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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: BI 811283 (d 1 and 15)
* Drug: Cytarabine
* Drug: BI 811283 (d1)
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female adult with previously untreated acute myeloid leukaemia (AML) Confirmed diagnosis of AML according to the WHO definition (except for acute promyelocytic leukaemia, APL) Patient is considered ineligible for intensive treatment Patient is eligible for low-dose cytarabine (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: Patient with APL (AML subtype M3 according to the French-American-British (FAB) classification). Relapsed or treatment refractory AML. Hypersensitivity to one of the trial drugs or the excipients. Other malignancy requiring treatment. Known central nervous system involvement. Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (ULN). INR > 1.5 x ULN for subjects not on therapeutic vitamin K antagonists (phenprocoumon, warfarin). Bilirubin greater than 1.5 mg/dl. Serum creatinine greater than 2.0 mg/dl. LVEF (Left ventricular ejection fraction) < 50% in echocardiography or clinical congestive heart failure New York Heart Association (NYHA) grade III or IV. Concomitant intercurrent illness, which would compromise the evaluation of efficacy or safety of the trial drug, e.g. active severe infection, unstable angina pectoris or cardiac arrhythmia. 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 (i.e. other chemo- or immunotherapy, see also section 4.2.2). Contraindications for cytarabine treatment according to the summary of product characteristics (SPC). Patients who are sexually active and unwilling to use a medically acceptable method of contraception during the trial (hormonal contraception, intrauterine device, condom with spermicide, etc.). Pregnant or nursing female patients. Patient unable to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Schedule A<br>BI 811283 on days 1 and 15 in combination with Cytarabine 20 mg twice daily on Days 1-10 | Drug: BI 811283 (d 1 and 15)<br>* BI 811283 (24 hours i.v.c.i.) on day 1 and 15 of a 4-week treatment cycle<br>Drug: Cytarabine<br>* Cytarabine 2 x 20 mg/d s.c. on days 1-10 of a 4-week treatment cycle<br>|
| Experimental: Schedule B<br>BI 811283 on Day 1 in combination with Cytarabine 20 mg twice daily on Days 1-10 | Drug: Cytarabine<br>* Cytarabine 2 x 20 mg/d s.c. on days 1-10 of a 4-week treatment cycle<br>Drug: BI 811283 (d1)<br>* BI 811283 (24 hours i.v.c.i.) on day 1 of a 4-week treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Tolerated Dose (MTD) of 2 Schedules of BI 811283 in Combination With Cytarabine. | 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. | up to 28 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (Complete Remission [CR], Complete Remission With Incomplete Blood Count Recovery [CRi]) | 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. | Data collected up to cut-off date 20Oct2011, Up to 1239 days | 
| Incidence and Intensity of AEs Graded According to CTCAE (Version 3.0) | 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. | Data from first treatment administration until cut-off date of 20 October 2011; up to 1239 days | 
| Incidence of Dose Limiting Toxicity (DLT) | Number of participants with DLT in the first cycle (28 days) for the determination of the maximum tolerated dose (MTD) | up to 28 days of treatment | 
| Partial Remission | 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. | Data collected up to cut-off date 20 Oct 2011, Up to 1239 days | 
| Event Free Survival (EFS) | 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. | Data collected up to cut-off date 20 Oct 2011, Up to 1239 days | 
| Relapse Free Survival | 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. | Data collected up to cut-off date 20 Oct 2011, Up to 1239 days | 
| Remission Duration | 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. | Data collected up to cut-off date 20 Oct 2011, Up to 1239 days | 
| Overall Survival (OS) | OS was defined for all patients that entered the trial, and measured from the date of randomization until death from any cause. | Data collected up to cut-off date 20 Oct 2011, Up to 1239 days | 
| Cmax (Maximum Measured Concentration of BI 811283 in Plasma) | Cmax (maximum measured concentration of BI 811283 in plasma) during Cycle 1 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| AUC(0-inf) (Area Under the Concentration-time Curve of BI 811283 in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 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 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| 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) | 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 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| Cmax,ss (Maximum Measured Concentration of BI 811283 in Plasma at Steady State) | Cmax (maximum measured concentration of BI 811283 in plasma at steady state) during Cycle 1 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| 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-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 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| 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 | 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 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| Tmax (Time From Dosing to Maximum Measured Concentration of BI 811283 in Plasma) | tmax (time from dosing to maximum measured concentration of BI 811283 in plasma) during Cycle 1 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| Tmax,ss (Time From Dosing to Maximum Measured Concentration of BI 811283 in Plasma at Steady State) | tmax,ss (time from dosing to maximum measured concentration of BI 811283 in plasma at steady state) during Cycle 1 | -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 | 
| Cmax (Maximum Measured Concentration of Cytarabine in Plasma) | Cmax of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283 | -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine | 
| Tmax (Time From Dosing to Maximum Measured Concentration of Cytarabine in Plasma) | Tmax of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283 | -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine | 
| AUC (0-inf) (Area Under the Concentration-time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | AUC (0-inf) of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283 | -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine | 
| 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) | AUC (0-tz) of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283 | -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine | 
| Pharmacodynamic Monitoring | 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. | On Day 5, i.e. 72 hours after the end of the first BI 811283 infusion, and on Day 28 in the first cycle only | 
| Pharmacokinetics of Cytarabine After a Single Dose and at Steady State When Given Alone | 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. | -0.05, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours |