Phase I/IIa Trial to Investigate BI 6727 (Volasertib) as Monotherapy or in Combination With Cytarabine in Acute Myeloid Leukaemia

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)).

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.

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.

• 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.

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.

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.

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.

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.

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 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.

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 Intravenous (i.v.) Administration of Volasertib.

Apparent Volume of Distribution of volasertib at steady state (VSS) following Intravenous (i.v.) 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.

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.

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.

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.

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.

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.

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.

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.

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.