A Study to Find the Best Dose of BI 836880 Alone and in C... | NCT03972150

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Part 1: 360 mg BI 836880	Experimental	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
Part 1: 720 mg BI 836880	Experimental	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
Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab	Experimental	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 836880 Drug: BI 754091
Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab	Experimental	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.

Name	Type	Description	Arm Group Labels	Other Names
BI 836880	Drug	Solution for infusion	Part 1: 360 mg BI 836880 Part 1: 720 mg BI 836880 Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab

Outcomes Module

Primary Outcomes

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]](streamdown:incomplete-link)	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 Outcomes

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.

Eligibility Module

Eligibility Criteria

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.

Facility	Status	City	State	ZIP	Country	Contacts
Shizuoka Cancer Center		Shizuoka, Sunto-gun		411-8777	Japan
National Cancer Center Hospital

PubMed Identifier	Type	Citation	Retractions
37140602	Derived	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.

Label	URL
Related Info	View source

Arm/Group Information

ID	Title	Description
FG000	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).
FG001	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).
FG002	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.
FG003	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.
FG004	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.

ID	Title	Description
BG000	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).
BG001

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
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]](streamdown:incomplete-link)	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.	Posted		Number		milligram		First treatment cycle, the first 21 days following the start of trial medication.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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).

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Aug 21, 2019	Sep 11, 2025	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Apr 14, 2021	Sep 11, 2025	SAP_001.pdf

ID	Title	Description
OG000	Part 1: Total BI 836880	Patients with advanced solid tumors were administered intravenously (i.v.) 360 milligram (mg) or 720 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).
OG001	Part 2: Total BI 836880/ 240 mg Ezabenlimab	Patients with advanced solid tumors were administered intravenously (i. v.) 120 milligram (mg) or 360 mg or 720 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.