Neoplasms, Neoplasm Metastasis, Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The main objective of the dose-escalation parts of the trial is to determine the maximum tolerated dose (MTD), based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and to evaluate its safety and tolerability by monitoring the occurrence and severity of adverse events (AEs). Secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and the preliminary assessment of anti-tumour activity.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
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) in accordance with International Conference of Harmonization-Good Clinical Practice (ICH-GCP) and local legislation prior to any trial-specific procedures, sampling, or analyses * Patients ≥18 years-of-age at the time of signature of the ICF * 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. * Eastern Cooperative Oncology Group (ECOG) score: 0 or 1 * Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement * For Parts A and B: Patients with a confirmed diagnosis of advanced, unresectable and/or metastatic solid tumours, who have failed standard treatment, or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies. Measurable lesions according to RECIST Version 1.1 must be present. Eligibility is limited to the following tumour subtypes in Part B: bladder, colon, breast, Non-small cell lung cancer (NSCLC), ovarian, pancreatic, renal, esophagogastric, sarcoma, prostate, and melanoma. * For Parts B and C: Patients must have measurable disease per RECIST v1.1, must have at least 1 tumour lesion amenable to biopsy, and must be willing to undergo a biopsy prior to first treatment and another biopsy while on therapy unless clinically contraindicated. * For Part C: Patients with metastatic NSCLC who developed disease progression (per RECIST v1.1) after the first scan (where SD, Partial Response (PR), or Complete Response (CR) was demonstrated at the first scan), and require new anti-cancer therapy after first line treatment with an anti programmed cell death protein 1 (PD-1)/anti programmed cell death ligand 1 (PD-L1) monoclonal antibody (mAb) (given either as single agent therapy or in combination with a platinum-based chemotherapy regimen).
Exclusion criteria
* Major surgery (major according to the Investigator's and/or Medical Monitor's assessment) performed within 12 weeks prior to randomization or planned within 12 months after screening (e.g., hip replacement) * Presence of other active invasive cancers other than the one treated in this trial within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin, or in situ carcinoma of uterine cervix, or other local tumours considered cured by local treatment * 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 * Previous administration of BI 891065 or BI 754091 * Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s), or receiving other investigational treatments. * Patients who have been treated with any other anticancer drug within 4 weeks or within 5 half-life periods (whichever come earlier) prior to first administration of BI 891065. At least 7 days must have elapsed between the last dose of such agent and the first dose of study drug. * Persistent toxicity from previous treatments that has not resolved to ≤ Grade 1 (except for alopecia and Grade 2 neuropathy due to prior platinum-based therapy) * Active, known or suspected autoimmune disease except vitiligo or resolved asthma/atopy * Interstitial lung disease * Any of the following cardiac criteria: * Mean resting corrected QT interval (QTcF) \>470 msec * Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting Electrocardiograms (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 with known or possible risk of QT interval prolongation * 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 \[ECHO\], multi-gated acquisition scan \[MUGA\]). 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. * Out of range laboratory values are defined as: * Alanine transaminase (ALT) and aspartate amino transferase (AST) \>3 times the Upper limit of normal (ULN) if no demonstrable liver metastases or \>5 times ULN in the presence of liver metastases * Total bilirubin \>1.5 times ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin \>3.0 times ULN or direct bilirubin \>1.5 times ULN * Human immunodeficiency virus (HIV) infection, acute or chronic viral hepatitis * Known hypersensitivity to the trial drugs or their excipients * Serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, such as cardiac, neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the Investigator and/or Medical Monitor would make the patient inappropriate for entry into the trial. * Chronic alcohol or drug abuse or any condition that, in the Investigator's and/or Medical Monitor's opinion, makes them an unreliable trial patient or unlikely to complete the trial * Women who are pregnant, nursing, or who plan to become pregnant while in the trial and for at least 6 months after the last administration of trial medication. * Men who plan to father a child while in the trial and for at least 6 months after the last administration of trial medication. * Known presence of symptomatic central nervous system (CNS) metastases, unless asymptomatic and off corticosteroids and/or anti-convulsant therapy for at least 2 weeks prior start of treatment. Patients with asymptomatic CNS metastases may be enrolled following a 2-week washout period. * Patients receiving systemic treatment with any immunosuppressive medication within 1 week prior treatment start (steroids of max. 10 mg prednisolone equivalent per day are allowed, topical and inhaled steroids are not considered as immunosuppressive). * For Parts A and B: