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BI 811283 on days 1 and 15 in combination with Cytarabine 20 mg twice daily on Days 1-10

BI 811283 on Day 1 in combination with Cytarabine 20 mg twice daily on Days 1-10

BI 811283 (24 hours i.v.c.i.) on day 1 and 15 of a 4-week treatment cycle

BI 811283 (d 1 and 15)

Cytarabine 2 x 20 mg/d s.c. on days 1-10 of a 4-week treatment cycle

BI 811283 (24 hours i.v.c.i.) on day 1 of a 4-week treatment cycle

BI 811283 (d1)

Boehringer Ingelheim

Investigation of maximum tolerated dose, safety, efficacy and pharmcokinetics of BI 811283 in combination with cytarabine (LD-Ara-C) in previously untreated acute myeloid leukaemia (AML) patients

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

An Open Phase I/IIa Trial to Investigate the Maximum Tolerated Dose, Safety, Efficacy and Pharmacokinetics of BI 811283 in Combination With Cytarabine in Patients With Previously Untreated Acute Myeloid Leukaemia 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.

5 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment Schedule A: BI 811283 on Days 1 + 15 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

5 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule A

15 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment Schedule A: BI 811283 on Days 1 + 15 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

15 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule A

30 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment Schedule A: BI 811283 on Days 1 + 15 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

30 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule A

60 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment Schedule A: BI 811283 on Days 1 + 15 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

60 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule A

100 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment Schedule A: BI 811283 on Days 1 + 15 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

100 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule A

120 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment Schedule A: BI 811283 on Days 1 + 15 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

120 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule A

5 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

5 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

40 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

40 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

80 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

80 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

160 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

160 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

240 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

240 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

300 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

300 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

360 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

360 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

420 mg of BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection);

Treatment schedule B: BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle);

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

420 mg BI 811283 + 20 mg Cytarabine - Treatment Schedule B

Total

Age, Continuous

Sex: Female, Male

68 participants were randomised, and 64 were treated with the study treatment hence the number of participants differs from the number of participants that started in the participant flow.

Boehringer Ingelheim Call Center

Subjects received BI 811283 on Days 1 + 15 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle).

BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection).

The starting dose for BI 811283 was 5 mg, with dose levels of 5, 15, 30, 60, 100 and 120 mg used in Schedule A.

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

Treatment Schedule A

Subjects received BI 811283 on Day 1 in combination with cytarabine 20 mg twice daily on Days 1-10 (28-day cycle).

BI 811283 (preconcentrate for infusion after dilution) in combination with cytarabine (solution for injection).

The starting dose for BI 811283 was 5 mg, with dose levels of 5, 40, 80, 160, 240, 300, 360 and 420 mg being used in Schedule B.

BI 811283: 24-hour continuous intravenous infusion Cytarabine: subcutaneous injection

Treatment Schedule B

Treated set (TS): All patients who received at least one single dose of trial medication (BI 811283 or cytarabine) were considered.

The Maximum Tolerated Dose (MTD) of 2 Schedules of BI 811283 in Combination With Cytarabine.

Response (Complete Remission [CR], Complete Remission With Incomplete Blood Count Recovery [CRi])

CTCAE Grade 1

CTCAE Grade 2

CTCAE Grade 3

CTCAE Grade 4

CTCAE Grade 5

Incidence and Intensity of AEs Graded According to CTCAE (Version 3.0)

Incidence of Dose Limiting Toxicity (DLT)

Partial Remission

Event Free Survival (EFS)

Treated set (Only patients with observed cases (OC) values were analysed)

Relapse Free Survival

240 mg BI 811283+ 20 mg Cytarabine - Treatment Schedule B

Remission Duration

Overall Survival (OS)

30 mg BI 811283 + 20 mg Cytarabine- Treatment Schedule A

120mg (BI 811283+ Cytarabine)- Treatment Schedule A

Treated Set (Only patients with observed cases (OC) values were analysed)

Cmax (Maximum Measured Concentration of BI 811283 in Plasma)

AUC(0-inf) (Area Under the Concentration-time Curve of BI 811283 in Plasma Over the Time Interval From 0 Extrapolated to Infinity)

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)

Treated set (Only patients with observed cases (OC) values were analysed). Steady state analyses is not applicable for Treatment Schedule B, since pharmacokinetic analyses was performed after a single dose for Treatment Schedule B.

Cmax,ss (Maximum Measured Concentration of BI 811283 in Plasma at Steady State)

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

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

Tmax (Time From Dosing to Maximum Measured Concentration of BI 811283 in Plasma)

Tmax,ss (Time From Dosing to Maximum Measured Concentration of BI 811283 in Plasma at Steady State)

Cmax (Maximum Measured Concentration of Cytarabine in Plasma)

Tmax (Time From Dosing to Maximum Measured Concentration of Cytarabine in Plasma)

AUC (0-inf) (Area Under the Concentration-time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated to Infinity)

AUC (0-tz) (Area Under the Concentration-time Curve of Cytarabine in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
BI 811283 in Combination With Cytarabine in Previously Untreated AML Ineligible for Intensive Treatment	NCT00632749	Leukemia, Myelo...	BI 811283 (d 1 ... Cytarabine BI 811283 (d1) Cytarabine	18 Years -	Boehringer Ingelheim
BI 811283 in Combination With Cytarabine in Previously Untreated AML Ineligible for Intensive Treatment	NCT00632749	Leukemia, Myelo...	BI 811283 (d 1 ... Cytarabine BI 811283 (d1) Cytarabine	18 Years -	Boehringer Ingelheim

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