Neoplasm Metastasis, Advanced Tumors, Metastatic Solid Tumors
Conditions
Brief summary
This is a study in adults with various types of advanced cancer. The purpose of the study is to test a medicine called BI 754091 in combination with several other cancer medicines. BI 754091 is an immunotherapy. This means it may help the immune system fight cancer. Such therapies are also called immune checkpoint inhibitors. How long the participants are in the study depends on whether they benefit from treatment and whether they experience unacceptable side effects. The participants are put into different groups. Each group receives BI 754091 in combination with another medicine. The doctors check whether the tumors shrink or disappear. The doctors also check the general health of the participants.
Interventions
DRUGEzabenlimab
240 mg of ezabenlimab (BI 754091), intravenously, on Day 1 of 21-day cycles.
DRUGBI 754111
600 mg of BI 754111, intravenously, on Day 1 of 21-day cycles.
DRUGBI 836880
720 mg of BI 836880, intravenously, on Day 1 of 21-day cycles.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Master Protocol: * Provision of signed and dated, written Master informed consent form (ICF) prior to any trial-specific procedures, sampling, or analyses. * Patient ≥18 years of age at the time of signature of the ICF. * Eastern Cooperative Oncology Group (ECOG) score: 0 or 1. * Patient must agree to a pre-treatment biopsy (if archival tissue is not available) and on-treatment tumour biopsy. If archived tumour tissue is available from the last treatment failure, sections may be supplied instead of a pre-treatment biopsy. * Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement. * Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be willing and able to use highly effective methods of birth control (that result in a low failure rate of less than 1% per year when used consistently and correctly) during trial participation and for at least 6 months after the last administration of trial medication. Acceptable highly effective methods of contraception include total sexual abstinence when this is in line with the preferred and usual lifestyle of the study participant (periodic abstinence such as calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception), an intrauterine device or intrauterine hormone-releasing system, bilateral tubal ligation, and vasectomised partner (with post-vasectomy proof of absence of sperm). Male patients with partners of childbearing potential must agree to use condoms and ensure their partners are using an additional highly effective method of birth control, during the trial and until at least 6 months after the end of the trial treatment. Module A: \- Histologically confirmed diagnosis of one of the following cohorts: * Cohort 1 GEC - Locally advanced, unresectable or metastatic gastric adenocarcinoma or gastro oesophageal adenocarcinoma (GEC) (defined as primary tumour localisation below the gastro oesophageal junction (GEJ) with prior anti-PD-1 or anti-PD-L1 based treated tumour. * Cohort 2 Patients with secondary resistance to anti-PD-1 or anti-PD-L1 based therapy: Any advanced or metastatic solid tumour with previously anti-PD-1 or anti-PD-L1 based treatment who progressed after achieving benefit * Cohort 3 Patients with primary resistance to anti-PD-1 or anti-PD-L1 based therapy: Select advanced or metastatic solid tumour types with previous anti-PD- 1/PD-L1 based treated tumour without achieving benefit. * All patients must have measurable lesions according to RECIST v1.1 * Patient must agree to pre- and on-treatment tumour biopsies. If archived tumour tissue is available from the last treatment failure, sections may be supplied instead of a pre-treatment biopsy. Module C: * Histologically confirmed diagnosis of one of the following cohorts: * Cohort 1: GEC: Locally advanced, unresectable or metastatic gastric adenocarcinoma or GEC. * Cohort 2: Patients with secondary resistance to anti-PD-1 or anti-PD-L1 based therapy: Any advanced or metastatic solid tumour (excluding NSCLC and melanoma) with previously anti-PD-1 or anti-PD-L1 based treatment which progressed after achieving benefit. * Cohort 3: Patients with primary resistance to anti-PD-1 or anti-PD-L1 based therapy: Select advanced or metastatic solid tumour types with previous anti-PD-1/PD-L1 based treated tumour without achieving benefit. * Cohort 4: Locally advanced, unresectable or metastatic second line or greater, microsatellite stable (MSS) colorectal cancer. * Cohort 5: Advanced Endometrial cancer: Endometrial carcinoma that is pMMR (Mismatch Repair-Proficient)/MSS and is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy. * All patients must have at least one measurable lesion according to RECIST v1.1 * Further inclusion criteria apply
Exclusion criteria
Master Protocol: * Any investigational treatment anti-tumour treatment within 4 weeks or within 5 half-life periods (whichever is shorter) prior to the initiation of trial treatment. * More than one anti-PD-(L)1-based treatment regimen prior to entering study study, more specifically defined in the modules. Note: once in a trial Module, patients may crossover to different Module if all other eligibility criteria are met. * Major surgery ('major' according to the Investigator's assessment) performed within 12 weeks prior to first trial treatment or planned within 12 months after screening, e.g., hip replacement. * Known history of severe hypersensitivity reactions to other mAbs or known hypersensitivity to the trial drugs or their excipients. * Presence of central nervous system (CNS) metastases, unless treated and asymptomatic and off corticosteroids and/or anticonvulsant therapy for at least 2 weeks prior to start of treatment. * Immunosuppressive corticosteroid doses (\>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of study treatment. * Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy. Patients who were permanently discontinued from previous anti-PD-1 or anti-PD-L1 therapy because of an immune-related adverse event (irAE). Module A: \- Previous treatment with an anti-LAG-3 Agent Module C: * Unresolved, Grade \>1 toxicity before the start of treatment with the study drug except for hair loss (alopecia) and hypothyroidism that requires thyroid hormone supplements but is asymptomatic under therapy. * Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within past 6 months, congestive heart failure \> New York Heart Association \[NYHA\] II) * History of severe haemorrhagic or thromboembolic event in the past 12 months * Known inherited predisposition to bleeding or to thrombosis, in the opinion of the investigator - Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| [Module C] Objective Response (OR) | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 188.3 weeks. | Confirmed objective response (OR), defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). Complete response (CR) was defined as the disappearance of all target lesions and partial response (PR) was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. |
| [Module C] Objective Response (OR) - Bayesian Hierarchical Model | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 188.3 weeks. | Confirmed objective response (OR), defined as the objective response rate (ORR) of participants with best overall response of complete response (CR) or partial response (PR), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). Complete response (CR) was defined as the disappearance of all target lesions and partial response (PR) was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. The estimated objective response rate is presented by the posterior medians of the Bayesian hierarchical model and by the correspondent credible intervals. |
