Neoplasms
Conditions
Brief summary
The primary objective of this trial is to determine the maximum tolerated dose (MTD)/optimal biological dose (OBD) of BI 905681 given as an intravenous infusion and to determine the recommended dose and dosing schedule for further trials in the development of BI 905681. The MTD will be defined based on the frequency of patients experiencing dose-limiting toxicities (DLTs) during the MTD/DLT evaluation period, which is defined as the first cycle of treatment. Separate MTDs will be determined for Schedule A and Schedule B. The secondary objective of the trial is to determine the pharmacokinetic (PK) profile of BI 905681.
Detailed description
Study was opened to recruitment until 29-Oct-2021, however from 15-Apr-2021 no patient was recruited.
Interventions
DRUGBI 905681
Infusion
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or metastatic non-haematologic malignancy. Patient must have measurable or evaluable lesions (according to Response Evaluation Criteria in Solid Tumours (RECIST) v 1.1). * Patient who has failed conventional treatment or for whom no therapy of proven efficacy exists or who is not eligible for established treatment options. * Patients willing to undergo mandatory tumour biopsy at the time points specified in the protocol. * Eastern Cooperative Oncology Group (ECOG) Score of 0 or 1 (R01-0787). * Adequate organ function defined as all of the following: * Absolute neutrophil count (ANC) ≥1.5 x 10\^9/L; haemoglobin ≥9.0 g/dL; platelets ≥100 x 10\^9/L without the use of haematopoietic growth factors within 4 weeks of start of study medication. * Total bilirubin ≤1.5 x the upper limit of normal (ULN), except for patients with Gilbert's syndrome: total bilirubin ≤3 x ULN or direct bilirubin ≤1.5 x ULN. * Creatinine ≤1.5 x ULN. If creatinine is \>1.5 x ULN, patient is eligible if concurrent creatinine clearance ≥50 ml/min (measured or calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or Japanese version of CKD-EPI formula for Japanese patients). * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x ULN if no demonstrable liver metastases, or otherwise ≤5 x ULN * Alkaline Phosphatase (ALP) \<5 x ULN * At least 18 years of age at the time of consent or over the legal age of consent in countries where that is greater than 18 years. * Signed and dated written informed consent in accordance with International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP) and local legislation prior to admission to the trial * Life expectancy ≥3 months at the start of treatment in the opinion of the investigator * Further inclusion criteria apply
Exclusion criteria
* Osteoporosis ≥ CTCAE Grade 2 * Osteoporotic compression fracture within 12 months prior to informed consent which is clinically significant in the opinion of the investigator. * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Maximum Tolerated Dose (MTD)/Optimal Biological Dose (OBD) of BI 905681 | The first cycle of treatment, up to 21 days. | The MTD/OBD of BI 905681. The MTD will be assessed based on the number of patients experiencing Dose Limiting Toxicities (DLTs), graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, in the first cycle of treatment (3 weeks). The MTD is defined as the highest dose with less than 25% risk of the true DLT rate being equal to or above 33%. |
| Number of Patients Experiencing Adverse Events (AEs) During the Entire Treatment Period | From the first administration of study till the last administration of study drug +42 days, up to 126 days. | Number of patients experiencing adverse events (AEs) during the entire treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Measured Concentration of BI 905681 in Serum After First Infusion | 5 minutes before and 1, 1.5, 4, 8, 24, 72, 168, 336 and 504 (5 minutes before 2nd infusion) hours following the first infusion. | Cmax: maximum measured concentration of BI 905681 in serum after first infusion. |
| AUC0-tz: Area Under the Serum Concentration-time Curve Over the Time Interval From 0 to the Last Measured Time Point (tz) | 5 minutes before and 1, 1.5, 4, 8, 24, 72, 168, 336 and 504 (5 minutes before 2nd infusion) hours following the first infusion. | AUC0-tz: area under the serum concentration-time curve over the time interval from 0 to the last measured time point (tz). |
Countries
United States
Participant flow
Recruitment details
This was a Phase I, open-label, non-randomised dose-escalation study of BI 905681 administered intravenously as a single agent in patients with advanced 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.
