Neoplasms
Conditions
Brief summary
This is a Phase I, non-randomized, uncontrolled, open-label, dose escalating study of BI 836880 administered intravenously. The eligible patient population will be patients with advanced solid tumours. At any time during the trial, it will not be permitted to escalate to a dose which does not fulfil the escalation with overdose control (EWOC) criterion
Interventions
DRUGBI 836880
BI 836880
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
* Age \>= 18 years * Histologically or cytologically confirmed malignancy which is locally advanced or metastatic solid tumor, and either refractory after standard therapy for the disease or for which standard therapy is not reliably effective, e.g. they do not tolerate or have contraindications to otherwise available standard therapy and tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-MRI at MTD. * ECOG performance status \<= 2 * Adequate hepatic, renal and bone marrow functions * Signed written informed consent. * Life expectancy min. 3 months in the opinion of the investigator * Recovery from all reversible adverse events of previous anti-cancer therapies to baseline or CTCAE grade 1, except for alopecia (any grade) sensory peripheral neuropathy CTCAE grade \<= 2 or considered not clinically significant. * adequate contraception by male and female patient during the trial and for at least 6 months after end of treatment.
Exclusion criteria
* Known hypersensitivity to the trial drugs or their excipients * Current or prior treatment with any systemic anti-cancer therapy either within 28 days or a minimum of 5 half-lives, whichever is shorter of trial onset. * 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 * 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 at baseline (\> 470 ms). QTcF will be calculated by Investigator as the mean of the 3 ECGs taken at screening. * Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within past 6 months, congestive heart failure \> NYHA II). Uncontrolled hypertension defined as: blood pressure in rested and relaxed condition \>=140 mmHg systolic, or \>=90 mmHg diastolic (with or without medication), measured according to protocol. * 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. * Patient with brain metastases that are symptomatic and/or require therapy. * Patients who require full-dose anticoagulation (according to local guidelines). * Active alcohol or drug abuse in the opinion of the investigator. * Patients who are under judicial protection and patients who are legally institutionalized. * Patients unable or unwilling to comply with protocol * Women who are pregnant, nursing, or who plan to become pregnant while in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Up to 3 weeks after the first administration of trial medication. | Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the true dose-limiting toxicity (DLT) rate being above 0.33 during the MTD evaluation period, defined as 3 weeks after first administration of trial medication (i.e. cycle 1). Patients who did not complete the MTD evaluation period for reasons other than DLT were excluded from the analysis of the primary endpoint. |
| Number of Patients With Dose-limiting Toxicities (DLT) in the Maximum Tolerated Dose (MTD) Period | Up to 3 weeks after the first administration of trial medication. | DTLs are defined as followed: * Drug-related Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 non-haematological toxicity * CTCAE Grade 4 neutropenia lasting \>7 days or complicated by infection (please note that in case of grade 4 neutropenia a more frequent follow up of patient was necessary * Febrile neutropenia of CTCAE Grade ≥3 * CTCAE Grade 4 thrombocytopenia or CTCAE Grade ≥3 thrombocytopenia with bleeding * Treatment delay for \>2 weeks due to unresolved drug-related AEs, which started within 3 weeks after the first treatment * Hypertension: increase of diastolic blood pressure (DBP) by 15 millimetre of mercury (mmHg) confirmed by a second measurement or by ambulatory blood pressure measurement (when indicated, e.g. white coat effect) which could not be controlled by hypertensive medication and required a dose reduction of BI 836880 for further treatment cycle * Proteinuria: urinary protein ≥3.5 gram/day (CTCAE Grade 3) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Drug-related Adverse Events Leading to Dose Reduction or Discontinuation During Treatment Period | From first drug infusion until 42 days (residual effect period) after last drug infusion, up to 828 days. | Number of patients with drug-related adverse events leading to dose reduction or discontinuation during treatment period. |
| Area Under the Serum Concentration-time Curve Over the Time Interval From 0 Extrapolated to Infinity (AUC0-tz) After the First Dose | 5 minutes before start of BI 836880 infusion and immediately after end of infusion (i.e. 1.5 hours (h) after start of infusion) and 2h, 3h, 5h, 8h, 24h, 72h, 168h, 336h and 504h after start of BI 826880 infusion in cycle 1. | Area under the serum concentration-time curve over the time interval from 0 extrapolated to infinity (AUC0-tz) after the first dose. |
| Terminal Half-life (t_1/2) of BI 836880 | 5 minutes before start of BI 836880 infusion and immediately after end of infusion (i.e. 1.5 hours (h) after start of infusion) and 2h, 3h, 5h, 8h, 24h, 72h, 168h, 336h and 504h after start of BI 826880 infusion in cycle 1. | Terminal half-life (t\_1/2) of BI 836880. |
Countries
France, Germany
Participant flow
Recruitment details
A non-randomized, open-label, multi-center dose escalation trial to determine the maximum tolerated dose and recommended Phase 2 dose of BI 836880 in patients with advanced or metastatic/refractory solid tumours.
