Carcinoma, Non-Small-Cell Lung, Head and Neck Neoplasms
Conditions
Brief summary
The main objective of this study is to determine the biodistribution and intra-tumor accumulation of \[89Zr\]Zr-BI 754111 at baseline and its change upon treatment
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The trial is divided in 2 Parts and will be conducted in a staggered approach, i.e. Part 2 follows Part 1. Part 2 will be initiated following a positive decision of the Study Monitoring Committee (SMC) after reviewing of all available data from Part 1 in order to assess whether a blockade of \[89Zr\]Zr-BI 754111 will be demonstrated.
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 of legal age (according to local legislation) at the time of signature of the ICF * Patients with histologically confirmed diagnosis of recurrent NSCLC who received anti- PD-1 or anti PD-L1 as Part of last treatment with at least 3 months of stable disease (i.e.patients with confirmed response (PR or CR) regardless of duration of response or stable disease (SD) for a minimum of 3 months) and have become refractory to anti-PD- 1/ anti-PD-L1 based treatment OR --Patients with histologically confirmed diagnosis of recurrent metastatic HNSCC who progressed after platinum based therapy or not indicated for receiving standard (radio) chemotherapy (previous treatment with anti- PD-1/ PD-L1 is allowed) * Eastern Cooperative Oncology Group (ECOG, R01-0787) score: 0 to 1 * Patient must have at least one PET imageable and evaluable tumor lesion of 20mm * Patients must have at least one tumor lesion amenable to biopsy. This lesion should be PET imageable and evaluable as defined above and the biopsy should be obtained before first BI 754091 administration, unless medically contra-indicated. In the latter case, 25 4μm sections from an archival biopsy taken at relapse after the previous treatment are acceptable * Must have evaluable lesion(s) according to Revised Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and iRECIST * 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)1 and men able to father a child must be ready and able to use highly effective methods of birth control per International Conference on Harmonisation (ICH) M3 (R2) (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
* Not having fully recovered from major surgery before they enter into the trial according to investigator judgment or planned for major surgery within 12 months after screening, e.g. hip replacement * 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 * Previous treatment in this trial * Any investigational or anti-tumor treatment 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-LAG-3 agents * Presence of other active invasive cancers other than the one treated in this trial, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors 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 * Any of the following cardiac criteria: * Mean resting corrected QT interval (QTc) \>470 msec * Any clinically important abnormalities 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 * Ejection fraction \<55% or the lower limit of normal of the institutional standard. * 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 patient or unlikely to complete the trial or unable to comply with the protocol procedures * Women who are pregnant, nursing, or who plan to become pregnant in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 1 | At 96 hours and 144 hours post-injection of [89Zr]Zr-BI 754111 in each cycle. | The standardized uptake values (SUVs) are calculated as the ratios of the image derived radioactivity concentration upon the whole body concentration of the injected radioactivity, i.e. image derived radioactivity concentration / injected radioactivity concentration upon the whole body - a unitless value since the unit has been cancelled out. The Standard uptake value (SUV) in a 1 milliliter (mL) sphere around highest SUV pixel (SUVpeak) of \[89Zr\]Zr-BI 754111 for tumor uptake for part 1 participants is reported. The SUVpeak (also unitless since it is a SUV value) is summarized for each imaging time point (96hour, 144hour) as the mean tumor uptake over all selected lesions for each treatment cycle, respectively. |
| Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 2 | At 96 hours and 144 hours post-injection of [89Zr]Zr-BI 754111 in each cycle. | The standardized uptake values (SUVs) are calculated as the ratios of the image derived radioactivity concentration upon the whole body concentration of the injected radioactivity, i.e. image derived radioactivity concentration / injected radioactivity concentration upon the whole body - a unitless value since the unit has been cancelled out. The Standard uptake value (SUV) in a 1 milliliter (mL) sphere around highest SUV pixel (SUVpeak) of \[89Zr\]Zr-BI 754111 for tumor uptake for part 2 participants is reported. The SUVpeak (also unitless since it is a SUV value) is summarized for each imaging time point (96hour, 144hour) as the mean tumor uptake over all selected lesions for each treatment cycle, respectively. |
Countries
Netherlands
Participant flow
Recruitment details
This was an open label Positron Emission Tomography (PET) imaging study to investigate the bio-distribution and tumor uptake of \[89Zr\]Zr-BI 754111 in patients with advanced non-small cell lung cancer and head and neck squamous cell carcinoma treated with BI 754111 in combination with BI 754091.