Patients with known epidermal growth factor receptor (EGFR), known anaplastic lymphoma kinase (ALK), or known ROS Proto-Oncogene 1 (ROS1) genomic tumour aberrations, unless disease has progressed following available EGFR or ALK targeted therapy (including osimertinib for EGFR T790M-mutated NSCLC) * Out of range lab values as defined: * Absolute neutrophil count (ANC) \<1.5 x 109/L (\<1500/mm3) * Platelet (PLT) count \<100 x 109/L * Haemoglobin \<90 g/L (\<9 g/dL) \-- Creatinine \>1.5 times ULN (patients may enter if creatinine is \>1.5 x ULN and estimated glomerular filtration rate (eGFR) \>30 mL/min/1.73 m2) (Chronic Kidney Disease Epidemiology \[CKD-EPI\] Collaboration equation); confirmation of eGRF is only required when creatinine is \>1.5 X ULN. * For Part C: Patients with EGFR, ALK, or (if known) ROS1 genomic tumor aberrations * For Part C: Patients with any CTLA-4 therapy * For Part C: One or more lines of anti-cancer therapy between previous anti-PD-1/anti-PDL1 mAb therapy and study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A - Maximum Tolerated Dose (MTD) of BI 891065 | First treatment cycle (MTD evaluation period), up to 21 days. | Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period. |
| Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | First treatment cycle (MTD evaluation period), up to 21 days. | DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1. |
| Part B: Maximum Tolerated Dose (MTD) of BI 891065 in Combination With Ezabenlimab | First treatment cycle (MTD evaluation period), up to 21 days. | Maximum tolerated dose (MTD) of BI 891065 in combination with ezabenlimab, defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period. |
| Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | First treatment cycle (MTD evaluation period), up to 21 days. | DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1. | Area under the concentration-time curve of BI 891065 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle. Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg. |
| Part B: Number of Patients With Dose-limiting Toxicities (DLTs) Observed During the Entire Treatment Period | From first drug administration until last drug administration plus residual effect period of 30 days, up to 386 days. | DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1. |
| Part B: Number of Patients With Objective Response (OR) | Up to 356 days. | OR based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, defined as the best overall response of complete response (CR) and partial response (PR), where the best overall response is the best time point response recorded from the first administration of study medication until the end of treatment. Number of patients with objective response is reported. |
| Part B: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1. | Area under the concentration-time curve of BI 891065 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle. |
| Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | From first drug administration until last drug administration plus residual effect period of 30 days, up to 282 days. | DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1. |
| Part B: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1. | Maximum measured plasma concentration of BI 891065 at steady state (Cmax,ss) in the first treatment cycle. |
| Part B: Maximum Measured Plasma Concentration (Cmax) of BI 754091 in the First Treatment Cycle | Predose and 1, 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 359.5, 383.917, 504, 998 and 999 hours after intake of BI 754091 at day 1, cycle 1. | Maximum measured plasma concentration (Cmax) of BI 754091 in the first treatment cycle. Results are reported for the overall group only since dose level of BI 754091 is fixed in this trial. |
| Part B: Area Under the Concentration-time Curve of BI 754091 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Predose and 1, 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 359.5, 383.917, 504, 998 and 999 hours after intake of BI 754091 at day 1, cycle 1. | Area under the concentration-time curve of BI 754091 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle. Results are reported for the overall group only since dose level of BI 754091 is fixed in this trial. |
| Part B: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1. | Area under the concentration time curve of BI 891065 over a dosing interval at steady state (AUCtau,ss) in the first treatment cycle. |
| Part A: Number of Patients With Objective Response (OR) | Up to 252 days. | OR based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, defined as the best overall response of complete response (CR) and partial response (PR), where the best overall response is the best time point response recorded from the first administration of study medication until the end of treatment Number of patients with objective response is reported. |
| Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1. | Maximum measured plasma concentration at steady state (cmax,ss) during the first treatment cycle. Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg. |
| Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1. | Area under the concentration time curve of BI 891065 over a dosing interval at steady state (AUCtau,ss). Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg. |
Countries
United States
Participant flow
Recruitment details
An open-label trial to investigate the maximum tolerated dose (MTD)/recommended dose for further development based on dose limiting toxicities (DLT), safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of BI 891065 alone and in combination with BI 754091 in patients with advanced and/or metastatic malignancies.
