A Study to Find the Best Dose of BI 836880 Alone and in Combination With BI 754091 in Japanese Patients With Different Types of Advanced Cancer

An Open Label, Phase I Study of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI 754091 in Japanese Patients With Advanced Solid Tumours

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 Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: BI 754091; Drug: BI 836880

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Shizuoka, Sunto-gun, Japan, 411-8777
    • Shizuoka Cancer Center
  • Tokyo, Chuo-ku, Japan, 104-0045
    • National Cancer Center Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: BI 836880; Solution for infusion
Experimental: 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).	Drug: BI 836880; Solution for infusion
Experimental: 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.	Drug: BI 754091; Solution for infusion; Drug: BI 836880; Solution for infusion
Experimental: 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.	Drug: BI 754091; Solution for infusion; Drug: BI 836880; Solution for infusion
Experimental: 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.	Drug: BI 754091; Solution for infusion; Drug: BI 836880; Solution for infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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]	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.	First treatment cycle, the first 21 days following the start of trial medication.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Yamamoto N, Koyama T, Shimizu T, Todaka A, Kawakami T, Erzen D, Sarashina A, Li B, Hou J, Yamazaki K. Phase I study of the VEGF/Ang-2 inhibitor BI 836880 alone or combined with the anti-programmed cell death protein-1 antibody ezabenlimab in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2023 Jun;91(6):469-480. doi: 10.1007/s00280-023-04527-6. Epub 2023 May 4.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2019
• Primary Completion (Actual): October 27, 2020
• Study Completion (Actual): March 28, 2022

Study Registration Dates

• First Submitted: May 31, 2019
• First Submitted That Met QC Criteria: May 31, 2019
• First Posted (Actual): June 3, 2019

Study Record Updates

• Last Update Posted (Estimated): October 6, 2025
• Last Update Submitted That Met QC Criteria: September 12, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 1336-0012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:

1. studies in products where Boehringer Ingelheim is not the license holder; 2. studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; 3. studies conducted in a single center or targeting rare diseases (because of limitations with anonymization). For more details refer to: https://www.mystudywindow.com/msw/datasharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No