In the phase IIa part, the combination of BI 6727 at MTD with LD-Ara-C and LD-Ara-C monotherapy will be investigated to explore the efficacy of the combination schedule in comparison to LD-Ara-C monotherapy in previously untreated AML patients that are not eligible for intensive treatment.
Interventions
DRUGVolasertib
Volasertib administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle).
DRUGCytarabine
Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment 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
Male or female adult with relapsed/refractory AML ineligible for intensive treatment (phase I part only) Male or female adult with previously untreated AML ineligible for intensive treatment (phase IIa part only) Confirmed diagnosis of AML according to the WHO definition (except for acute promyelocytic leukaemia, APL) Patient is eligible for LD-Ara-C treatment Life expectancy \> 3 months Eastern co-operative oncology group (ECOG, R01-0787) performance score \<=2 at screening Signed written informed consent consistent with international conference on harmonisation, good clinical practice (ICH-GCP) and local legislation
Exclusion criteria
Previously untreated AML (phase I part only) Relapsed or treatment refractory AML (phase IIa part only) Patient with APL (AML subtype M3 according to the French-American-British (FAB) classification) Hypersensitivity to one of the trial drugs or the excipients Other malignancy requiring treatment Symptomatic central nervous system involvement Clinically relevant QT prolongation (e.g. long QT syndrome, QTcF\>470 ms) Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (ULN), or AST or ALT greater than 5 times the ULN in case of known leukaemia liver involvement Prothrombin time (PT) \> 1.5 x ULN for subjects not on therapeutic vitamin K antagonists (phenprocoumon, warfarin) Bilirubin greater than 1.5 mg/dl (\> 26 mcmol/L) Serum creatinine greater than 2.0 mg/dl Concomitant intercurrent illness, which would compromise the evaluation of efficacy or safety of the trial drug, e.g. active severe infection, unstable angina pectoris, cardiac arrhythmia or severe heart failure/cardiac insufficiency. Psychiatric illness or social situation that would limit compliance with trial requirements Concomitant therapy, which is considered relevant for the evaluation of the efficacy or safety of the trial drug Contraindications for cytarabine treatment according to the SPC Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial, i.e. combination of two forms of effective contraception (hormonal contraception, intrauterine device, condom with spermicide, etc.). Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial Pregnant or nursing female patients Patient unable to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose (MTD) of Volasertib in Combination With LDAC (Schedule A) and Volasertib Monotherapy (Schedule B) | First Treatment cycle, up to 28 days. | To determine the Maximum tolerated dose (MTD), dose escalation was conducted following the 3+3 design with de-escalation. The MTD was defined as the highest dose at which 6 patients had been treated and less than 2 patients experienced a Dose limiting toxicity (DLT) within the first cycle of treatment. The MTD was defined based on safety data from the first cycle only. DLT is defined as drug related Common terminology criteria for adverse events (CTCAE) grade ≥ 3 nonhaematological toxicity (excluding: untreated nausea, untreated vomiting, CTCAE grade 3 untreated diarrhoea, CTCAE grade 3 febrile neutropenia and CTCAE grade 3 infection with grade 3 or 4 neutrophils). In patients with complete remission with incomplete blood count recovery (CRi) or partial remission (PR), persistent CTCAE grade 4 neutropenia or thrombocytopenia until three weeks after the end of the treatment cycle will be regarded a DLT. |
| Phase II: Number of Patients With Objective Response (Complete Remission (CR) + Complete Remission With Incomplete Blood Count Recovery (CRi)) | The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 869 days. | Phase II: Number of patients with Objective Response (Complete remission (CR) + Complete remission with incomplete blood count recovery (CRi)). Complete remission (CR): morphologically leukaemia-free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no Auer rods, no evidence of extramedullary leukaemia) and absolute neutrophil count ≥1,000/microliter (μL) and platelets \>100,000/μL. Complete remission with incomplete blood count recovery (incomplete CR, CRi): all of the above criteria for CR were met except that neutrophils \<1,000/μL or platelets \<100,000/μL in the blood were not achieved. |
| Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | First Treatment cycle, up to 28 days. | A DLT was defined as a drug related CTCAE (Common Toxicity Criteria for Adverse Events) Grade ≥3 non-haematological toxicity (excluding untreated nausea, untreated vomiting, Grade 3 untreated diarrhea, Grade 3 febrile neutropenia, and Grade 3 infection with Grade 3 or 4 neutrophils). In patients with CRi (Complete Remission with Incomplete Blood Count Recovery) or PR (Partial Remission), persistent Grade 4 neutropenia or thrombocytopenia for 3 weeks after the end of the treatment cycle was regarded as a DLT unless the respective Grade 4 cytopenia was preexistent. In patients who required platelet substitution to maintain a Grade \<4 before treatment, a Grade 4 thrombocytopenia after treatment did not constitute a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Overall Survival | The patients that entered the trial, and measured from the date of randomisation until death from any cause, up to 1100 days.. | Overall survival \[days\] = (date of death - date of randomisation + 1 day), for patients with known date of death. Overall survival (censored) \[days\] = (date of last trial visit or follow-up - date of randomisation + 1 day), for patients who were still alive at time of database lock. Overall survival (OS) was analysed with the Kaplan-Meier method for each of the treatment arms. |
| Phase II: Relapse - Free Survival | The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence or death from any cause, whichever occurred first, up to 900 days. | Relapse-free survival \[days\] = (date of first recurrence of disease or death after entering the trial - date of first occurrence of CR or CRi after entering the trial+ 1 day) for patients with a recurrence (this value should be positive). Relapse-free survival (censored) \[days\] = (date of last trial visit or follow-up - date of first occurrence of CR or CRi after entering the trial + 1 day) for patients who did not experience recurrence of disease or death at the time of analysis. |
| Phase II: Remission Duration | The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse), up to 900 days. | Remission duration analysis was defined only for patients who achieved Complete remission (CR) or Complete remission with incomplete blood count recovery (CRi), and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse). For patients who died without report of relapse, remission duration was censored on the date of death, regardless of cause. |