Pre-assignment details
Only patients that met all inclusion and none of the exclusion criteria were included in this trial. Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. Patients who discontinued from trial medication are reported as not completed.
Participants by arm
| Arm | Count |
|---|---|
| Part A: 5 mg BI 891065 1 film-coated tablet of 5 milligram (mg) of BI 891065 was administered orally once daily in patients with advanced and/or metastatic malignancies. Treatment cycles were 21 days. Patients continued treatment with BI 891065 as long as they derived clinical benefit. (Up to 252 days).
Patients were asked to fast overnight, at least 10 hours prior to day 1 and day 15 in cycle 1. | 3 |
| Part A: 15 mg BI 891065 3 film-coated tablets of 5 mg (15 mg total) of BI 891065 were administered orally once daily in patients with advanced and/or metastatic malignancies. Treatment cycles were 21 days. Patients continued treatment with BI 891065 as long as they derived clinical benefit. (Up to 252 days). Patients were asked to fast overnight, at least 10 hours prior to day 1 and day 15 in cycle 1. | 1 |
| Part A: 25 mg BI 891065 1 film-coated tablet of 5 mg plus 1 film-coated tablet of 20 mg (25 mg in total) of BI 891065 were administered orally once daily in patients with advanced and/or metastatic malignancies. Treatment cycles were 21 days. Patients continued treatment with BI 891065 as long as the derived clinical benefit. (Up to 252 days). Patients were asked to fast overnight, at least 10 hours prior to day 1 and day 15 in cycle 1. | 3 |
| Part A: 50 mg BI 891065 1 film-coated tablet of 50 mg of BI 891065 was administered orally once daily in patients with advanced and/or metastatic malignancies. Treatment cycles were 21 days. Patients continued treatment with BI 891065 as long as the derived clinical benefit. (Up to 252 days). Patients were asked to fast overnight, at least 10 hours prior to day 1 and day 15 in cycle 1. | 4 |
| Part A: 100 mg BI 891065 2 film-coated tablets of 50 mg (100 mg in total) of BI 891065 were administered orally once daily in patients with advanced and/or metastatic malignancies. Treatment cycles were 21 days. Patients continued treatment with BI 891065 as long as the derived clinical benefit. (Up to 252 days). Patients were asked to fast overnight, at least 10 hours prior to day 1 and day 15 in cycle 1. | 3 |
| Part A: 200 mg BI 891065 4 film-coated tablets of 50 mg of BI 891065 (200 mg in total) were administered orally once daily in patients with advanced and/or metastatic malignancies. Treatment cycles were 21 days. Patients continued treatment with BI 891065 as long as the derived clinical benefit. (Up to 252 days). Patients were asked to fast overnight, at least 10 hours prior to day 1 and day 15 in cycle 1. | 3 |
| Part A: 400 mg BI 891065 8 film-coated tablets of 50 mg (400 mg in total) of BI 891065 were administered orally once daily in patients with advanced and/or metastatic malignancies. Treatment cycles were 21 days. Patients continued treatment with BI 891065 as long as the derived clinical benefit. (Up to 252 days). Patients were asked to fast overnight, at least 10 hours prior to day 1 and day 15 in cycle 1. | 8 |
| Part B: 50 mg BI 891065 QD + 240 mg BI 754091 1 film-coated tablet of 50 mg of BI 891065 was administered orally once daily (QD) in combination with 240 mg BI 754091, administered as intravenous infusion, on day 1 of each treatment cycle. Treatment cycles were 21 days. Patients were allowed to continue treatment with BI 891065 and BI 754091 as long as they derived clinical benefit. (Up to 356 days). Patients were asked to fast overnight, at least 10 hours prior to day 1, day 15 and day 16 in cycle 1. | 6 |
| Part B: 200 mg BI 891065 QD + 240 mg BI 754091 4 film-coated tablets of 50 mg, or 2 film-coated tablets of 100 mg (200 mg total) of BI 891065 were administered orally once daily (QD) in combination with 240 mg BI 754091, administered as intravenous infusion, on day 1 of each treatment cycle. Treatment cycles were 21 days. Patients were allowed to continue treatment with BI 891065 and BI 754091 as long as they derived clinical benefit. (Up to 356 days). Patients were asked to fast overnight, at least 10 hours prior to day 1, day 15 and day 16 in cycle 1. | 14 |
| Part B: 400 mg BI 891065 QD + 240 mg BI 754091 4 film-coated tablets of 100 mg (400 mg total) of BI 891065 were administered orally once daily (QD) in combination with 240 mg BI 754091, administered as intravenous infusion, on day 1 of each treatment cycle. Treatment cycles were 21 days. Patients were allowed to continue treatment with BI 891065 and BI 754091 as long as they derived clinical benefit. (Up to 356 days). Patients were asked to fast overnight, at least 10 hours prior to day 1, day 15 and day 16 in cycle 1. | 8 |