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 |
|---|---|
| 40 mg BI 836880 40 milligrams (mg) BI 836880 solution for infusion were administered intravenous as rate-controlled infusion once per treatment cycle (21 days) in patients with advanced or metastatic solid tumour. Administration was continued until disease progression or until intolerable toxicities had been observed, up to 786 days. The pharmaceutical formulation was diluted with 50ml/vial to prepare solution for infusion of BI 836880. | 3 |
| 120 mg BI 836880 120 mg BI 836880 solution for infusion were administered intravenous as rate-controlled infusion once per treatment cycle (21 days) in patients with advanced or metastatic solid tumour. Administration was continued until disease progression or until intolerable toxicities had been observed, up to 786 days. The pharmaceutical formulation was diluted with 50ml/vial to prepare solution for infusion of BI 836880. | 2 |
| 360 mg BI 836880 360 mg BI 836880 solution for infusion were administered intravenous as rate-controlled infusion once per treatment cycle (21 days) in patients with advanced or metastatic solid tumour. Administration was continued until disease progression or until intolerable toxicities had been observed, up to 786 days. The pharmaceutical formulation was diluted with 50ml/vial to prepare solution for infusion of BI 836880. | 2 |
| 720 mg BI 836880 720 mg BI 836880 solution for infusion were administered intravenous as rate-controlled infusion once per treatment cycle (21 days) in patients with advanced or metastatic solid tumour. Administration was continued until disease progression or until intolerable toxicities had been observed, up to 786 days. The pharmaceutical formulation was diluted with 50ml/vial to prepare solution for infusion of BI 836880. | 17 |
| 1000 mg BI 836880 1000 mg BI 836880 solution for infusion were administered intravenous as as rate-controlled infusion once per treatment cycle (21 days) in patients with advanced or metastatic solid tumour. Administration was continued until disease progression or until intolerable toxicities had been observed, up to 786 days. The pharmaceutical formulation was diluted with 50ml/vial to prepare solution for infusion of BI 836880. | 5 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Dose-limiting toxicity | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other adverse event or clinical progression | 0 | 1 | 0 | 3 | 0 |
| Overall Study | Personal Reasons | 1 | 0 | 0 | 1 | 1 |
| Overall Study | Progressive Disease | 2 | 1 | 1 | 13 | 2 |
Baseline characteristics
| Characteristic | 360 mg BI 836880 | 40 mg BI 836880 | 120 mg BI 836880 | 720 mg BI 836880 | 1000 mg BI 836880 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 47.0 Years STANDARD_DEVIATION 9.9 | 57.7 Years STANDARD_DEVIATION 8.1 | 70.5 Years STANDARD_DEVIATION 6.4 | 56.7 Years STANDARD_DEVIATION 14.2 | 49.4 Years STANDARD_DEVIATION 13.2 | 55.8 Years STANDARD_DEVIATION 13.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants | 14 Participants | 2 Participants | 20 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | 1 Participants | 2 Participants | 1 Participants | 14 Participants | 2 Participants | 20 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 12 Participants | 3 Participants | 18 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 2 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 2 | 0 / 2 | 4 / 17 | 2 / 5 | 9 / 29 |
| other Total, other adverse events | 3 / 3 | 2 / 2 | 2 / 2 | 17 / 17 | 5 / 5 | 29 / 29 |
| serious Total, serious adverse events | 1 / 3 | 2 / 2 | 1 / 2 | 6 / 17 | 5 / 5 | 15 / 29 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the true dose-limiting toxicity (DLT) rate being above 0.33 during the MTD evaluation period, defined as 3 weeks after first administration of trial medication (i.e. cycle 1). Patients who did not complete the MTD evaluation period for reasons other than DLT were excluded from the analysis of the primary endpoint.