| [Module A] Objective Response (OR) | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 152.4 weeks. | Confirmed objective response (OR), defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). Complete response (CR) was defined as the disappearance of all target lesions and partial response (PR) was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. |
| [Module A] Objective Response (OR) - Bayesian Hierarchical Model | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 152.4 weeks. | Confirmed objective response (OR), defined as the objective response rate (ORR) of participants with best overall response of complete response (CR) or partial response (PR), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). Complete response (CR) was defined as the disappearance of all target lesions and partial response (PR) was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. The estimated objective response rate is presented by the posterior medians of the Bayesian hierarchical model and by the correspondent credible intervals. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| [Module C] Duration of Response (DoR) | From first documented CR or PR (RECIST v1.1) until the earlier of disease progression or death. Up to 174.6 weeks. | Duration of response (DoR) was defined as the time from first documented complete response (CR) or partial response (PR) (RECIST v1.1) among patients with objective response (OR), according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). Complete response (CR) was defined as the disappearance of all target lesions and partial response (PR) was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. DoR parameters were calculated based on Kaplan-Meier estimation. The analysis was performed on the unconfirmed OR. |
| [Module C] Disease Control (DC) | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 188.3 weeks. | Disease Control (DC) defined as the percentage of patients with best overall response of complete response (CR), partial response (PR), or stable disease (SD), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). CR was defined as the disappearance of all target lesions, PR was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference, SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study, and PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
| [Module C] Disease Control (DC) - Bayesian Hierarchical Model | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 188.3 weeks. | Disease Control (DC), defined as the disease control rate (DCR) of participants with best overall response of complete response (CR), partial response (PR), or stable disease (SD), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). CR was defined as the disappearance of all target lesions, PR was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference, SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study, and PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The estimated DCR is presented by the posterior medians of the bayesian hierarchical model and by the correspondent credible intervals. |
| [Module C] Progression-free Survival (PFS) | From first drug administration until PD or death, whichever occurred earlier. Up to approximately 186.1 weeks. | Progression-free survival (PFS) was defined as the time from first treatment administration until progressive disease (PD), according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1), or death from any cause, whichever occurred earlier. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. PFS parameters were calculated based on Kaplan-Meier estimation. |
| [Module A] Duration of Response (DoR) | From first documented CR or PR (RECIST v1.1) until the earlier of disease progression or death. Up to 63.6 weeks. | Duration of response (DoR) was defined as the time from first documented complete response (CR) or partial response (PR) (RECIST v1.1) among patients with objective response (OR), according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). Complete response (CR) was defined as the disappearance of all target lesions and partial response (PR) was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. DoR parameters were calculated based on Kaplan-Meier estimation. The analysis was performed on the unconfirmed OR. |
| [Module A] Disease Control (DC) | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 152.4 weeks. | Disease Control (DC) defined as the percentage of patients with best overall response of complete response (CR), partial response (PR), or stable disease (SD), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). CR was defined as the disappearance of all target lesions, PR was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference, SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study, and PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
| [Module A] Disease Control (DC) - Bayesian Hierarchical Model | From first drug administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy. Up to approximately 152.4 weeks. | Disease Control (DC), defined as the disease control rate (DCR) of participants with best overall response of complete response (CR), partial response (PR), or stable disease (SD), assessed by the investigator according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1). CR was defined as the disappearance of all target lesions, PR was defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference, SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study, and PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The estimated DCR is presented by the posterior medians of the bayesian hierarchical model and by the correspondent credible intervals. |
| [Module A] Progression-free Survival (PFS) | From first drug administration until PD, death, or cut-off date of July 2021, whichever occurred earlier. Up to approximately 104.7 weeks. | Progression-free survival (PFS) was defined as the time from first treatment administration until progressive disease (PD), according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (v1.1), or death from any cause, whichever occurred earlier. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. PFS parameters were calculated based on Kaplan-Meier estimation. Progression free survival was collected, according to the clinical trial protocol until July 2021. |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
Platform trial evaluating the safety and efficacy of different ezabenlimab (BI 754091) treatment regimens on patients with different types of advanced or metastatic tumors: module C evaluated the efficacy and safety of ezabenlimab (BI 754091) in combination with BI 836880 and module A evaluated the efficacy and safety of ezabenlimab (BI 754091) in combination with BI 754111.
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.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 66.4 Years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 39 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants |
| Race/Ethnicity, Customized Other | 42 Participants |
| Race/Ethnicity, Customized White | 7 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 20 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 24 / 28 | 20 / 30 | 22 / 28 | 17 / 30 | 4 / 18 | 0 / 2 | 29 / 33 | 32 / 42 |
| other Total, other adverse events | 27 / 28 | 27 / 30 | 26 / 28 | 29 / 30 | 18 / 18 | 2 / 2 | 33 / 33 | 41 / 42 |
| serious Total, serious adverse events | 11 / 28 | 18 / 30 | 12 / 28 | 13 / 30 | 11 / 18 | 1 / 2 | 13 / 33 | 12 / 42 |
Outcome results
None listed