The primary objective of this trial is: Part I * To determine Maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BI 836880 monotherapy Part II * To determine MTD and/or RP2D of the combination therapy of BI 836880 and BI 754091 The secondary objectives are: Part I * To document the safety and tolerability, and characterise pharmacokinetics (PK) of BI 836880 as monotherapy Part II * To document the safety and tolerability, and characterise PK of the combination therapy of BI 836880 and BI 754091
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Solution for infusion
Solution for infusion
Shizuoka Cancer Center
Shizuoka, Sunto-gun, Japan
National Cancer Center Hospital
Tokyo, Chuo-ku, Japan
Maximum Tolerated Dose (MTD) of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI754091
Maximum tolerated dose (MTD) of BI 836880 monotherapy (Part 1) and combination therapy of BI 836880 and BI75409 (Part 2). The MTD was defined as the highest dose with less than 25% risk of the true dose-limiting toxicity (DLT) rate being equal or above 0.33 (EWOC criterion) during the MTD evaluation period. The analysis of the MTD was based on a Bayesian logistic regression model (BLRM) guided by the escalation with overdose control principle. The estimated probability of a DLT at each dose level from the model was summarized using the following intervals: Underdosing: \[0.00, 0.16) Targeted toxicity: \[0.16, 0.33) Over toxicity: \[0.33, 1.00\]
Time frame: First treatment cycle, the first 21 days following the start of trial medication.
Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle
Number of participants with DLT occurring during the first treatment cycle. DLT was defined as any of the following adverse events related to the treatment: Haematologic toxicities: -Any Grade 5 toxicity,-Neutropenia Grade 4 lasting for \>7 days,-Grade ≥3 documented infection with neutropenia,-Febrile neutropenia (absolute neutrophil count \<1.0 X 109 cells/L and fever ≥38.5C or a sustained temperature of ≥38.0 Centigrade (C) for more than 1 hour),-Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding,-Thrombocytopenia of any Grade which requires platelet transfusions,-Grade 4 anaemia unexplained by underlying disease,-Anaemia of any Grade which requires blood transfusions. Non-haematological toxicities: - Aspartate transaminase (AST) or Alanin-Aminotransferase (ALT) \>3 times Upper Level of Normal (ULN) and concurrent total bilirubin \>2 times ULN without initial findings of cholestasis,-≥ Grade 4 AST or ALT of any duration.
Time frame: First treatment cycle, the first 21 days following the start of trial medication.
Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 1
Maximum measured concentration of BI 836880 at Cycle 1 in Part 1 (monotherapy) and Part 2 (combination therapy) in plasma (Cmax) is reported.
Time frame: Part 1(P1): Within 5 minutes(min) before, at 1 hour(h), 1.5h, 2.5h, 4.5h, 7.5h, 24h, 48h, 168h, 336h after Cycle 1 dose. Part 2(P2): Within 5 min before and at 1h, 2h15min, 6h, 24h, 168h, 336h after Cycle 1 dose. P1,P2: Within 5min before Cycle 2 dose.
Area Under the Concentration-time Curve of BI 836880 in Part 1 and Part 2 in Plasma Over the Time Interval From 0 to 504 Hours (AUC0-504h) at Cycle 1
Area under the concentration-time curve of BI 836880 in Part 1 (monotherapy) and in Part 2 (combination therapy) in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported.
Time frame: Part 1(P1): Within 5 minutes(min) before and at 1 hour(h), 1.5h, 2.5h, 4.5h, 7.5h, 24h, 48h, 168h, 336h after Cycle 1 dose. Part 2(P2): Within 5min before and at 1h, 2h15min, 6h, 24h, 168h, 336h after Cycle 1 dose. P1,P2: Within 5min before Cycle 2 dose.
Maximum Measured Concentration of BI 836880 in Part 1 in Plasma (Cmax) at Cycle 2
Maximum measured concentration of BI 836880 at Cycle 2 in Part 1 (monotherapy) in plasma (Cmax) is reported.
Time frame: Within 5 minutes (min) before and at 1 hour (h), 1.5h, 2.5h, 4.5h, 7.5h, 24h, 48h, 168h, 336h after dose in Cycle 2. Also, Within 5 min before Cycle 3 dose.
Area Under the Concentration-time Curve of BI 836880 in Part 1 in Plasma Over the Time Interval From 0 to 504 Hours (AUC0-504h) at Cycle 2
Area under the concentration-time curve of BI 836880 in Part 1 (monotherapy) at Cycle 2 in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported.
Time frame: Within 5 minutes (min) before and at 1 hour (h), 1.5h, 2.5h, 4.5h, 7.5h, 24h, 48h, 168h, 336h after dose in Cycle 2. Also, Within 5 min before Cycle 3 dose.
Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 4
Maximum measured concentration of BI 836880 at Cycle 4 in Part 1 (monotherapy) and Part 2 (combination therapy) in plasma (Cmax) is reported.
Time frame: Part 1(P1): Within 5 minutes (min) before and at 1 hour (h), 1.5h, 2.5h, 4.5h, 7.5h, 24h, 168h, 336h after Cycle 4 dose. Part 2(P2): Within 5min before and at 1 h, 2h15min, 6h, 24h, 168h, 336h after Cycle 4 dose. P1,P2: Within 5min before Cycle 5 dose.
Area Under the Concentration-time Curve of BI 836880 in Part1 and Part 2 in Plasma Over the Time Interval From 0 to 504 Hours (AUC0-504h) at Cycle 4
Area under the concentration-time curve of BI 836880 in Part 1 (monotherapy) and in Part 2 (combination therapy) at Cycle 4 in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported.
Time frame: Part 1(P1): Within 5 minutes (min) before and at 1 hour (h), 1.5h, 2.5h, 4.5h, 7.5h, 24h, 168h, 336h after Cycle 4 dose. Part 2(P2): Within 5min before and at 1 h, 2h15min, 6h, 24h, 168h, 336h after Cycle 4 dose. P1,P2: Within 5min before Cycle 5 dose.
Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 1
Maximum measured concentration of Ezabenlimab (BI 754091) at Cycle 1 in Part 2 (combination therapy) in plasma (Cmax) is reported.
Time frame: Within 5 min before and at 1h, 2h15min, 6h, 24h, 168h, 336h after Cycle 1 dose. Also, Within 5 min before Cycle 2 dose.
Area Under the Concentration-time Curve of Ezabenlimab (BI 754091) in Part 2 in Plasma Over the Time Interval From 0 to 504 Hours (AUC0-504h) at Cycle 1
Area under the concentration-time curve of Ezabenlimab (BI 754091) in Part 2 (combination therapy) in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported.
Time frame: Within 5 min before and at 1h, 2h15min, 6h, 24h, 168h, 336h after Cycle 1 dose. Also, Within 5 min before Cycle 2 dose.
Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 4
Maximum measured concentration of Ezabenlimab (BI 754091) at Cycle 4 in Part 2 (combination therapy) in plasma (Cmax) is reported.
Time frame: Within 5 min before and at 1 h, 2h15min, 6h, 24h, 168h, 336h after dosing in Cycle 4. Also, Within 5 min before Cycle 5 dose.
Area Under the Concentration-time Curve of Ezabenlimab (BI 754091) in Part 2 in Plasma Over the Time Interval From 0 to 504 Hours (AUC0-504h) at Cycle 4
Area under the concentration-time curve of Ezabenlimab (BI 754091) in Part 2 (combination therapy) in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported.
Time frame: Within 5 min before and at 1 h, 2h15min, 6h, 24h, 168h, 336h after dosing in Cycle 4. Also, Within 5 min before Cycle 5 dose.
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