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: Ezabenlimab 240mg + BI 754111 600mg Baseline assessment phase (Cycle 1): 240 milligrams (mg) solution for infusion of BI 754091 (ezabenlimab) were administered by intravenous infusion on Day 1 of Cycle 1, followed by 4 milligrams solution for infusion of \[89Zr\]Zr-BI 754111 (4mg BI 754111 - 37 MBq) administered via intravenous infusion no later than Day 8 of Cycle 1.
On-treatment phase (Cycle 2): 600 mg solution for infusion of BI 754111 together with 240 mg solution for infusion of BI 754091 (ezabenlimab) were administered by intravenous infusion on Day 1 of Cycle 2, followed by 4 milligrams solution for infusion of \[89Zr\]Zr-BI 754111 (4mg BI 754111 - 37 MBq) administered via intravenous infusion no later than Day 8 of Cycle 2.
On-treatment phase (Cycle 3 and the following cycles): 600 mg solution for infusion of BI 754111 together with 240 mg solution for infusion of BI 754091 (ezabenlimab) were administered by intravenous infusion on Day 1 of each cycle.
Each cycle last for 3 weeks. From Cycle 2 onwards, intravenous infusions of BI 754111 plus BI 754091 (ezabenlimab) once every 3 weeks until progression of disease, unacceptable toxicity, or maximum treatment duration of 1 year. | 3 |
| Part 2: Ezabenlimab 240mg + BI 754111 40mg Baseline assessment phase (Cycle 1): 240 milligrams (mg) solution for infusion of BI 754091 (ezabenlimab) were administered by intravenous infusion on Day 1 of Cycle 1, followed by 4 milligrams solution for infusion of \[89Zr\]Zr-BI 754111 (4mg BI 754111 - 37 MBq) administered via intravenous infusion no later than Day 8 of Cycle 1.
On-treatment phase (Cycle 2): 40 mg solution for infusion of BI 754111 together with 240 mg solution for infusion of BI 754091 (ezabenlimab) were administered by intravenous infusion on Day 1 of Cycle 2, followed by 4 milligrams solution for infusion of \[89Zr\]Zr-BI 754111 (4mg BI 754111 - 37 MBq) administered via intravenous infusion no later than Day 8 of Cycle 2.
On-treatment phase (Cycle 3 and the following cycles): 600 mg solution for infusion of BI 754111 together with 240 mg solution for infusion of BI 754091 (ezabenlimab) were administered by intravenous infusion on Day 1 of each cycle.
Each cycle last for 3 weeks. From Cycle 2 onwards, intravenous infusions of BI 754111 plus BI 754091 (ezabenlimab) once every 3 weeks until progression of disease, unacceptable toxicity, or maximum treatment duration of 1 year. | 5 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Progression of disease | 3 | 4 |
Baseline characteristics
| Characteristic | Part 2: Ezabenlimab 240mg + BI 754111 40mg | Total | Part 1: Ezabenlimab 240mg + BI 754111 600mg |
|---|---|---|---|
| Age, Continuous | 64.6 Years STANDARD_DEVIATION 8.6 | 64.9 Years STANDARD_DEVIATION 8.1 | 65.3 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 8 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 8 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 |
| other Total, other adverse events | 3 / 3 | 4 / 5 |
| serious Total, serious adverse events | 2 / 3 | 2 / 5 |
Outcome results
Primary
Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 1
The standardized uptake values (SUVs) are calculated as the ratios of the image derived radioactivity concentration upon the whole body concentration of the injected radioactivity, i.e. image derived radioactivity concentration / injected radioactivity concentration upon the whole body - a unitless value since the unit has been cancelled out. The Standard uptake value (SUV) in a 1 milliliter (mL) sphere around highest SUV pixel (SUVpeak) of \[89Zr\]Zr-BI 754111 for tumor uptake for part 1 participants is reported. The SUVpeak (also unitless since it is a SUV value) is summarized for each imaging time point (96hour, 144hour) as the mean tumor uptake over all selected lesions for each treatment cycle, respectively.
