Neoplasms, Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This is a study in adults with advanced solid tumors including non-small cell lung cancer. The study tests the combination of two medicines called BI 754111 and BI 754091 that may help the immune system to fight the cancer. Such medicines are called immune checkpoint inhibitors. The study has two parts. In the first part, doctors want to find out the highest dose of 2 medicines that people with solid tumors can tolerate. This dose is then used for the second part of the study. In the second part, the combination of the two medicines is tested in patients with non-small cell lung cancer and other types of solid cancer. These patients had gotten treatment with anti-PD-1 or anti-PD-L1 medicines but their tumors have come back. The doctors check whether the combination of BI 754111 and BI 754091 makes tumors shrink. Both medicines are given as an infusion into the vein every 3 weeks. If there is benefit for the patients and if they can tolerate it, the treatment is given for maximum of 1 year. During the entire study doctors will regularly check the health of the patients.
Interventions
DRUGEzabenlimab
240 mg ezabenlimab given as an intravenous infusion on day 1 of 21-day cycles (q3w)
DRUGBI 754111
Different dosages of BI 754111 given as an intravenous infusion on day 1 of 21-day cycles (q3w).
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of signed and dated, written Informed consent form (ICF) prior to any trial-specific procedures, sampling, or analyses * Patients ≥18 years of age at the time of signature of the ICF * Part I (dose escalation): --Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumours (any type) * For whom no therapy of proven efficacy exists, or who are not amenable to standard therapies. * Must have measurable lesions according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 * Previous treatment with an anti-programmed cell death 1 (receptor) (PD-1) monoclonal antibody (mAb) is allowed as long as the last administration of the anti-PD-1 mAb on the previous treatment is a minimum of 60 days prior to starting treatment in this trial. * Part II (dose expansion): * Patients must have measurable disease per RECIST v1.1 criteria, must have at least 1 tumour lesion amenable to biopsy, and must be medically fit and willing to undergo a biopsy before first treatment (if adequate archival tissue is not available) and, unless clinically contraindicated, after 6 weeks on therapy. * Dose Expansion Cohorts: Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumours of one of the following types: * Second and 3rd line Non-small cell lung cancer (NSCLC) patients: * Must have progressed on anti-PD-1 or anti-programmed cell death ligand 1 (PD-L1) treatment after having achieved radiologically confirmed benefit (minimum of stable disease) * Must have had a minimum duration of benefit of 4 months and minimum treatment duration of 2 months on the previous anti- PD-1 or anti-PD-L1 treatment without experiencing disease progression during that period. * The anti-PD-1- or anti-PD-L1-containing treatment must have been the latest treatment regimen prior to enrolling in this trial * Must be within \>4 and \<12 weeks since the latest treatment and their first dose in this trial. Patients who have had anti-PD-1 or anti-PD-L1 monotherapy as their first-line NSCLC treatment regimen must have a PD-L1 expression level of ≥1% at baseline (local validated testing). * Anti-PD-1 or anti-PD-L1 treatment-naïve patients with microsatellite stable Metastatic colorectal Cancer (mCRC): * Patients must have had ≥ 1 line treatment * Must have microsatellite stable disease (identified using any validated test) * Must be anti-PD-1 and anti-PD-L1 treatment naïve * Anti-PD-1 or anti-PD-L1 pretreated patients with any high Tumour mutational burden (TMB) (≥10 mutations/Mb) and/or Microsatellite instability high (MSI-H) and/or DNA MMRd solid tumours * Patients must have high TMB (≥ 10 mutations/Mb) and/or MSI-H and/or DNA mismatch repair deficient (MMRd) (measured using any validated test). * Patients must have received 1 prior anti-PD-1 or anti-PD-L1 treatment regimen. * 1st-line squamous or non-squamous NSCLC patients: * Patients must be treatment naïve * Must be epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild type (only applicable to patients with non-squamous NSCLC) * Regardless of PD-L1 expression level. However, the number of patients with high level of PD-L1 expression (≥50% PD-L1) will be limited to a maximum of 10 patients * Eastern Cooperative Oncology Group (ECOG, R01-0787) score: 0 to 1 * 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 ready 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. A list of contraception methods meeting these criteria is provided in the patient information.