| Part B: 200 mg BI 891065 BID + 240 mg BI 754091 2 film-coated tablets of 100 mg (200 mg total) of BI 891065 were administered orally twice daily (BID) in combination with 240 mg BI 754091, administered as intravenous infusion, on day 1 of each treatment cycle. Treatment cycles were 21 days. Patients were allowed to continue treatment with BI 891065 and BI 754091 as long as they derived clinical benefit. (Up to 356 days). Patients were asked to fast overnight, at least 10 hours prior to day 1, day 15 and day 16 in cycle 1. | 9 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 2 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 |
| Overall Study | Progressive disease | 2 | 1 | 3 | 4 | 2 | 2 | 5 | 6 | 11 | 5 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A: 5 mg BI 891065 | Part A: 15 mg BI 891065 | Part A: 25 mg BI 891065 | Part A: 50 mg BI 891065 | Part A: 100 mg BI 891065 | Part A: 200 mg BI 891065 | Part A: 400 mg BI 891065 | Part B: 50 mg BI 891065 QD + 240 mg BI 754091 | Part B: 200 mg BI 891065 QD + 240 mg BI 754091 | Part B: 400 mg BI 891065 QD + 240 mg BI 754091 | Part B: 200 mg BI 891065 BID + 240 mg BI 754091 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 76.0 Years STANDARD_DEVIATION 2.6 | 58.0 Years | 65.7 Years STANDARD_DEVIATION 5.5 | 70.8 Years STANDARD_DEVIATION 9.5 | 63.0 Years STANDARD_DEVIATION 5.3 | 56.7 Years STANDARD_DEVIATION 15.4 | 66.5 Years STANDARD_DEVIATION 9.9 | 73.3 Years STANDARD_DEVIATION 6.7 | 60.4 Years STANDARD_DEVIATION 10.2 | 65.5 Years STANDARD_DEVIATION 10.3 | 58.7 Years STANDARD_DEVIATION 6.2 | 64.42 Years STANDARD_DEVIATION 9.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 8 Participants | 5 Participants | 12 Participants | 8 Participants | 9 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 8 Participants | 6 Participants | 13 Participants | 8 Participants | 9 Participants | 58 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 5 Participants | 4 Participants | 9 Participants | 4 Participants | 4 Participants | 37 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 4 Participants | 5 Participants | 25 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 | 1 / 3 | 1 / 1 | 2 / 3 | 3 / 4 | 2 / 3 | 1 / 3 | 2 / 8 | 2 / 6 | 2 / 14 | 0 / 8 | 3 / 9 |
| other Total, other adverse events | 3 / 3 | 1 / 1 | 3 / 3 | 4 / 4 | 3 / 3 | 2 / 3 | 8 / 8 | 6 / 6 | 13 / 14 | 8 / 8 | 9 / 9 |
| serious Total, serious adverse events | 1 / 3 | 0 / 1 | 1 / 3 | 1 / 4 | 2 / 3 | 1 / 3 | 2 / 8 | 0 / 6 | 3 / 14 | 3 / 8 | 2 / 9 |
Outcome results
Primary
Part A - Maximum Tolerated Dose (MTD) of BI 891065
Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Population: MTD Evaluation Set (Part A): All patients who received BI 891065 and completed the safety assessments required during cycle 1 or who experienced a DLT during cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: BI 891065 | Part A - Maximum Tolerated Dose (MTD) of BI 891065 | NA Milligram |
Primary
Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Population: MTD Evaluation Set (Part A): All patients who received BI 891065 and completed the safety assessments required during cycle 1 or who experienced a DLT during cycle 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: BI 891065 | Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 15 mg BI 891065 | Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 25 mg BI 891065 | Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 50 mg BI 891065 | Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 100 mg BI 891065 | Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 200 mg BI 891065 | Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 400 mg BI 891065 | Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
Primary
Part B: Maximum Tolerated Dose (MTD) of BI 891065 in Combination With Ezabenlimab
Maximum tolerated dose (MTD) of BI 891065 in combination with ezabenlimab, defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Population: MTD Evaluation Set (Part B): All patients who received BI 891065 and BI 754091, and completed the safety assessments required during cycle 1 or who experienced a DLT during cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: BI 891065 | Part B: Maximum Tolerated Dose (MTD) of BI 891065 in Combination With Ezabenlimab | NA Milligram |
Primary
Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: First treatment cycle (MTD evaluation period), up to 21 days.