Time frame: Up to 3 weeks after the first administration of trial medication.
Population: Dose-finding cohort treated set: All patients enrolled in dose finding and confirmation of MTD cohort of the trial who were documented to have taken at least 1 dose of study medication and were evaluable for the MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 836880 - All Dose Groups | Maximum Tolerated Dose (MTD) | 720 Milligram |
Primary
Number of Patients With Dose-limiting Toxicities (DLT) in the Maximum Tolerated Dose (MTD) Period
DTLs are defined as followed: * Drug-related Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 non-haematological toxicity * CTCAE Grade 4 neutropenia lasting \>7 days or complicated by infection (please note that in case of grade 4 neutropenia a more frequent follow up of patient was necessary * Febrile neutropenia of CTCAE Grade ≥3 * CTCAE Grade 4 thrombocytopenia or CTCAE Grade ≥3 thrombocytopenia with bleeding * Treatment delay for \>2 weeks due to unresolved drug-related AEs, which started within 3 weeks after the first treatment * Hypertension: increase of diastolic blood pressure (DBP) by 15 millimetre of mercury (mmHg) confirmed by a second measurement or by ambulatory blood pressure measurement (when indicated, e.g. white coat effect) which could not be controlled by hypertensive medication and required a dose reduction of BI 836880 for further treatment cycle * Proteinuria: urinary protein ≥3.5 gram/day (CTCAE Grade 3)
Time frame: Up to 3 weeks after the first administration of trial medication.
Population: Dose-finding cohort treated set: All patients enrolled in dose finding and confirmation of MTD cohort of the trial who were documented to have taken at least 1 dose of study medication and were evaluable for the MTD determination.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BI 836880 - All Dose Groups | Number of Patients With Dose-limiting Toxicities (DLT) in the Maximum Tolerated Dose (MTD) Period | 0 Participants |
| 120 mg BI 836880 | Number of Patients With Dose-limiting Toxicities (DLT) in the Maximum Tolerated Dose (MTD) Period | 0 Participants |
| 360 mg BI 836880 | Number of Patients With Dose-limiting Toxicities (DLT) in the Maximum Tolerated Dose (MTD) Period | 0 Participants |
| 720 mg BI 836880 | Number of Patients With Dose-limiting Toxicities (DLT) in the Maximum Tolerated Dose (MTD) Period | 0 Participants |
| 1000 mg BI 836880 | Number of Patients With Dose-limiting Toxicities (DLT) in the Maximum Tolerated Dose (MTD) Period | 1 Participants |
Secondary
Area Under the Serum Concentration-time Curve Over the Time Interval From 0 Extrapolated to Infinity (AUC0-tz) After the First Dose
Area under the serum concentration-time curve over the time interval from 0 extrapolated to infinity (AUC0-tz) after the first dose.
Time frame: 5 minutes before start of BI 836880 infusion and immediately after end of infusion (i.e. 1.5 hours (h) after start of infusion) and 2h, 3h, 5h, 8h, 24h, 72h, 168h, 336h and 504h after start of BI 826880 infusion in cycle 1.
