The main objective of the dose-escalation parts of the trial is to determine the maximum tolerated dose (MTD), based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and to evaluate its safety and tolerability by monitoring the occurrence and severity of adverse events (AEs). Secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and the preliminary assessment of anti-tumour activity.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
62
Part A, Part B
Part B
Florida Cancer Specialists
Sarasota, Florida, United States
Sarah Cannon Research Institute
Nashville, Tennessee, United States
Froedtert and The Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Part A - Maximum Tolerated Dose (MTD) of BI 891065
Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Part B: Maximum Tolerated Dose (MTD) of BI 891065 in Combination With Ezabenlimab
Maximum tolerated dose (MTD) of BI 891065 in combination with ezabenlimab, defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: From first drug administration until last drug administration plus residual effect period of 30 days, up to 282 days.
Part A: Number of Patients With Objective Response (OR)
OR based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, defined as the best overall response of complete response (CR) and partial response (PR), where the best overall response is the best time point response recorded from the first administration of study medication until the end of treatment Number of patients with objective response is reported.
Time frame: Up to 252 days.
Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss)
Maximum measured plasma concentration at steady state (cmax,ss) during the first treatment cycle. Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg.
Time frame: Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.
Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss)
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Area under the concentration time curve of BI 891065 over a dosing interval at steady state (AUCtau,ss). Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg.
Time frame: Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.
Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 891065 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle. Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg.
Time frame: Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.
Part B: Number of Patients With Dose-limiting Toxicities (DLTs) Observed During the Entire Treatment Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: From first drug administration until last drug administration plus residual effect period of 30 days, up to 386 days.
Part B: Number of Patients With Objective Response (OR)
OR based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, defined as the best overall response of complete response (CR) and partial response (PR), where the best overall response is the best time point response recorded from the first administration of study medication until the end of treatment. Number of patients with objective response is reported.
Time frame: Up to 356 days.
Part B: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 891065 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle.
Time frame: At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1.
Part B: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss)
Area under the concentration time curve of BI 891065 over a dosing interval at steady state (AUCtau,ss) in the first treatment cycle.
Time frame: At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1.
Part B: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss)
Maximum measured plasma concentration of BI 891065 at steady state (Cmax,ss) in the first treatment cycle.
Time frame: At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1.
Part B: Maximum Measured Plasma Concentration (Cmax) of BI 754091 in the First Treatment Cycle
Maximum measured plasma concentration (Cmax) of BI 754091 in the first treatment cycle. Results are reported for the overall group only since dose level of BI 754091 is fixed in this trial.
Time frame: Predose and 1, 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 359.5, 383.917, 504, 998 and 999 hours after intake of BI 754091 at day 1, cycle 1.
Part B: Area Under the Concentration-time Curve of BI 754091 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 754091 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle. Results are reported for the overall group only since dose level of BI 754091 is fixed in this trial.
Time frame: Predose and 1, 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 359.5, 383.917, 504, 998 and 999 hours after intake of BI 754091 at day 1, cycle 1.