Time frame: At 96 hours and 144 hours post-injection of [89Zr]Zr-BI 754111 in each cycle.
Population: Treated Set (TS): This patient set includes all patients who were documented to have received at least one dose of \[89Zr\]Zr-BI 754111, BI 754111, or BI 754091 (ezabenlimab). Only participants from part 1 are included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 1 | Cycle 2 (on-treatment phase) - 144 hours | 7.0 SUV ratio | Standard Deviation 3.6 |
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 1 | Cycle 1 (baseline phase) - 96 hours | 5.5 SUV ratio | Standard Deviation 1 |
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 1 | Cycle 1 (baseline phase) - 144 hours | 5.2 SUV ratio | Standard Deviation 1 |
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 1 | Cycle 2 (on-treatment phase) - 96 hours | 6.2 SUV ratio | Standard Deviation 2.7 |
Comparison: The mean relative change is calculated as first deriving the relative change from baseline for each selected lesion at each time point (96hours, 144hours):~100 \* (SUVpeak,lesion,timepoint,cycle2 - SUVpeak,lesion,timepoint,cycle1) / SUVpeak,lesion,timepoint,cycle1 Then, we calculate the mean over all evaluable lesions (at each time point) At last, the mean relative change is the lower mean value across time points.
Primary
Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 2
The standardized uptake values (SUVs) are calculated as the ratios of the image derived radioactivity concentration upon the whole body concentration of the injected radioactivity, i.e. image derived radioactivity concentration / injected radioactivity concentration upon the whole body - a unitless value since the unit has been cancelled out. The Standard uptake value (SUV) in a 1 milliliter (mL) sphere around highest SUV pixel (SUVpeak) of \[89Zr\]Zr-BI 754111 for tumor uptake for part 2 participants is reported. The SUVpeak (also unitless since it is a SUV value) is summarized for each imaging time point (96hour, 144hour) as the mean tumor uptake over all selected lesions for each treatment cycle, respectively.
Time frame: At 96 hours and 144 hours post-injection of [89Zr]Zr-BI 754111 in each cycle.
Population: Treated Set (TS): This patient set includes all patients who were documented to have received at least one dose of \[89Zr\]Zr-BI 754111, BI 754111, or BI 754091 (ezabenlimab). Only participants from part 2 and have non-missing results are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 2 | Cycle 1 (baseline phase) - 96 hours | 5.8 SUV ratio | Standard Deviation 4.4 |
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 2 | Cycle 2 (on-treatment phase) - 96 hours | 4.6 SUV ratio | Standard Deviation 1.9 |
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 2 | Cycle 1 (baseline phase) - 144 hours | 4.9 SUV ratio | Standard Deviation 3.6 |
| Part 1: Ezabenlimab 240mg + BI 754111 600mg | Standard Uptake Value (SUV) in a 1ml Sphere Around Highest SUV Pixel (SUVpeak) of [89Zr]Zr-BI 754111 for Tumor Uptake - Part 2 | Cycle 2 (on-treatment phase) - 144 hours | 4.3 SUV ratio | Standard Deviation 2 |
Comparison: The mean relative change is calculated as first deriving the relative change from baseline for each selected lesion at each time point (96hours, 144hours):~100 \* (SUVpeak,lesion,timepoint,cycle2 - SUVpeak,lesion,timepoint,cycle1) / SUVpeak,lesion,timepoint,cycle1 Then, we calculate the mean over all evaluable lesions (at each time point) At last, the mean relative change is the lower mean value across time points.