| Phase II: Time to Remission | The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse), up to 158 days. | Time to remission \[days\] = (date of first occurrence of CR or CRi after entering the trial-date of randomisation + 1 day) for patients with an objective response. |
| Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Baseline and End of Treatment (up to 869 days). | ECOG performance score change from baseline to last visit of last cycle = ECOG performance score at last visit of the last cycle - ECOG performance score at baseline. ECOG performance score changes from baseline were also categorised on a 3-point categorical scale: deteriorated (-1), unchanged (0), and improved (1). The number of participants for category of ECOG score change is reported. |
| Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration. | Total Clearance (CL) of Volasertib in Plasma after Intravenous (i.v.) Administration of Volasertib. |
| Apparent Volume of Distribution of Volasertib at Steady State (VSS) | Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration. | Apparent Volume of Distribution of volasertib at steady state (VSS) following Intravenous (i.v.) administration. |
| Dose Normalized Maximum Measured Concentration of Cytarabine in Plasma (Cmax, Norm) | Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration. | Cmax, norm: Maximum measured concentration of Cytarabine in plasma. The dose normalisation was done by dividing by the dose applied. Unit: nanogram/milliliter/milligram: ((ng/mL)/mg). Dose groups of Phase I were combined by dose normalizing as pre specified in the study protocol. |
| Best Overall Response | The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 869 days. | * CR * CR+CRi * Partial remission: CR except bone marrow (BM) contained ≥5% but \<25% blasts (or ≤50% initial blasts), or \<5% blasts in presence of Auer rods or abnormal morphology. * No change: survived ≥7 days (d) after 1st cycle with persistent leukemia in last peripheral blood smear or BM, or with persistent extramedullary disease, without further deterioration due to leukemia or increase of blasts in BM or peripheral blood. * Aplasia: survived ≥7d after 1st cycle, died whilst cytopenic, with last post-treatment BM result aplastic or hypoplastic and without leukemia blasts. * Indeterminate: survived \<7 d after 1st cycle or survived ≥7d after 1st cycle, died with no persistent leukemia in peripheral smear but no post-treatment BM examination or did not complete 1st cycle. * Progressive disease: survived ≥7d after 1st cycle with increase of blast population in BM or peripheral blood or aggravation or new extramedullary disease or further deterioration or death due to leukemia. |
| Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals | Baseline (Days -14 to -1) and day 1 (1 hour and 24 hours) after start of infusion. | ECG (Electro Cardio Gram) Measurements: Absolute QTcF (QT Interval (interval from the beginning of the QRS complex to the end of the T wave) Corrected for Heart Rate Using Fridericia's Formula) Intervals. The 350 mg + LDAC arm of phase I and II were combined into one arm to provide maximum information on QT changes and presented together with the Phase I schedule B 450 mg arm, as pre specified in the study protocol. |
| QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Change From Baseline at Cycle 1 | Baseline (Days -14 to -1) and day 1 (1 hour and 24 hours) after start of infusion. | ECG Measurements: QTcF (QT Interval (interval from the beginning of the QRS complex to the end of the T wave) changes from baseline at each time point: The QTcF post baseline measurement obtained at time t minus baseline QTcF measurement. The 350 mg + LDAC arm of phase I and II were combined into one arm to provide maximum information on QT changes and presented together with the Phase I schedule B 450 mg arm, as pre specified in the study protocol. |
| Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | First treatment cycle, up to 28 days. | Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported. |
| Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | First treatment cycle, up to 28 days. | Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported. |
| Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 615 days. | Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported. |
| Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 597 days. | Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported. |
| Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 890 days. | Number of patients with AEs following in the in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported. |
| Dose Normalized Area Under the Concentration-Time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated up to 4 Hours | Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h after first drug administration. | AUC0-4,norm: Area under the concentration-time curve of Cytarabine in plasma over the time interval from zero extrapolated to 4 hours. The dose normalisation was done by dividing by dose applied. Unit: nanogram\*hour/milliliter/milligram: ((ng\*h/mL)/mg). Dose groups of Phase I were combined by dose normalizing as pre specified in the study protocol. |
| Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 594 days. | Phase I: Number of patients with Objective Response (Complete remission (CR) + Complete remission with incomplete blood count recovery (CRi)). Complete remission (CR): morphologically leukaemia-free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no Auer rods, no evidence of extramedullary leukaemia) and absolute neutrophil count ≥1,000/microliter (μL) and platelets \>100,000/μL. Complete remission with incomplete blood count recovery (incomplete CR, CRi): all of the above criteria for CR were met except that neutrophils \<1,000/μL or platelets \<100,000/μL in the blood were not achieved. |
| Phase II: Event Free Survival | The patients that entered the trial, and measured from the date of randomization to the date of disease progression (treatment failure), relapse or death from any cause, whichever occurred first, up to 1000 days.. | Event-free survival (EFS) \[days\] was the shortest duration of the following: (a) Date of assessment indicating PD on the response page of the eCRF (Electronic Case Report Form) - date of randomisation + 1 day (b) Date of assessment indicating clinical progressive disease (PD) on the disease or responses pages of the of eCRF- date of randomisation + 1 day (c) Date of assessment indicating PD on the patient status page of the eCRF - date of randomisation +1 day (for patients who had not been censored before this time point) (d) Death date - date of randomisation +1 day Patients not being assessed PD, clinical PD, or death during the trial were censored. EFS was analysed with the Kaplan-Meier method for each of the treatment arms. |
Countries
Austria, Belgium, Canada, France, Germany, Italy, Norway
Participant flow
Recruitment details
Open-label, randomized, dose escalation study. In this trial 180 patients were entered and randomised. However 3 patients were entered but not treated in Phase I and 2 patients were not treated in Phase II. Thus total 175 patients were treated in this trial.
