Neoplasms
Conditions
Brief summary
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
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Of legal age (according to local legislation) at screening. No upper limit. * Signed and dated written informed consent in accordance with International Council on Harmonisation (ICH) Good Clinical Practice (GCP) and local legislation prior to admission to the trial. * Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly, starting with the screening visit and through 6 months after the last dose of study treatment. A list of contraception methods meeting these criteria is provided in the patient information. The requirement of contraception does not apply to women of no childbearing potential and men not able to father a child, but they must have an evidence of such at screening. * Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumours (any type). Measurable lesion not mandatory for participation in this trial. * Patients with no therapy of proven efficacy, or who are not amenable to standard therapies. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. * Recovery from all reversible adverse events of previous anti-cancer therapies to baseline or Common Terminology Criteria for Adverse Events (CTCAE) grade 1, except for alopecia (any grade), sensory peripheral neuropathy, must be ≤ CTCAE grade 2 or considered not clinically significant. * Adequate organ function. * Further inclusion criteria apply.
Exclusion criteria
* Known hypersensitivity to the trial drugs or their excipients or risk of allergic of anaphylactic reaction to drug product according to Investigator judgement (e.g. patient with history of anaphylactic reaction or autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs (NSAIDs), inhaled corticosteroids, or the equivalent of ≤10 mg/day prednisone). * Known history of human immunodeficiency virus (HIV) infection. Test results obtained in routine diagnostics are acceptable if done within 14 days before the informed consent date. * Any of the following laboratory evidence of hepatitis virus infection. * Positive results of hepatitis B surface (HBs) antigen * Presence of hepatitis B core (HBc) antibody together with hepatitis virus B (HBV) Deoxyribonucleic acid (DNA) * Presence of hepatitis virus C (HCV) Ribonucleic acid (RNA) Test results obtained in routine diagnostics are acceptable if done within 14 days before the informed consent date. * History of severe known hypersensitivity reactions to other mAbs. * Immunosuppressive corticosteroid doses (\>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of trial medication. * Any investigational or anti-tumour treatment within 4 weeks or 5 half-life periods (whichever is shorter) prior to the initiation of trial treatment. * Serious concomitant disease, especially those affecting compliance with trial requirements or which are considered relevant for the evaluation of the endpoints of the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers (gastrointestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the investigator would make the patient inappropriate for entry into the trial. * Major injuries and/or surgery or bone fracture within 4 weeks of start of treatment, or planned surgical procedures during the trial period. * Patients with personal or family history of QT prolongation and/or long QT syndrome, or prolonged QTcF (Corrected QT interval by Fridericia) at screening (\>470 ms). * Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within past 6 months, congestive heart failure \>NYHA \[New York Heart Association\] class II). Uncontrolled hypertension is defined as follows: Blood pressure in rested and relaxed condition ≥140 mmHg, systolic or ≥90 mmHg diastolic (with or without medication) * Left Ventricular Ejection Fraction (LVEF) \<50% measured locally by echocardiography * History of severe haemorrhagic or thromboembolic event in the past 12 months (excluding central venous catheter thrombosis and peripheral deep vein thrombosis). * Known inherited predisposition to bleeding or to thrombosis in the opinion of the investigator. * Untreated brain metastasis(es) that may be considered active. Patients with previously treated brain metastases may participate provided they are stable (i.e., without evidence of progressive disease (PD) by imaging for at least 4 weeks prior to the first dose of trial treatment, and any neurologic symptoms have returned to baseline), and there is no evidence of new or enlarging brain metastases * Patients who require full-dose anticoagulation (according to local guidelines). No Vitamin K antagonist and other anticoagulation allowed; Low Molecular Weight Heparin (LMWH) allowed only for prevention not for curative treatment. * History (including current) of interstitial lung disease or pneumonitis within the last 5 years. * Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial * Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled. (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator's opinion, makes the patient an unreliable trial participant). * Patients who were previously treated in this trial. * Patients with haematological malignancies. * Women who are pregnant, nursing, or who plan to become pregnant while in the trial. Female patients of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to taking study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible. Women who are nursing can be enrolled if they stop nursing. In this case, the patient cannot resume nursing even after discontinuation of study treatment. * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI754091 | First treatment cycle, the first 21 days following the start of trial medication. | 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: \[0.33, 1.00\] |
| Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | First treatment cycle, the first 21 days following the start of trial medication. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of BI 836880 in Part 1 in Plasma (Cmax) at Cycle 2 | 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 at Cycle 2 in Part 1 (monotherapy) in plasma (Cmax) is reported. |
| 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 | 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 (monotherapy) at Cycle 2 in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported. |
| Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 4 | 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 BI 836880 at Cycle 4 in Part 1 (monotherapy) and Part 2 (combination therapy) in plasma (Cmax) is reported. |
| 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 | 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 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. |
| Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 1 | 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. | Maximum measured concentration of BI 836880 at Cycle 1 in Part 1 (monotherapy) and Part 2 (combination therapy) in plasma (Cmax) is reported. |
| 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 | 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 (combination therapy) in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported. |
| Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 4 | 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. | Maximum measured concentration of Ezabenlimab (BI 754091) at Cycle 4 in Part 2 (combination therapy) in plasma (Cmax) is reported. |
| 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 | 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 (combination therapy) in plasma over the time interval from 0 to 504 hours (AUC0-504h) is reported. |
| Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 1 | 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) at Cycle 1 in Part 2 (combination therapy) in plasma (Cmax) is reported. |
| 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 | 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. | 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. |
Countries
Japan
Participant flow
Recruitment details
This was a phase I, open label, uncontrolled, non-randomized, two parts, dose-escalation design trial assessing the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (Pd) of BI 836880 monotherapy, and combination therapy of BI 836880 and BI 754091 in Japanese patients with different types of advanced cancer.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: 360 mg BI 836880 Patients with advanced solid tumors were administered intravenously (i.v.) 360 milligram (mg) of BI 836880 solution for infusion on Day 1 of each 3-week cycle until progressive disease, unacceptable toxicity, or other withdrawal criteria were met (Part 1). | 3 |
| Part 1: 720 mg BI 836880 Patients with advanced solid tumors were administered intravenously (i. v.) 720 milligram (mg) of BI 836880 solution for infusion on Day 1 of each 3-week cycle until progressive disease, unacceptable toxicity, or other withdrawal criteria were met (Part 1). | 6 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab Patients with advanced solid tumors were administered intravenously (i. v.) 120 milligram (mg) of BI 836880 solution for infusion and 240 mg Ezabenlimab (BI 754091) solution for infusion on Day 1 of each 3-week cycle until progressive disease, unacceptable toxicity, or other withdrawal criteria were met (Part 2). Part 2 commenced after completion of Part 1. | 3 |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab Patients with advanced solid tumors were administered intravenously (i. v.) 360 milligram (mg) of BI 836880 solution for infusion and 240 mg Ezabenlimab (BI 754091) solution for infusion on Day 1 of each 3-week cycle until progressive disease, unacceptable toxicity, or other withdrawal criteria were met (Part 2). Part 2 commenced after completion of Part 1. | 3 |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab Patients with advanced solid tumors were administered intravenously (i. v.) 720 milligram (mg) of BI 836880 solution for infusion and 240 mg Ezabenlimab (BI 754091) solution for infusion on Day 1 of each 3-week cycle until progressive disease, unacceptable toxicity, or other withdrawal criteria were met (Part 2). Part 2 commenced after completion of Part 1. | 6 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Progressive disease | 3 | 5 | 2 | 2 | 3 |
Baseline characteristics
| Characteristic | Part 1: 360 mg BI 836880 | Part 1: 720 mg BI 836880 | Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.7 Years STANDARD_DEVIATION 15.7 | 54.8 Years STANDARD_DEVIATION 14.7 | 51.7 Years STANDARD_DEVIATION 12 | 57.3 Years STANDARD_DEVIATION 15.5 | 62.0 Years STANDARD_DEVIATION 8.8 | 57.9 Years STANDARD_DEVIATION 12.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants | 3 Participants | 6 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 3 Participants | 3 Participants | 6 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 6 | 1 / 3 | 1 / 3 | 3 / 6 |
Outcome results
Primary
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.