Population: MTD Evaluation Set (Part B): All patients who received BI 891065 and BI 754091, and completed the safety assessments required during cycle 1 or who experienced a DLT during cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 15 mg BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| Part A: 25 mg BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 1 Participants |
| Part A: 50 mg BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
Secondary
Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 891065 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle. Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg.
Time frame: Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part A): All patients in the TS (Part A) who have at least one valid secondary pharmacokinetic (PK) endpoint available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 281 Nanomol * hours per Liter | Geometric Coefficient of Variation 44.6 |
| Part A: 15 mg BI 891065 | Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 1930 Nanomol * hours per Liter | — |
| Part A: 25 mg BI 891065 | Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 5030 Nanomol * hours per Liter | Geometric Coefficient of Variation 113 |
| Part A: 50 mg BI 891065 | Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 5820 Nanomol * hours per Liter | Geometric Coefficient of Variation 38.8 |
| Part A: 100 mg BI 891065 | Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 12900 Nanomol * hours per Liter | Geometric Coefficient of Variation 73.5 |
| Part A: 200 mg BI 891065 | Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 25200 Nanomol * hours per Liter | Geometric Coefficient of Variation 8.49 |
| Part A: 400 mg BI 891065 | Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 35800 Nanomol * hours per Liter | Geometric Coefficient of Variation 51 |
Secondary
Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss)
Area under the concentration time curve of BI 891065 over a dosing interval at steady state (AUCtau,ss). Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg.
Time frame: Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part A): All patients in the TS (Part A) who have at least one valid secondary pharmacokinetic (PK) endpoint available. Only patients with available data for this endpoint were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 713 Nanomol * hours per Liter | Geometric Coefficient of Variation 33.8 |
| Part A: 15 mg BI 891065 | Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 2070 Nanomol * hours per Liter | — |
| Part A: 25 mg BI 891065 | Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 10600 Nanomol * hours per Liter | Geometric Coefficient of Variation 190 |
| Part A: 50 mg BI 891065 | Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 10700 Nanomol * hours per Liter | Geometric Coefficient of Variation 91.5 |
| Part A: 100 mg BI 891065 | Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 18800 Nanomol * hours per Liter | Geometric Coefficient of Variation 72.2 |
| Part A: 200 mg BI 891065 | Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 51300 Nanomol * hours per Liter | Geometric Coefficient of Variation 87.5 |
| Part A: 400 mg BI 891065 | Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 48500 Nanomol * hours per Liter | Geometric Coefficient of Variation 57.5 |
Secondary
Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss)
Maximum measured plasma concentration at steady state (cmax,ss) during the first treatment cycle. Timeframe description: \*: Timepoint measured only for dose group 5 mg, 15 mg, 25 mg, and 50 mg. \*\*: Timepoint measured only for dose group 50 mg, 100 mg, 200 mg and 400 mg.
