BI 811283 in Combination With Cytarabine in Previously Untreated AML Ineligible for Intensive Treatment

The MTD was defined as the highest dose at which 6 patients were treated and less than 2 patients who experienced a dose limiting toxicities (DLT) within the first cycle of treatment.The MTD was defined based on safety data from the first cycle only.

It was determined using a standard "3 + 3 design with de-escalation".

Response to treatment was evaluated according to the following criteria (modified from the National Cancer Institute/Cancer and Leukemia Group B criteria:

The best overall response was defined as the best overall response recorded during the time period from the start of the treatment until the end of the treatment period, progression or death (whichever was earlier). Possible categories for best overall response were CR, CRi, Partial remission (PR), no change (NC), Progressive disease (PD) and no assessment.

• 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/μL and platelets > 100,000/μL.
• Complete remission with incomplete blood count recovery ("incomplete" CR, CRi).All of the above criteria for CR had to be met, except that neutrophils < 1,000/μL or platelets < 100,000/μL in the blood.

The severity and timing of AEs indicates how well the treatment regimen was tolerated.

Toxicities were evaluated using the common terminology criteria for adverse events (CTCAE) grading scheme.

Number of participants with DLT in the first cycle (28 days) for the determination of the maximum tolerated dose (MTD)

Response to treatment was evaluated according to the following criteria (modified from the National Cancer Institute/Cancer and Leukemia Group B criteria; The best overall response was defined as the best overall response recorded during the time period from the start of the treatment until the end of the treatment period, progression or death (whichever was earlier). Possible categories for best overall response were CR, CRi, Partial remission (PR), no change (NC), Progressive disease (PD) and no assessment.

Partial remission (PR). All of the criteria for CR had to be met, except that the bone marrow had to contain ≥ 5% but less than 25% blasts (or ≤ 50% of initial blast count), or < 5% blasts in the presence of Auer rods or abnormal morphology.

EFS was defined as the duration of time from randomisation to time of treatment failure (i.e. PD), relapse from CR, or death from any cause, whichever came first.

Relapse-free survival was defined only for patients who achieved CR/CRi and was measured from the date of attaining CR/CRi until the date of recurrence or death from any cause, whichever occurred first.

Number of patients having relapse free survival are presented.

Remission duration analysis was defined only for patients who achieved CR, and was measured from the date of attaining CR 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 the cause.

OS was defined for all patients that entered the trial, and measured from the date of randomization until death from any cause.

Cmax (maximum measured concentration of BI 811283 in plasma) during Cycle 1

AUC(0-inf) (area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 extrapolated to infinity) during Cycle 1

AUC0-tz (area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 to the time of the last quantifiable data point) during Cycle 1

Cmax (maximum measured concentration of BI 811283 in plasma at steady state) during Cycle 1

AUC (0-inf, ss)(area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 extrapolated to infinity) at steady state during Cycle 1

AUC (0-tz,ss) (area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 to the time of the last quantifiable data point) at steady state during Cycle 1

tmax (time from dosing to maximum measured concentration of BI 811283 in plasma) during Cycle 1

tmax,ss (time from dosing to maximum measured concentration of BI 811283 in plasma at steady state) during Cycle 1

Cmax of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

Tmax of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

AUC (0-inf) of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

AUC (0-tz) of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

Pharmacodynamic monitoring: drug effect on leukaemia cells (e.g. polyploidy, histone H3 phosphorylation, morphologic changes).

An evaluation of this secondary endpoint is not possible due to missing samples / samples of poor quality of the provided material.

The study protocol originally included a phase II part with a treatment arm in which Cytarabine was given alone, however the sponsor discontinued the clinical development of BI 811283, therefore the protocol was amended and the reference therapy arm was removed from the study protocol" -> (Protocol Amendment 5, version 19 -May-2010, approved 28-Jun-2010).

Since there was never a treatment arm in which Cytarabine was given alone; hence pharmacokinetics are not calculated.