Participants by arm
| Arm | Count |
|---|---|
| 1.0 Milligram/Kilogram BI 905681 Subjects received an intravenous infusion of 1.0 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. | 3 |
| 2.5 Milligram/Kilogram BI 905681 Subjects received an intravenous infusion of 2.5 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. | 4 |
| 5.0 Milligram/Kilogram BI 905681 Subjects received an intravenous infusion of 5.0 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. | 5 |
| 7.0 Milligram/Kilogram BI 905681 Subjects received an intravenous infusion of 7.0 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. | 4 |
| 8.5 Milligram/Kilogram BI 905681 Subjects received an intravenous infusion of 8.5 milligram/kilogram BI 905681 on day 1 of each cycle (1 cycle = 21 days). Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met. | 5 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Clinical Disease Progression | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 3 | 3 | 4 | 4 | 3 |
Baseline characteristics
| Characteristic | 1.0 Milligram/Kilogram BI 905681 | 2.5 Milligram/Kilogram BI 905681 | 5.0 Milligram/Kilogram BI 905681 | 7.0 Milligram/Kilogram BI 905681 | 8.5 Milligram/Kilogram BI 905681 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 56.7 years STANDARD_DEVIATION 6.5 | 63.8 years STANDARD_DEVIATION 2.1 | 55.6 years STANDARD_DEVIATION 17.6 | 66.3 years STANDARD_DEVIATION 11.1 | 62.0 years STANDARD_DEVIATION 9.6 | 60.9 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 4 Participants | 4 Participants | 5 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 1 Participants | 4 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 11 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 4 | 2 / 5 | 0 / 4 | 0 / 5 |
| other Total, other adverse events | 2 / 3 | 4 / 4 | 5 / 5 | 4 / 4 | 4 / 5 |
| serious Total, serious adverse events | 1 / 3 | 1 / 4 | 2 / 5 | 1 / 4 | 0 / 5 |
Outcome results
Primary
Number of Patients Experiencing Adverse Events (AEs) During the Entire Treatment Period
Number of patients experiencing adverse events (AEs) during the entire treatment period.
Time frame: From the first administration of study till the last administration of study drug +42 days, up to 126 days.
Population: Treated Set (TS): includes all patients who received at least one infusion of BI 905681.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BI 905681 | Number of Patients Experiencing Adverse Events (AEs) During the Entire Treatment Period | 2 Participants |
| 2.5 Milligram/Kilogram BI 905681 | Number of Patients Experiencing Adverse Events (AEs) During the Entire Treatment Period | 4 Participants |
| 5.0 Milligram/Kilogram BI 905681 | Number of Patients Experiencing Adverse Events (AEs) During the Entire Treatment Period | 5 Participants |
| 7.0 Milligram/Kilogram BI 905681 | Number of Patients Experiencing Adverse Events (AEs) During the Entire Treatment Period | 4 Participants |
| 8.5 Milligram/Kilogram BI 905681 | Number of Patients Experiencing Adverse Events (AEs) During the Entire Treatment Period | 4 Participants |
Primary
The Maximum Tolerated Dose (MTD)/Optimal Biological Dose (OBD) of BI 905681
The MTD/OBD of BI 905681. The MTD will be assessed based on the number of patients experiencing Dose Limiting Toxicities (DLTs), graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, in the first cycle of treatment (3 weeks). The MTD is defined as the highest dose with less than 25% risk of the true DLT rate being equal to or above 33%.
Time frame: The first cycle of treatment, up to 21 days.