Exclusion criteria
* 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 * Patients who must or wish to continue the intake of restricted medications (see Section 4.2.2.2) or any drug considered likely to interfere with the safe conduct of the trial * Previous enrolment in this trial * Any investigational or anti-tumour treatment, except BI 754091, within 4 weeks or within 5 half-life periods (whichever is shorter) prior to the initiation of trial treatment. * Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 neuropathy due to prior platinum-based therapy * Prior treatment with anti-Lymphocyte-activation gene 3 (LAG-3) agents * Patients with NSCLC that has EGFR mutations or ALK rearrangements (only applicable to patients with non-squamous NSCLC). * Presence of other active invasive cancers other than the one treated in this trial within 5 years prior to screening, with the exception of appropriately treated basal-cell carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumours considered cured by local treatment * 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 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. * Inadequate organ function or bone marrow reserve as demonstrated by the laboratory values presented in Table 3.3.3: 1. * Any of the following cardiac criteria: * Mean resting corrected QT interval (QTc) \>470 msec * Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval * Patients with an ejection fraction (EF) \<55% or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan). A historic measurement of EF no older than 6 months prior to first administration of study drug can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or of the treating physician or both. * History of pneumonitis within the last 5 years * History of severe hypersensitivity reactions to other mAbs * 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 * Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at start of treatment in this trial * Known history of human immunodeficiency virus infection or an active hepatitis B or C virus infection * Interstitial lung disease * Chronic alcohol or drug abuse or any condition that, in the Investigator's opinion, makes him/her an unreliable trial subject, unlikely to complete the trial, or unable to comply with the protocol procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Maximum-tolerated Dose (MTD) of the BI 754111 Plus Ezabenlimab Combination | First treatment cycle, the first 21 days following the start of trial medication. | The MTD is defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33%. DLTs include: Haematologic toxicities: * Any Grade 5 toxicity * Neutropenia ≥ Grade 4 for \>5 days * Any duration febrile neutropenia * Grade 4 thrombocytopenia or Grade 3 with bleeding/platelet transfusion need * Unexplained Grade 4 anaemia. Non-haematological toxicities: * Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) \>3x Upper limit of normal (ULN) and total bilirubin \>2x ULN without cholestasis signs * ≥Grade 4 AST or ALT of any duration * Any ≥Grade 3 non-haematologic toxicity with exceptions * Any Grade 4 or 5 adverse event (AE) * Any Grade 2 pneumonitis * Any Grade 2 uveitis, eye pain, or blurred vision not improving to Grade 1 within 2 weeks or requiring systemic treatment * Any ≥ Grade 2 toxicity causing inability to administer BI 754091 on Cycle 2 Day 1. |
| Dose Escalation: Number of Patients Experiencing DLTs During the Combination MTD Evaluation Period | First treatment cycle, the first 21 days following the start of trial medication. | Number of patients experiencing DLTs during the combination MTD evaluation period (first cycle of BI 754111 plus ezabenlimab combination therapy) in patients with solid tumours. |
| Dose Expansion: Number of Patients With Objective Response (OR) - Confirmed Complete Response (CR) and Partial Response (PR) | From the date of the first administration of trial treatment until the date of the last administration of trial treatment + 30 days (residual effect period), up to 818 days. | Dose expansion: Number of patients with objective response (OR) - confirmed complete response (CR) and partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 as assessed by the Investigator during the entire treatment. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Number of Patients With Objective Response (OR) - Confirmed Complete Response (CR) and Partial Response (PR) | From the date of the first administration of trial treatment until the date of the last administration of trial treatment + 30 days (residual effect period), up to 1286 days. | Dose escalation: Number of patients with objective response (OR) - confirmed complete response (CR) and partial response (PR) according to RECIST Version 1.1 as assessed by the Investigator during the entire treatment. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Dose Escalation: Number of Patients Experiencing DLTs | From the date of the first administration of trial treatment until the date of the last administration of trial treatment + 30 days (residual effect period), up to 1286 days. | Dose escalation: Number of patients experiencing DLTs from start of treatment until end of treatment (in all cycles). |