Pre-assignment details
Patients were assigned to two treatment schedules (A and B) in the phase I part of the trial (dose escalation phase to determine maximum tolerated dose (MTD)). In the phase IIa part of the trial (after MTD was determined), patients were randomised to two treatment schedules (A and C).
Participants by arm
| Arm | Count |
|---|---|
| Phase I Schedule A. Volasertib 150 mg+LDAC Volasertib 150 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle. | 4 |
| Phase I Schedule A. Volasertib 200 mg+LDAC Volasertib 200 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle. | 3 |
| Phase I Schedule A. Volasertib 250 mg+LDAC Volasertib 250 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle. | 5 |
| Phase I Schedule A. Volasertib 300 mg+LDAC Volasertib 300 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle. | 9 |
| Phase I Schedule A. Volasertib 350 mg+LDAC Volasertib 350 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle. | 8 |
| Phase I Schedule A. Volasertib 400 mg+LDAC Volasertib 400 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle) and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 day treatment cycle. | 3 |
| Phase I Schedule B. Volasertib 150 mg Volasertib 150 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle). | 11 |
| Phase I Schedule B. Volasertib 200 mg Volasertib 200 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle). | 2 |
| Phase I Schedule B. Volasertib 350 mg Volasertib 350 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle). | 5 |
| Phase I Schedule B. Volasertib 400 mg Volasertib 400 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle). | 6 |
| Phase I Schedule B. Volasertib 450 mg Volasertib 450 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle). | 23 |
| Phase I Schedule B. Volasertib 500 mg Volasertib 500 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle). | 5 |
| Phase I Schedule B. Volasertib 550 mg Volasertib 550 milligram (mg) administered by Intravenous Infusion (IV) over 60 minutes on Days 1 and 15 (28-day cycle). | 4 |
| Phase II Schedule C. LDAC Low-dose cytarabine (LDAC) monotherapy 2x20 milligram (mg) per day administered by subcutaneous injection on days 1-10 of each 28 days treatment cycle. | 45 |
| Phase II Schedule A. Volasertib 350 mg+LDAC Volasertib 350 milligram (mg) on Days 1 and 15 (28-day cycle) administered by Intravenous Infusion (IV) over 60 minutes and Low-dose cytarabine (LDAC) 2x20mg per day administered by subcutaneous injection on days 1-10 of each 28 days treatment cycle. | 42 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Dose Limiting Toxicity (DLT) | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Non compliance with protocol | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Other Adverse Event | 1 | 1 | 1 | 2 | 2 | 1 | 3 | 0 | 0 | 1 | 5 | 2 | 0 | 6 | 13 |
| Overall Study | Other reason than listed above | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 3 | 1 | 1 | 10 | 3 |
| Overall Study | Progressive Disease | 3 | 2 | 4 | 6 | 4 | 1 | 8 | 2 | 4 | 5 | 12 | 2 | 2 | 26 | 20 |
| Overall Study | Refused to continue medication | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 1 | 1 | 5 |
Baseline characteristics
| Characteristic | Phase I Schedule A. Volasertib 150 mg+LDAC | Total | Phase II Schedule A. Volasertib 350 mg+LDAC | Phase II Schedule C. LDAC | Phase I Schedule B. Volasertib 550 mg | Phase I Schedule B. Volasertib 500 mg | Phase I Schedule B. Volasertib 450 mg | Phase I Schedule B. Volasertib 400 mg | Phase I Schedule B. Volasertib 350 mg | Phase I Schedule B. Volasertib 200 mg | Phase I Schedule B. Volasertib 150 mg | Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule A. Volasertib 200 mg+LDAC |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 69.5 Years STANDARD_DEVIATION 12.1 | 72.5 Years STANDARD_DEVIATION 7.7 | 75.6 Years STANDARD_DEVIATION 4.9 | 75.2 Years STANDARD_DEVIATION 5.5 | 69.8 Years STANDARD_DEVIATION 4.1 | 66.4 Years STANDARD_DEVIATION 7.3 | 68.2 Years STANDARD_DEVIATION 7.7 | 65.2 Years STANDARD_DEVIATION 20.1 | 70.6 Years STANDARD_DEVIATION 2.9 | 73.0 Years STANDARD_DEVIATION 4.2 | 73.5 Years STANDARD_DEVIATION 3.9 | 73.3 Years STANDARD_DEVIATION 7.6 | 72.5 Years STANDARD_DEVIATION 6.1 | 67.9 Years STANDARD_DEVIATION 12 | 71.2 Years STANDARD_DEVIATION 6.8 | 67.0 Years STANDARD_DEVIATION 3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 17 Participants | 7 Participants | 8 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 153 Participants | 34 Participants | 35 Participants | 4 Participants | 5 Participants | 21 Participants | 6 Participants | 5 Participants | 2 Participants | 11 Participants | 3 Participants | 8 Participants | 8 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 79 Participants | 19 Participants | 20 Participants | 3 Participants | 1 Participants | 16 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 96 Participants | 23 Participants | 25 Participants | 1 Participants | 4 Participants | 7 Participants | 4 Participants | 2 Participants | 1 Participants | 8 Participants | 2 Participants | 5 Participants | 6 Participants | 3 Participants | 3 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 45 / 45 | 4 / 4 | 3 / 3 | 4 / 5 | 9 / 9 | 8 / 8 | 38 / 42 | 3 / 3 | 11 / 11 | 2 / 2 | 3 / 5 | 6 / 6 | 21 / 23 | 5 / 5 | 4 / 4 |
| other Total, other adverse events | 43 / 45 | 4 / 4 | 3 / 3 | 5 / 5 | 9 / 9 | 8 / 8 | 41 / 42 | 3 / 3 | 11 / 11 | 2 / 2 | 5 / 5 | 6 / 6 | 23 / 23 | 5 / 5 | 4 / 4 |
| serious Total, serious adverse events | 29 / 45 | 2 / 4 | 3 / 3 | 3 / 5 | 7 / 9 | 6 / 8 | 34 / 42 | 3 / 3 | 7 / 11 | 1 / 2 | 3 / 5 | 3 / 6 | 16 / 23 | 3 / 5 | 3 / 4 |
Outcome results
Primary
Phase II: Number of Patients With Objective Response (Complete Remission (CR) + Complete Remission With Incomplete Blood Count Recovery (CRi))
Phase II: Number of patients with Objective Response (Complete remission (CR) + Complete remission with incomplete blood count recovery (CRi)). Complete remission (CR): morphologically leukaemia-free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no Auer rods, no evidence of extramedullary leukaemia) and absolute neutrophil count ≥1,000/microliter (μL) and platelets \>100,000/μL. Complete remission with incomplete blood count recovery (incomplete CR, CRi): all of the above criteria for CR were met except that neutrophils \<1,000/μL or platelets \<100,000/μL in the blood were not achieved.