Population: MTD Evaluation Set (MTDS): includes all patients who received at least one infusion of BI 905681 and who were not replaced for the MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 905681 | The Maximum Tolerated Dose (MTD)/Optimal Biological Dose (OBD) of BI 905681 | NA milligram/kilogram |
Secondary
AUC0-tz: Area Under the Serum Concentration-time Curve Over the Time Interval From 0 to the Last Measured Time Point (tz)
AUC0-tz: area under the serum concentration-time curve over the time interval from 0 to the last measured time point (tz).
Time frame: 5 minutes before and 1, 1.5, 4, 8, 24, 72, 168, 336 and 504 (5 minutes before 2nd infusion) hours following the first infusion.
Population: Pharmacokinetics Analysis Set (PKS): All patients who received at least one infusion of BI 905681 and who provide at least one observation for at least one pharmacokinetic (PK) endpoint without important protocol violations relevant to the evaluation of PK. one subject (8.5 mg/kg group) was excluded due to not being able to receive the full dose for safety reasons.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 905681 | AUC0-tz: Area Under the Serum Concentration-time Curve Over the Time Interval From 0 to the Last Measured Time Point (tz) | 4260 hour*microgram/milliliter | Geometric Coefficient of Variation 27.8 |
| 2.5 Milligram/Kilogram BI 905681 | AUC0-tz: Area Under the Serum Concentration-time Curve Over the Time Interval From 0 to the Last Measured Time Point (tz) | 7640 hour*microgram/milliliter | Geometric Coefficient of Variation 10.6 |
| 5.0 Milligram/Kilogram BI 905681 | AUC0-tz: Area Under the Serum Concentration-time Curve Over the Time Interval From 0 to the Last Measured Time Point (tz) | 18200 hour*microgram/milliliter | Geometric Coefficient of Variation 53.2 |
| 7.0 Milligram/Kilogram BI 905681 | AUC0-tz: Area Under the Serum Concentration-time Curve Over the Time Interval From 0 to the Last Measured Time Point (tz) | 30000 hour*microgram/milliliter | Geometric Coefficient of Variation 23.8 |
| 8.5 Milligram/Kilogram BI 905681 | AUC0-tz: Area Under the Serum Concentration-time Curve Over the Time Interval From 0 to the Last Measured Time Point (tz) | 18900 hour*microgram/milliliter | Geometric Coefficient of Variation 217 |
Secondary
Cmax: Maximum Measured Concentration of BI 905681 in Serum After First Infusion
Cmax: maximum measured concentration of BI 905681 in serum after first infusion.
Time frame: 5 minutes before and 1, 1.5, 4, 8, 24, 72, 168, 336 and 504 (5 minutes before 2nd infusion) hours following the first infusion.
Population: Pharmacokinetics Analysis Set (PKS): All patients who received at least one infusion of BI 905681 and who provide at least one observation for at least one pharmacokinetic (PK) endpoint without important protocol violations relevant to the evaluation of PK. two subjects were excluded, one subject due to having a prolonged infusion (1mg/kg group) and one subject (8.5 mg/kg group) was not able to receive the full dose due to safety reasons.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 905681 | Cmax: Maximum Measured Concentration of BI 905681 in Serum After First Infusion | NA microgram/milliliter | — |
| 2.5 Milligram/Kilogram BI 905681 | Cmax: Maximum Measured Concentration of BI 905681 in Serum After First Infusion | 49.6 microgram/milliliter | Geometric Coefficient of Variation 19.7 |
| 5.0 Milligram/Kilogram BI 905681 | Cmax: Maximum Measured Concentration of BI 905681 in Serum After First Infusion | 157 microgram/milliliter | Geometric Coefficient of Variation 18 |
| 7.0 Milligram/Kilogram BI 905681 | Cmax: Maximum Measured Concentration of BI 905681 in Serum After First Infusion | 185 microgram/milliliter | Geometric Coefficient of Variation 23.1 |
| 8.5 Milligram/Kilogram BI 905681 | Cmax: Maximum Measured Concentration of BI 905681 in Serum After First Infusion | 201 microgram/milliliter | Geometric Coefficient of Variation 21.4 |