Time frame: Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part A): All patients in the TS (Part A) who have at least one valid secondary pharmacokinetic (PK) endpoint available. Only patients with available data for this endpoint were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 86.3 nanomol per Liter (nmol/L) | Geometric Coefficient of Variation 39.6 |
| Part A: 15 mg BI 891065 | Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 163 nanomol per Liter (nmol/L) | — |
| Part A: 25 mg BI 891065 | Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 948 nanomol per Liter (nmol/L) | Geometric Coefficient of Variation 61.5 |
| Part A: 50 mg BI 891065 | Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 708 nanomol per Liter (nmol/L) | Geometric Coefficient of Variation 123 |
| Part A: 100 mg BI 891065 | Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 1410 nanomol per Liter (nmol/L) | Geometric Coefficient of Variation 56 |
| Part A: 200 mg BI 891065 | Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 3070 nanomol per Liter (nmol/L) | Geometric Coefficient of Variation 88.3 |
| Part A: 400 mg BI 891065 | Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 2550 nanomol per Liter (nmol/L) | Geometric Coefficient of Variation 68.5 |
Secondary
Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: From first drug administration until last drug administration plus residual effect period of 30 days, up to 282 days.
Population: Treated Set (TS) (Part A): The TS (Part A) included all patients who received at least 1 dose of BI 891065.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: BI 891065 | Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | 0 Participants |
| Part A: 15 mg BI 891065 | Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | 0 Participants |
| Part A: 25 mg BI 891065 | Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | 0 Participants |
| Part A: 50 mg BI 891065 | Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | 0 Participants |
| Part A: 100 mg BI 891065 | Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | 0 Participants |
| Part A: 200 mg BI 891065 | Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | 0 Participants |
| Part A: 400 mg BI 891065 | Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period | 0 Participants |
Secondary
Part A: Number of Patients With Objective Response (OR)
OR based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, defined as the best overall response of complete response (CR) and partial response (PR), where the best overall response is the best time point response recorded from the first administration of study medication until the end of treatment Number of patients with objective response is reported.
Time frame: Up to 252 days.
Population: Treated Set (TS) (Part A): The TS (Part A) included all patients who received at least 1 dose of BI 891065.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: BI 891065 | Part A: Number of Patients With Objective Response (OR) | No | 3 Participants |
| Part A: BI 891065 | Part A: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 15 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | No | 1 Participants |
| Part A: 15 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 25 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | No | 3 Participants |
| Part A: 25 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 50 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | No | 4 Participants |
| Part A: 50 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 100 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | No | 3 Participants |
| Part A: 100 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 200 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | No | 3 Participants |
| Part A: 200 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 400 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | No | 8 Participants |
| Part A: 400 mg BI 891065 | Part A: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
Secondary
Part B: Area Under the Concentration-time Curve of BI 754091 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 754091 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle. Results are reported for the overall group only since dose level of BI 754091 is fixed in this trial.
Time frame: Predose and 1, 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 359.5, 383.917, 504, 998 and 999 hours after intake of BI 754091 at day 1, cycle 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part B): All patients in the TS (Part B) who have at least one valid secondary pharmacokinetic (PK) endpoint available. As pre-specified in the protocol, the four cohorts in Part B were treated with the same dosage of BI 754091 and analyzed together.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part B: Area Under the Concentration-time Curve of BI 754091 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 13100 Hours*micorgram/milliliter | Geometric Coefficient of Variation 48.7 |
Secondary
Part B: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 891065 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the first treatment cycle.
Time frame: At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part B): All patients in the TS (Part B) who have at least one valid secondary pharmacokinetic (PK) endpoint available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part B: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 3450 Hours*nanomol / Liter | Geometric Coefficient of Variation 44.4 |
| Part A: 15 mg BI 891065 | Part B: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 17200 Hours*nanomol / Liter | Geometric Coefficient of Variation 82.9 |
| Part A: 25 mg BI 891065 | Part B: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 31400 Hours*nanomol / Liter | Geometric Coefficient of Variation 56.5 |
| Part A: 50 mg BI 891065 | Part B: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 20300 Hours*nanomol / Liter | Geometric Coefficient of Variation 71.6 |
Secondary
Part B: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss)
Area under the concentration time curve of BI 891065 over a dosing interval at steady state (AUCtau,ss) in the first treatment cycle.
Time frame: At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part B): All patients in the TS (Part B) who have at least one valid secondary pharmacokinetic (PK) endpoint available. Only patients with available data for this endpoint were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part B: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 7260 Hours*nanomol/Liter | Geometric Coefficient of Variation 91 |
| Part A: 15 mg BI 891065 | Part B: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 50600 Hours*nanomol/Liter | Geometric Coefficient of Variation 78 |
| Part A: 25 mg BI 891065 | Part B: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 44000 Hours*nanomol/Liter | Geometric Coefficient of Variation 49.1 |
| Part A: 50 mg BI 891065 | Part B: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss) | 34400 Hours*nanomol/Liter | Geometric Coefficient of Variation 88 |
Secondary
Part B: Maximum Measured Plasma Concentration (Cmax) of BI 754091 in the First Treatment Cycle
Maximum measured plasma concentration (Cmax) of BI 754091 in the first treatment cycle. Results are reported for the overall group only since dose level of BI 754091 is fixed in this trial.