Time frame: The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 869 days.
Population: Treated set-phase II part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase II: Number of Patients With Objective Response (Complete Remission (CR) + Complete Remission With Incomplete Blood Count Recovery (CRi)) | 6 Participants |
| Phase I Schedule B. Volasertib | Phase II: Number of Patients With Objective Response (Complete Remission (CR) + Complete Remission With Incomplete Blood Count Recovery (CRi)) | 13 Participants |
Comparison: Analysis for Objective Responsep-value: 0.052395% CI: [0.99, 8.58]Regression, Logistic
Primary
Phase I: Maximum Tolerated Dose (MTD) of Volasertib in Combination With LDAC (Schedule A) and Volasertib Monotherapy (Schedule B)
To determine the Maximum tolerated dose (MTD), dose escalation was conducted following the 3+3 design with de-escalation. The MTD was defined as the highest dose at which 6 patients had been treated and less than 2 patients experienced a Dose limiting toxicity (DLT) within the first cycle of treatment. The MTD was defined based on safety data from the first cycle only. DLT is defined as drug related Common terminology criteria for adverse events (CTCAE) grade ≥ 3 nonhaematological toxicity (excluding: untreated nausea, untreated vomiting, CTCAE grade 3 untreated diarrhoea, CTCAE grade 3 febrile neutropenia and CTCAE grade 3 infection with grade 3 or 4 neutrophils). In patients with complete remission with incomplete blood count recovery (CRi) or partial remission (PR), persistent CTCAE grade 4 neutropenia or thrombocytopenia until three weeks after the end of the treatment cycle will be regarded a DLT.
Time frame: First Treatment cycle, up to 28 days.
Population: Treated Set-phase I part: Treated Set was defined as all patients who received at least a single dose of either Volasertib (BI 6727) or LDAC (Low-Dose Cytarabine), including patients who were replaced for any reason.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase I: Maximum Tolerated Dose (MTD) of Volasertib in Combination With LDAC (Schedule A) and Volasertib Monotherapy (Schedule B) | 350 milligram (mg) |
| Phase I Schedule B. Volasertib | Phase I: Maximum Tolerated Dose (MTD) of Volasertib in Combination With LDAC (Schedule A) and Volasertib Monotherapy (Schedule B) | 450 milligram (mg) |
Primary
Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
A DLT was defined as a drug related CTCAE (Common Toxicity Criteria for Adverse Events) Grade ≥3 non-haematological toxicity (excluding untreated nausea, untreated vomiting, Grade 3 untreated diarrhea, Grade 3 febrile neutropenia, and Grade 3 infection with Grade 3 or 4 neutrophils). In patients with CRi (Complete Remission with Incomplete Blood Count Recovery) or PR (Partial Remission), persistent Grade 4 neutropenia or thrombocytopenia for 3 weeks after the end of the treatment cycle was regarded as a DLT unless the respective Grade 4 cytopenia was preexistent. In patients who required platelet substitution to maintain a Grade \<4 before treatment, a Grade 4 thrombocytopenia after treatment did not constitute a DLT.
Time frame: First Treatment cycle, up to 28 days.
Population: Treated Set-Phase I part: Treated Set was defined as all patients who received at least a single dose of either Volasertib (BI 6727) or LDAC (Low-Dose Cytarabine), including patients who were replaced for any reason.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Phase I Schedule B. Volasertib | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 1 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 Participants |
| Total Phase I Combined. Schedule A. | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 4 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 1 Participants |
| Phase I Schedule B. Volasertib 200 mg | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Phase I Schedule B. Volasertib 400 mg | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 1 Participants |
| Phase I Schedule B. Volasertib 450 mg | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 1 Participants |
| Phase I Schedule B. Volasertib 500 mg | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 Participants |
| Phase I Schedule B. Volasertib 550 mg | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 2 Participants |
| Total Phase I Combined. Schedule B. | Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 7 Participants |
Secondary
Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals
ECG (Electro Cardio Gram) Measurements: Absolute QTcF (QT Interval (interval from the beginning of the QRS complex to the end of the T wave) Corrected for Heart Rate Using Fridericia's Formula) Intervals. The 350 mg + LDAC arm of phase I and II were combined into one arm to provide maximum information on QT changes and presented together with the Phase I schedule B 450 mg arm, as pre specified in the study protocol.
Time frame: Baseline (Days -14 to -1) and day 1 (1 hour and 24 hours) after start of infusion.
Population: Treated Set-Phase I part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason. Only participants with non-missing values are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals | Individual baseline | 411.6 milliseconds (ms) | Standard Deviation 20.7 |
| Phase I Schedule A. Volasertib+LDAC | Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals | 1 hour after start of infusion | 430.0 milliseconds (ms) | Standard Deviation 20.4 |
| Phase I Schedule A. Volasertib+LDAC | Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals | 24 hour after start of infusion | 414.0 milliseconds (ms) | Standard Deviation 21.3 |
| Phase I Schedule B. Volasertib | Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals | 1 hour after start of infusion | 441.1 milliseconds (ms) | Standard Deviation 20 |
| Phase I Schedule B. Volasertib | Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals | Individual baseline | 412.4 milliseconds (ms) | Standard Deviation 18.7 |
| Phase I Schedule B. Volasertib | Absolute QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Intervals | 24 hour after start of infusion | 411.9 milliseconds (ms) | Standard Deviation 18.4 |
Secondary
Apparent Volume of Distribution of Volasertib at Steady State (VSS)
Apparent Volume of Distribution of volasertib at steady state (VSS) following Intravenous (i.v.) administration.