Population: Dose escalation cohort treated set in monotherapy/combination therapy:~This patients sets included all patients enrolled in dose escalation cohort of monotherapy/combination therapy who were documented to have administrated at least one dose of study medication and were evaluable for the MTD determination. This set is used for dose finding and MTD determination in Part I/Part II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Total BI 836880 | Maximum Tolerated Dose (MTD) of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI754091 | NA milligram |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | Maximum Tolerated Dose (MTD) of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI754091 | NA milligram |
Primary
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.
Population: Dose escalation cohort treated set in monotherapy/combination therapy:~This patients sets included all patients enrolled in dose escalation cohort of monotherapy/combination therapy who were documented to have administrated at least one dose of study medication and were evaluable for the MTD determination. This set is used for dose finding and MTD determination in Part I/Part II.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Total BI 836880 | Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | 0 Participants |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | 0 Participants |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | 0 Participants |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | 0 Participants |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | 0 Participants |
Secondary
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.
Population: PK parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one Pharmacokinetic (PK) parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | 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 | 22300 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 24.4 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | 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 | 50400 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 24.5 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | 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 | 8220 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 7.68 |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | 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 | 21100 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 28.5 |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | 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 | 50000 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 24.3 |
Secondary
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.
Population: PK parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded. Only patients with no missing values are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | 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 | 35500 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 46.6 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | 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 | 122000 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 14.2 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | 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 | 10600 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 6.81 |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | 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 | 31400 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 37.4 |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | 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 | 79100 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 16.4 |
Secondary
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.
Population: PK parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | 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 | 27600 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 31.3 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | 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 | 64900 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 36.8 |
Secondary
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.
Population: PK parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | 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 | 18400 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 5.28 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | 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 | 15300 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 23.8 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | 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 | 16600 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 26.4 |
Secondary
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.
Population: PK parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded. Only patients with no missing values are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | 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 | 32200 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 12.7 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | 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 | 22900 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 46 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | 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 | 27600 hour*microgram/milliliter (h*µg/mL) | Geometric Coefficient of Variation 27.1 |
Secondary
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.
Population: Pharmacokinetics parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one Pharmacokinetics (PK) parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 1 | 131 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 20.6 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 1 | 281 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 22.7 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 1 | 50.4 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 8.71 |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 1 | 121 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 21.6 |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 1 | 316 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 21.1 |
Secondary
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.
Population: Pharmacokinetics parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded. Only patients with no missing values are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 4 | 184 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 27.6 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 4 | 621 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 6.83 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 4 | 55.9 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 12.8 |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 4 | 159 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 31.6 |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 and Part 2 in Plasma (Cmax) at Cycle 4 | 398 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 32.3 |
Secondary
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.
Population: Pharmacokinetics parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | Maximum Measured Concentration of BI 836880 in Part 1 in Plasma (Cmax) at Cycle 2 | 178 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 22 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of BI 836880 in Part 1 in Plasma (Cmax) at Cycle 2 | 319 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 24 |
Secondary
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.
Population: Pharmacokinetics parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 1 | 83.9 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 6.01 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 1 | 75.3 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 25.4 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 1 | 104 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 19.8 |
Secondary
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.
Population: Pharmacokinetics parameter analysis set (PKS): The PK parameter analysis set (PKS) included all subjects from the Treated Set (TS) who provide at least one PK parameter that was not excluded. Only patients with no missing values are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Total BI 836880 | Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 4 | 129 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 13.8 |
| Part 2: Total BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 4 | 106 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 40.2 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Maximum Measured Concentration of Ezabenlimab (BI 754091) in Part 2 in Plasma (Cmax) at Cycle 4 | 132 microgram / milliliter (µg/mL) | Geometric Coefficient of Variation 37.9 |