Time frame: Predose and 1, 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 359.5, 383.917, 504, 998 and 999 hours after intake of BI 754091 at day 1, cycle 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part B): All patients in the TS (Part B) who have at least one valid secondary pharmacokinetic (PK) endpoint available. As pre-specified in the protocol, the four cohorts in Part B were treated with the same dosage of BI 754091 and analyzed together.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part B: Maximum Measured Plasma Concentration (Cmax) of BI 754091 in the First Treatment Cycle | 79.7 Microgram/milliliter | Geometric Coefficient of Variation 22.2 |
Secondary
Part B: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss)
Maximum measured plasma concentration of BI 891065 at steady state (Cmax,ss) in the first treatment cycle.
Time frame: At 1.417, 2, 2.5, 3.5, 4.5, 6.5, 7.5, 8.5, 9.5, 11.5, 25.417, 167.917, 263.917, 335.917, 336.5, 337, 338, 339, 341, 342, 343, 344, 346, 359.5, 360.5, 361, 362, 363, 365, 366, 367, 368, 370 and 383.917 hours after intake of BI 891065 at day 1, cycle 1.
Population: Pharmacokinetic Parameter Set (PKS) (Part B): All patients in the TS (Part B) who have at least one valid secondary pharmacokinetic (PK) endpoint available. Only patients with available data for this endpoint were analyzed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: BI 891065 | Part B: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 623 Nanomol/Liter | Geometric Coefficient of Variation 77 |
| Part A: 15 mg BI 891065 | Part B: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 3010 Nanomol/Liter | Geometric Coefficient of Variation 67.8 |
| Part A: 25 mg BI 891065 | Part B: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 3220 Nanomol/Liter | Geometric Coefficient of Variation 33.4 |
| Part A: 50 mg BI 891065 | Part B: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss) | 3460 Nanomol/Liter | Geometric Coefficient of Variation 79.5 |
Secondary
Part B: Number of Patients With Dose-limiting Toxicities (DLTs) Observed During the Entire Treatment Period
DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.
Time frame: From first drug administration until last drug administration plus residual effect period of 30 days, up to 386 days.
Population: Treated Set (TS) (Part B): The TS (Part B) included all patients who received at least one dose of BI 891065 or BI 754091.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) Observed During the Entire Treatment Period | 0 Participants |
| Part A: 15 mg BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) Observed During the Entire Treatment Period | 1 Participants |
| Part A: 25 mg BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) Observed During the Entire Treatment Period | 1 Participants |
| Part A: 50 mg BI 891065 | Part B: Number of Patients With Dose-limiting Toxicities (DLTs) Observed During the Entire Treatment Period | 1 Participants |
Secondary
Part B: Number of Patients With Objective Response (OR)
OR based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, defined as the best overall response of complete response (CR) and partial response (PR), where the best overall response is the best time point response recorded from the first administration of study medication until the end of treatment. Number of patients with objective response is reported.
Time frame: Up to 356 days.
Population: Treated Set (TS) (Part B): The TS (Part B) included all patients who received at least one dose of BI 891065 or BI 754091.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: BI 891065 | Part B: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: BI 891065 | Part B: Number of Patients With Objective Response (OR) | No | 6 Participants |
| Part A: 15 mg BI 891065 | Part B: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 15 mg BI 891065 | Part B: Number of Patients With Objective Response (OR) | No | 14 Participants |
| Part A: 25 mg BI 891065 | Part B: Number of Patients With Objective Response (OR) | No | 8 Participants |
| Part A: 25 mg BI 891065 | Part B: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 50 mg BI 891065 | Part B: Number of Patients With Objective Response (OR) | Yes | 0 Participants |
| Part A: 50 mg BI 891065 | Part B: Number of Patients With Objective Response (OR) | No | 9 Participants |