Time frame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration.
Population: Pharmacokinetic (PK) set which included all patients in the treated set who had at least 1 evaluable blood sample during cycle 1. Phase I Schedule B Volasertib 200mg+LDAC was not analysed as there was not enough plasma concentrations at the terminal phase of the curve to calculate the half-life for one of the two subjects.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 10600 Liter (L) | Geometric Coefficient of Variation 111 |
| Phase I Schedule B. Volasertib | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 8640 Liter (L) | Geometric Coefficient of Variation 14.1 |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 7000 Liter (L) | Geometric Coefficient of Variation 26.6 |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 6320 Liter (L) | Geometric Coefficient of Variation 35.9 |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 5270 Liter (L) | Geometric Coefficient of Variation 58.2 |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 4830 Liter (L) | Geometric Coefficient of Variation 56.7 |
| Total Phase I Combined. Schedule A. | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 10300 Liter (L) | Geometric Coefficient of Variation 36.3 |
| Phase I Schedule B. Volasertib 150 mg | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | NA Liter (L) | — |
| Phase I Schedule B. Volasertib 200 mg | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 5800 Liter (L) | Geometric Coefficient of Variation 35.1 |
| Phase I Schedule B. Volasertib 350 mg | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 7150 Liter (L) | Geometric Coefficient of Variation 70.6 |
| Phase I Schedule B. Volasertib 400 mg | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 5740 Liter (L) | Geometric Coefficient of Variation 38.7 |
| Phase I Schedule B. Volasertib 450 mg | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 6360 Liter (L) | Geometric Coefficient of Variation 50.1 |
| Phase I Schedule B. Volasertib 500 mg | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 5680 Liter (L) | Geometric Coefficient of Variation 81.9 |
| Phase I Schedule B. Volasertib 550 mg | Apparent Volume of Distribution of Volasertib at Steady State (VSS) | 6130 Liter (L) | Geometric Coefficient of Variation 42 |
Secondary
Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment
ECOG performance score change from baseline to last visit of last cycle = ECOG performance score at last visit of the last cycle - ECOG performance score at baseline. ECOG performance score changes from baseline were also categorised on a 3-point categorical scale: deteriorated (-1), unchanged (0), and improved (1). The number of participants for category of ECOG score change is reported.
Time frame: Baseline and End of Treatment (up to 869 days).
Population: Treated Set-Phase I part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason. Phase II part, the Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC. Only participants with non-missing values are reported.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 1 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 3 Participants |
| Phase I Schedule B. Volasertib | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 2 Participants |
| Phase I Schedule B. Volasertib | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 1 Participants |
| Phase I Schedule B. Volasertib | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 5 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 2 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 2 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 1 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 5 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 0 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 3 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 1 Participants |
| Total Phase I Combined. Schedule A. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 3 Participants |
| Total Phase I Combined. Schedule A. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 7 Participants |
| Total Phase I Combined. Schedule A. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 17 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 0 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 9 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 1 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 1 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 1 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 1 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 4 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 1 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 1 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 4 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 5 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 3 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 14 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 1 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 2 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 2 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 3 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 0 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 0 Participants |
| Total Phase I Combined. Schedule B. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 14 Participants |
| Total Phase I Combined. Schedule B. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 33 Participants |
| Total Phase I Combined. Schedule B. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 6 Participants |
| Phase II Schedule C. LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 8 Participants |
| Phase II Schedule C. LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 12 Participants |
| Phase II Schedule C. LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 22 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 15 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 13 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 11 Participants |
| Total Phase II Combined. Schedule A and C. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Improved | 21 Participants |
| Total Phase II Combined. Schedule A and C. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Unchanged | 37 Participants |
| Total Phase II Combined. Schedule A and C. | Best Eastern Co-operative Oncology Group (ECOG) Performance Score From Baseline Until End of Treatment | Deteriorated | 23 Participants |
Secondary
Best Overall Response
* CR * CR+CRi * Partial remission: CR except bone marrow (BM) contained ≥5% but \<25% blasts (or ≤50% initial blasts), or \<5% blasts in presence of Auer rods or abnormal morphology. * No change: survived ≥7 days (d) after 1st cycle with persistent leukemia in last peripheral blood smear or BM, or with persistent extramedullary disease, without further deterioration due to leukemia or increase of blasts in BM or peripheral blood. * Aplasia: survived ≥7d after 1st cycle, died whilst cytopenic, with last post-treatment BM result aplastic or hypoplastic and without leukemia blasts. * Indeterminate: survived \<7 d after 1st cycle or survived ≥7d after 1st cycle, died with no persistent leukemia in peripheral smear but no post-treatment BM examination or did not complete 1st cycle. * Progressive disease: survived ≥7d after 1st cycle with increase of blast population in BM or peripheral blood or aggravation or new extramedullary disease or further deterioration or death due to leukemia.
Time frame: The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 869 days.