| Dose Expansion: Duration of Response | From the date of objective response until first date that recurrent or PD has been documented, up to 100 weeks. | Duration of response is measured from the time measurements criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started). |
| Dose Expansion: Percentage of Patients With Disease Control | From the date of the first administration of trial treatment until the date of the last administration of trial treatment + 30 days (residual effect period), up to 818 days. | Dose expansion: Percentage of patients with disease control (CR, PR, or stable disease (SD) according to RECIST Version 1.1) as assessed by the Investigator. |
| Dose Expansion: Progression-free Survival (PFS) | From the date of the first administration of trial treatment until the date of the last administration of trial treatment + 30 days (residual effect period), up to 818 days. | Dose expansion: Progression-free survival (PFS) is defined as time from first drug intake until disease progression or death from any cause, whichever occurs earlier. The date of progression will be based on the Investigator assessment according to RECIST 1.1. For patients with 'event' as an outcome for PFS: • PFS \[days\] = date of outcome - date of start of treatment + 1 For patients with 'censored' as an outcome for PFS: • PFS (censored) \[days\] = date of outcome - date of start of treatment + 1 Days were converted into months for reporting. |
| Dose Expansion: Number of Patients Experiencing DLTs | From the date of the first administration of trial treatment until the date of the last administration of trial treatment + 30 days (residual effect period), up to 818 days. | Dose expansion: Number of patients experiencing DLTs from start of treatment until end of treatment. |
| Dose Escalation: AUC0-504: Area Under the Concentration-time Curve of Ezabenlimab in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the first treatment cycle. | Dose escalation: AUC0-504: area under the concentration-time curve of ezabenlimab in plasma over the time interval from 0 to 504 hours. |
| Dose Escalation: AUC0-504 Steady State: Area Under the Concentration-time Curve of Ezabenlimab in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the fourth treatment cycle. | Dose escalation: AUC0-504 steady state: area under the concentration-time curve of ezabenlimab in plasma over the time interval from 0 to 504 hours at steady state. |
| Dose Escalation: AUC0-504: Area Under the Concentration-time Curve of BI 754111 in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the first treatment cycle. | Dose escalation: AUC0-504: area under the concentration-time curve of BI 754111 in plasma over the time interval from 0 to 504 hours. |
| Dose Escalation: AUC0-504 Steady State: Area Under the Concentration-time Curve of BI 754111 in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the fourth treatment cycle. | Dose escalation: AUC0-504 steady state: area under the concentration-time curve of BI 754111 in plasma over the time interval from 0 to 504 hours at steady state. |
| Dose Escalation: Cmax: Maximum Measured Concentration of Ezabenlimab in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the first treatment cycle. | Dose escalation: Cmax: maximum measured concentration of ezabenlimab in plasma over the time interval from 0 to 504 hours. |
| Dose Escalation: Cmax Steady State: Maximum Measured Concentration of Ezabenlimab in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the fourth treatment cycle. | Dose escalation: Cmax steady state: maximum measured concentration of ezabenlimab in plasma over the time interval from 0 to 504 hours at steady state. |
| Dose Escalation: Cmax: Maximum Measured Concentration of BI 754111 in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the first treatment cycle. | Dose escalation: Cmax: maximum measured concentration of BI 754111 in plasma over the time interval from 0 to 504 hours. |
| Dose Escalation: Cmax Steady State: Maximum Measured Concentration of BI 754111 in Plasma Over the Time Interval From 0 to 504 Hours | Within 1 hour before and 1, 4, 7, 24, 72, 168, 336 and 504 hours following the start of infusion in the fourth treatment cycle. | Dose escalation: Cmax steady state: maximum measured concentration of BI 754111 in plasma over the time interval from 0 to 504 hours at steady state. |
Countries
Canada, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This was an an open label, Phase I dose-finding study in patients with advanced solid cancers followed by expansion cohorts at the selected dose of the combination in patients with non-small cell lung cancer and other solid tumors.
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 | 62.3 years STANDARD_DEVIATION 10.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 151 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 9 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 | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 3 / 9 | 2 / 9 | 1 / 9 | 2 / 9 | 3 / 9 | 0 / 6 | 16 / 21 | 27 / 40 | 25 / 39 | 11 / 17 |
| other Total, other adverse events | 4 / 4 | 9 / 9 | 9 / 9 | 8 / 9 | 9 / 9 | 9 / 9 | 6 / 6 | 18 / 21 | 39 / 40 | 36 / 39 | 16 / 17 |
| serious Total, serious adverse events | 1 / 4 | 1 / 9 | 1 / 9 | 1 / 9 | 4 / 9 | 2 / 9 | 2 / 6 | 8 / 21 | 16 / 40 | 21 / 39 | 8 / 17 |
Outcome results
None listed