Population: Pharmacokinetic (PK) analysis set: All patients who were treated and provided at least 1 observation for at least 1 PK endpoint without an important protocol deviation relevant to PK evaluations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 836880 - All Dose Groups | Area Under the Serum Concentration-time Curve Over the Time Interval From 0 Extrapolated to Infinity (AUC0-tz) After the First Dose | 2180 Microgram * hours/ milliliter | Geometric Coefficient of Variation 152 |
| 120 mg BI 836880 | Area Under the Serum Concentration-time Curve Over the Time Interval From 0 Extrapolated to Infinity (AUC0-tz) After the First Dose | 4100 Microgram * hours/ milliliter | Geometric Coefficient of Variation 38.7 |
| 360 mg BI 836880 | Area Under the Serum Concentration-time Curve Over the Time Interval From 0 Extrapolated to Infinity (AUC0-tz) After the First Dose | 15000 Microgram * hours/ milliliter | Geometric Coefficient of Variation 71.1 |
| 720 mg BI 836880 | Area Under the Serum Concentration-time Curve Over the Time Interval From 0 Extrapolated to Infinity (AUC0-tz) After the First Dose | 32900 Microgram * hours/ milliliter | Geometric Coefficient of Variation 28.1 |
| 1000 mg BI 836880 | Area Under the Serum Concentration-time Curve Over the Time Interval From 0 Extrapolated to Infinity (AUC0-tz) After the First Dose | 40000 Microgram * hours/ milliliter | Geometric Coefficient of Variation 66.6 |
Secondary
Number of Patients With Drug-related Adverse Events Leading to Dose Reduction or Discontinuation During Treatment Period
Number of patients with drug-related adverse events leading to dose reduction or discontinuation during treatment period.
Time frame: From first drug infusion until 42 days (residual effect period) after last drug infusion, up to 828 days.
Population: Treated Set (TS): The TS included all patients enrolled in the trial who were documented to have taken at least 1 dose of trial medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BI 836880 - All Dose Groups | Number of Patients With Drug-related Adverse Events Leading to Dose Reduction or Discontinuation During Treatment Period | 0 Participants |
| 120 mg BI 836880 | Number of Patients With Drug-related Adverse Events Leading to Dose Reduction or Discontinuation During Treatment Period | 0 Participants |
| 360 mg BI 836880 | Number of Patients With Drug-related Adverse Events Leading to Dose Reduction or Discontinuation During Treatment Period | 0 Participants |
| 720 mg BI 836880 | Number of Patients With Drug-related Adverse Events Leading to Dose Reduction or Discontinuation During Treatment Period | 1 Participants |
| 1000 mg BI 836880 | Number of Patients With Drug-related Adverse Events Leading to Dose Reduction or Discontinuation During Treatment Period | 1 Participants |
Secondary
Terminal Half-life (t_1/2) of BI 836880
Terminal half-life (t\_1/2) of BI 836880.
Time frame: 5 minutes before start of BI 836880 infusion and immediately after end of infusion (i.e. 1.5 hours (h) after start of infusion) and 2h, 3h, 5h, 8h, 24h, 72h, 168h, 336h and 504h after start of BI 826880 infusion in cycle 1.
Population: Pharmacokinetic (PK) analysis set: All patients who were treated and provided at least 1 observation for at least 1 PK endpoint without an important protocol deviation relevant to PK evaluations. Only participants with available data were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 836880 - All Dose Groups | Terminal Half-life (t_1/2) of BI 836880 | 241 Hours | Geometric Coefficient of Variation 16.3 |
| 120 mg BI 836880 | Terminal Half-life (t_1/2) of BI 836880 | 210 Hours | Geometric Coefficient of Variation 5.07 |
| 360 mg BI 836880 | Terminal Half-life (t_1/2) of BI 836880 | 265 Hours | Geometric Coefficient of Variation 7.42 |
| 720 mg BI 836880 | Terminal Half-life (t_1/2) of BI 836880 | 289 Hours | Geometric Coefficient of Variation 19.1 |
| 1000 mg BI 836880 | Terminal Half-life (t_1/2) of BI 836880 | 279 Hours | Geometric Coefficient of Variation 8.96 |