Population: Treated Set-phase I part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason. Phase II part, the Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | Progressive disease | 2 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | No change | 2 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | CRi | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | No change | 1 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | Progressive disease | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule B. Volasertib | Best Overall Response | CRi | 2 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | Progressive disease | 1 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | CRi | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | Complete remission | 2 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Best Overall Response | No change | 2 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | No change | 1 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | Indeterminate | 2 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | Progressive disease | 3 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | Missing | 1 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | Not evaluable | 1 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Best Overall Response | CRi | 1 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Progressive disease | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | CRi | 1 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | No change | 1 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Indeterminate | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | Progressive disease | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | CRi | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | Indeterminate | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | No change | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Best Overall Response | Complete remission | 0 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | Not evaluable | 1 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | Missing | 1 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | Complete remission | 2 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | CRi | 4 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | Partial remission | 0 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | No change | 8 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | Aplasia | 0 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | Progressive disease | 10 Participants |
| Total Phase I Combined. Schedule A. | Best Overall Response | Indeterminate | 6 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | CRi | 0 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | Indeterminate | 1 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | No change | 4 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | Progressive disease | 6 Participants |
| Phase I Schedule B. Volasertib 150 mg | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | Progressive disease | 2 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | CRi | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Best Overall Response | No change | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | Progressive disease | 1 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | Partial remission | 1 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | No change | 2 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | CRi | 1 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | Aplasia | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | Aplasia | 1 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | Progressive disease | 1 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | No change | 2 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | CRi | 2 Participants |
| Phase I Schedule B. Volasertib 400 mg | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | Partial remission | 2 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | Not evaluable | 2 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | CRi | 2 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | Aplasia | 3 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | Progressive disease | 7 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib 450 mg | Best Overall Response | No change | 7 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | CRi | 0 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | No change | 3 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | Partial remission | 0 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | Aplasia | 1 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | Progressive disease | 1 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | Not evaluable | 0 Participants |
| Phase I Schedule B. Volasertib 500 mg | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | Progressive disease | 1 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | Missing | 0 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | Partial remission | 1 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | Not evaluable | 1 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | CRi | 0 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | Indeterminate | 0 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | Aplasia | 1 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | Complete remission | 0 Participants |
| Phase I Schedule B. Volasertib 550 mg | Best Overall Response | No change | 0 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | Progressive disease | 19 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | Partial remission | 4 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | Not evaluable | 3 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | Indeterminate | 1 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | Missing | 0 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | Complete remission | 0 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | Aplasia | 6 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | CRi | 5 Participants |
| Total Phase I Combined. Schedule B. | Best Overall Response | No change | 18 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | Indeterminate | 3 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | Aplasia | 0 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | Missing | 0 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | Progressive disease | 14 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | No change | 18 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | Partial remission | 2 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | Not evaluable | 2 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | CRi | 3 Participants |
| Phase II Schedule C. LDAC | Best Overall Response | Complete remission | 3 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Partial remission | 2 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Progressive disease | 7 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Complete remission | 6 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | No change | 15 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | CRi | 7 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Aplasia | 0 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Missing | 0 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Indeterminate | 5 Participants |
| Phase II Schedule A. Volasertib 350 mg+LDAC | Best Overall Response | Not evaluable | 0 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | Progressive disease | 21 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | Partial remission | 4 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | CRi | 10 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | Indeterminate | 8 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | Complete remission | 9 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | Not evaluable | 2 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | No change | 33 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | Aplasia | 0 Participants |
| Total Phase II Combined. Schedule A and C. | Best Overall Response | Missing | 0 Participants |
Secondary
Dose Normalized Area Under the Concentration-Time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated up to 4 Hours
AUC0-4,norm: Area under the concentration-time curve of Cytarabine in plasma over the time interval from zero extrapolated to 4 hours. The dose normalisation was done by dividing by dose applied. Unit: nanogram\*hour/milliliter/milligram: ((ng\*h/mL)/mg). Dose groups of Phase I were combined by dose normalizing as pre specified in the study protocol.
Time frame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h after first drug administration.
Population: Pharmacokinetic (PK) set which included all patients in the treated set who had at least 1 evaluable blood sample during cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Dose Normalized Area Under the Concentration-Time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated up to 4 Hours | 3.84 (ng*h/mL)/mg | Geometric Coefficient of Variation 30.6 |
| Phase I Schedule B. Volasertib | Dose Normalized Area Under the Concentration-Time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated up to 4 Hours | 4.00 (ng*h/mL)/mg | Geometric Coefficient of Variation 35.6 |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Dose Normalized Area Under the Concentration-Time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated up to 4 Hours | 3.94 (ng*h/mL)/mg | Geometric Coefficient of Variation 43.8 |
Secondary
Dose Normalized Maximum Measured Concentration of Cytarabine in Plasma (Cmax, Norm)
Cmax, norm: Maximum measured concentration of Cytarabine in plasma. The dose normalisation was done by dividing by the dose applied. Unit: nanogram/milliliter/milligram: ((ng/mL)/mg). Dose groups of Phase I were combined by dose normalizing as pre specified in the study protocol.
Time frame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration.
Population: Pharmacokinetic (PK) set which included all patients in the treated set who had at least 1 evaluable blood sample during cycle 1, Only participants with non-missing values are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Dose Normalized Maximum Measured Concentration of Cytarabine in Plasma (Cmax, Norm) | 2.92 (ng/mL)/mg | Geometric Coefficient of Variation 61.3 |
| Phase I Schedule B. Volasertib | Dose Normalized Maximum Measured Concentration of Cytarabine in Plasma (Cmax, Norm) | 2.83 (ng/mL)/mg | Geometric Coefficient of Variation 52.8 |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Dose Normalized Maximum Measured Concentration of Cytarabine in Plasma (Cmax, Norm) | 2.36 (ng/mL)/mg | Geometric Coefficient of Variation 77.6 |
Secondary
Phase II: Event Free Survival
Event-free survival (EFS) \[days\] was the shortest duration of the following: (a) Date of assessment indicating PD on the response page of the eCRF (Electronic Case Report Form) - date of randomisation + 1 day (b) Date of assessment indicating clinical progressive disease (PD) on the disease or responses pages of the of eCRF- date of randomisation + 1 day (c) Date of assessment indicating PD on the patient status page of the eCRF - date of randomisation +1 day (for patients who had not been censored before this time point) (d) Death date - date of randomisation +1 day Patients not being assessed PD, clinical PD, or death during the trial were censored. EFS was analysed with the Kaplan-Meier method for each of the treatment arms.
Time frame: The patients that entered the trial, and measured from the date of randomization to the date of disease progression (treatment failure), relapse or death from any cause, whichever occurred first, up to 1000 days..
Population: Treated Set-Phase II part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase II: Event Free Survival | 69.0 Days |
| Phase I Schedule B. Volasertib | Phase II: Event Free Survival | 169.0 Days |
Comparison: An exploratory (non-stratified) logrank test was used to compare the different treatment arms.p-value: 0.020895% CI: [0.35, 0.92]Log Rank
Secondary
Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles
Number of patients with AEs following in the in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported.
Time frame: From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 890 days.
Population: Treated set-Phase II part: the treated set (Phase II) was defined as all patients in Phase II who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 13 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 13 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 6 Participants |
| Phase I Schedule B. Volasertib | Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 12 Participants |
| Phase I Schedule B. Volasertib | Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 20 Participants |
| Phase I Schedule B. Volasertib | Phase II: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 8 Participants |
Secondary
Phase II: Overall Survival
Overall survival \[days\] = (date of death - date of randomisation + 1 day), for patients with known date of death. Overall survival (censored) \[days\] = (date of last trial visit or follow-up - date of randomisation + 1 day), for patients who were still alive at time of database lock. Overall survival (OS) was analysed with the Kaplan-Meier method for each of the treatment arms.
Time frame: The patients that entered the trial, and measured from the date of randomisation until death from any cause, up to 1100 days..
Population: Treated Set-Phase II part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase II: Overall Survival | 158.0 Days |
| Phase I Schedule B. Volasertib | Phase II: Overall Survival | 245.0 Days |
Comparison: An exploratory (non-stratified) logrank test was used to compare the different treatment arms.p-value: 0.046595% CI: [0.4, 1]Log Rank
Secondary
Phase II: Relapse - Free Survival
Relapse-free survival \[days\] = (date of first recurrence of disease or death after entering the trial - date of first occurrence of CR or CRi after entering the trial+ 1 day) for patients with a recurrence (this value should be positive). Relapse-free survival (censored) \[days\] = (date of last trial visit or follow-up - date of first occurrence of CR or CRi after entering the trial + 1 day) for patients who did not experience recurrence of disease or death at the time of analysis.
Time frame: The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence or death from any cause, whichever occurred first, up to 900 days.
Population: Patients in Treated Set-Phase II with objective response. Treated Set-Phase II part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase II: Relapse - Free Survival | 304.0 Days |
| Phase I Schedule B. Volasertib | Phase II: Relapse - Free Survival | 563.0 Days |
Secondary
Phase II: Remission Duration
Remission duration analysis was defined only for patients who achieved Complete remission (CR) or Complete remission with incomplete blood count recovery (CRi), and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse). For patients who died without report of relapse, remission duration was censored on the date of death, regardless of cause.
Time frame: The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse), up to 900 days.
Population: Patients in Treated Set-Phase II with objective response. Treated Set-Phase II part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase II: Remission Duration | 367.0 Days |
| Phase I Schedule B. Volasertib | Phase II: Remission Duration | 687.0 Days |
Secondary
Phase II: Time to Remission
Time to remission \[days\] = (date of first occurrence of CR or CRi after entering the trial-date of randomisation + 1 day) for patients with an objective response.
Time frame: The patients who achieved CR or CRi, and was measured from the date of attaining CR or CRi until the date of disease recurrence (relapse), up to 158 days.
Population: Patients in Treated Set-Phase II with objective response. Treated Set-Phase II part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase II: Time to Remission | 63.5 Days |
| Phase I Schedule B. Volasertib | Phase II: Time to Remission | 71.0 Days |
Secondary
Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi)
Phase I: Number of patients with Objective Response (Complete remission (CR) + Complete remission with incomplete blood count recovery (CRi)). Complete remission (CR): morphologically leukaemia-free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no Auer rods, no evidence of extramedullary leukaemia) and absolute neutrophil count ≥1,000/microliter (μL) and platelets \>100,000/μL. Complete remission with incomplete blood count recovery (incomplete CR, CRi): all of the above criteria for CR were met except that neutrophils \<1,000/μL or platelets \<100,000/μL in the blood were not achieved.
Time frame: The best overall response recorded during the time period from the start of the treatment until end of the treatment period, progression or death (whichever was earlier), up to 594 days.
Population: Treated Set-phase I part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 0 Participants |
| Phase I Schedule B. Volasertib | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 2 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 2 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 1 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 0 Participants |
| Total Phase I Combined. Schedule A. | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 6 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 0 Participants |
| Phase I Schedule B. Volasertib 200 mg | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 0 Participants |
| Phase I Schedule B. Volasertib 350 mg | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 1 Participants |
| Phase I Schedule B. Volasertib 400 mg | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 2 Participants |
| Phase I Schedule B. Volasertib 450 mg | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 2 Participants |
| Phase I Schedule B. Volasertib 500 mg | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 0 Participants |
| Phase I Schedule B. Volasertib 550 mg | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 0 Participants |
| Total Phase I Combined. Schedule B. | Phase I: Number of Patients With Objective Response: Complete Remission or Complete Remission With Incomplete Blood Count Recovery (CR+CRi) | 5 Participants |
Secondary
Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles
Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported.
Time frame: From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 615 days.
Population: Treated set-Phase I part: Treated set was defined as all patients in Phase I who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 1 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 1 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 1 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 3 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 0 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 5 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 5 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 1 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 2 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 2 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 1 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 7 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 18 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 5 Participants |
Secondary
Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1
Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported.
Time frame: First treatment cycle, up to 28 days.
Population: Treated set-Phase I part: Treated set was defined as all patients in Phase I who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 2 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 0 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 3 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 0 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 1 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 3 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 5 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 1 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 2 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 2 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 1 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 6 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 17 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule A: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 5 Participants |
Secondary
Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles
Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported.
