A Phase I/II, Multicentre, Open-label, Dose Escalation and Randomized Trial of BI 836858 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes

Maximum Tolerated Dose (MTD) (Phase I)

时间窗: From the first administration of BI 836858 to start of the third administration of BI 836858, excluding the day of the third administration of BI 836858, up to 28 days

The MTD is defined as the highest dose of BI 836858 with less than 25% risk of the true dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period. MTD determination will be based on a Bayesian logistic regression model with overdose control. For any dose-escalation cohort, at least 3 patients (pts) will be required. However, in the case that only 2 pts are evaluable and neither has experienced a DLT within the first cycle (2 administrations - 28 days), then dose-escalation can occur based on these 2 pts. After all pts in a cohort have either experienced a DLT or have been observed for at least one cycle (2 administrations - 28 days) without experiencing a DLT, the Bayesian model will be updated with the newly accumulated data. The MTD may be considered reached if either the posterior probability of the true DLT rate in the target interval (16%-33%) is above 50%, or at least 12 pts have been treated at MTD, including the two expansion cohorts.

Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase II)

时间窗: From first administration of BI 836858 until discontinuation of the treatment. Up to 168 days (6 cycles, each of 28 days)

Red blood cell (RBC) transfusion independence and platelet transfusion independence will be evaluated in patients who are transfusion dependent at baseline. Percentages will be calculated using all treated patients as the denominator. A patient is considered transfusion independent at baseline if the patient has had no transfusions during the 56 days prior to and including the first day of treatment. Otherwise, the patient is considered to be transfusion dependent. A patient is considered transfusion independent if the patient has had no transfusions over the course of ≥ 56 consecutive days.

Number of Patients With Dose Limiting Toxicity (DLT) (Phase I)

时间窗: From the first administration of BI 836858 to start of the third administration of BI 836858, excluding the day of the third administration of BI 836858, up to 28 days

Dose Limiting Toxicity (DLT): * Grade (G) ≥ 3 (CTCAE 4.0), non disease-related, non-hematologic adverse events (AE), except: * Laboratory abnormality, not significant by investigator or resolves spontaneously or can be recovered with appropriate treatment (T) within 5 d * Neutrophils (NP) \<500 /microliters (μL) at T start, febrile neutropenia with NP \<500 /μL or infection with NP \<500 /μL will not constitute a DLT if they can be recovered with appropriate T within 14 d * Inability to deliver study drug full dose according to the assigned dose level within cycle 1 due to drug-related AEs * Absence of hematological recovery as following: * NPs: G 4 (if G 0/1 at baseline (BL)) OR \<100 /μL and decrease of \>75% from BL (if G ≥2 at BL) for \>7 d * Platelets: G 4 (if G 0/1 at BL) OR \< 10000/μL for \>7 d and decrease of \>75% from BL (if G ≥2 at BL) * T delay of ≥4 weeks of start of Cycle 2 --If Cycle 2 is not started until 57th d as a result of drug related AE, it is considered as DLT