Time frame: From first drug administration until 21 days after the last trial drug administration in the last treatment cycle, up to 597 days.
Population: Treated set-Phase I part: the treated set was defined as all patients in Phase I who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 2 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 4 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 5 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 1 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 1 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 1 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 3 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 5 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 3 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 15 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 2 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 1 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 3 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 0 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 1 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 4 | 32 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 5 | 9 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During All Cycles | Grade 3 | 9 Participants |
Secondary
Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1
Number of patients with AEs following in the categories 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related AE) of CTCAE is reported.
Time frame: First treatment cycle, up to 28 days.
Population: Treated set-Phase I part: Treated set was defined as all patients in Phase I who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 1 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 5 Participants |
| Phase I Schedule A. Volasertib+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 4 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 1 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 1 Participants |
| Phase I Schedule B. Volasertib | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 3 Participants |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 1 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 0 Participants |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 4 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 2 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 14 Participants |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 5 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 0 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 1 Participants |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 1 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 1 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 3 Participants |
| Total Phase I Combined. Schedule A. | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 0 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 5 | 6 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 4 | 30 Participants |
| Phase I Schedule B. Volasertib 150 mg | Phase I Schedule B: Number of Participants With Adverse Events (AEs) Graded According to Common Terminology Criteria for Adverse Events (CTCAE), Based on the Number of Patients With AEs With CTCAE Grade ≥3 During Cycle 1 | Grade 3 | 11 Participants |
Secondary
QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Change From Baseline at Cycle 1
ECG Measurements: QTcF (QT Interval (interval from the beginning of the QRS complex to the end of the T wave) changes from baseline at each time point: The QTcF post baseline measurement obtained at time t minus baseline QTcF measurement. The 350 mg + LDAC arm of phase I and II were combined into one arm to provide maximum information on QT changes and presented together with the Phase I schedule B 450 mg arm, as pre specified in the study protocol.
Time frame: Baseline (Days -14 to -1) and day 1 (1 hour and 24 hours) after start of infusion.
Population: Treated Set-Phase I part: Treated Set was defined as all patients who received at least a single dose of either Volasertib or LDAC, including patients who were replaced for any reason. Only participants with non-missing values are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Change From Baseline at Cycle 1 | Change from baseline after 1 hour | 18.5 millisecond (ms) | Standard Deviation 10.4 |
| Phase I Schedule A. Volasertib+LDAC | QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Change From Baseline at Cycle 1 | Change from baseline after 24 hour | 1.9 millisecond (ms) | Standard Deviation 10.5 |
| Phase I Schedule B. Volasertib | QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Change From Baseline at Cycle 1 | Change from baseline after 1 hour | 29.6 millisecond (ms) | Standard Deviation 8.1 |
| Phase I Schedule B. Volasertib | QTcF (QT Interval Corrected for Heart Rate Using Fridericia's Formula) Change From Baseline at Cycle 1 | Change from baseline after 24 hour | -0.5 millisecond (ms) | Standard Deviation 9.8 |
Secondary
Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib
Total Clearance (CL) of Volasertib in Plasma after Intravenous (i.v.) Administration of Volasertib.
Time frame: Cycle 1: -0:05 hour (h), 0:30h, 1:00h, 1:30h, 2h, 3h, 4h, 24h, 96h, 216h, 335:55h, 336:30h, 337h, 337:30h, 338h, 339h, 340h, 648h after first drug administration.
Population: Pharmacokinetic (PK) set which included all patients in the treated set who had at least 1 evaluable blood sample during cycle 1. Phase I Schedule B Volasertib 200mg+LDAC was not analysed as there was not enough plasma concentrations at the terminal phase of the curve to calculate the half-life for one of the two subjects.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I Schedule A. Volasertib+LDAC | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 1280 millilitre/minute (mL/min) | Geometric Coefficient of Variation 52.8 |
| Phase I Schedule B. Volasertib | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 972 millilitre/minute (mL/min) | Geometric Coefficient of Variation 26.6 |
| Phase I Schedule A. Volasertib 250 mg+LDAC | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 864 millilitre/minute (mL/min) | Geometric Coefficient of Variation 27.6 |
| Phase I Schedule A. Volasertib 300 mg+LDAC | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 1150 millilitre/minute (mL/min) | Geometric Coefficient of Variation 34.4 |
| Phase I Schedule A. Volasertib 350 mg+LDAC | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 1000 millilitre/minute (mL/min) | Geometric Coefficient of Variation 36.2 |
| Phase I Schedule A. Volasertib 400 mg+LDAC | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 852 millilitre/minute (mL/min) | Geometric Coefficient of Variation 49.6 |
| Total Phase I Combined. Schedule A. | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 1330 millilitre/minute (mL/min) | Geometric Coefficient of Variation 29.3 |
| Phase I Schedule B. Volasertib 150 mg | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | NA millilitre/minute (mL/min) | — |
| Phase I Schedule B. Volasertib 200 mg | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 810 millilitre/minute (mL/min) | Geometric Coefficient of Variation 35.1 |
| Phase I Schedule B. Volasertib 350 mg | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 1120 millilitre/minute (mL/min) | Geometric Coefficient of Variation 62.1 |
| Phase I Schedule B. Volasertib 400 mg | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 920 millilitre/minute (mL/min) | Geometric Coefficient of Variation 36.2 |
| Phase I Schedule B. Volasertib 450 mg | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 1140 millilitre/minute (mL/min) | Geometric Coefficient of Variation 38.5 |
| Phase I Schedule B. Volasertib 500 mg | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 939 millilitre/minute (mL/min) | Geometric Coefficient of Variation 93.2 |
| Phase I Schedule B. Volasertib 550 mg | Total Clearance (CL) of Volasertib in Plasma After i.v (Intravenous) Administration of Volasertib | 897 millilitre/minute (mL/min) | Geometric Coefficient of Variation 42.8 |