Phase I Trial of BI 836845 for Various Solid Cancer

In the absence of MTD, the relevant biological dose (RBD) of BI 836845 during the first treatment course of the dose escalation phase was reported. The MTD was defined as the highest dose level of BI 836845 at which no more than 1 out of 6 patients experienced a drug related dose limiting toxicity (DLT) during the first course of treatment. Starting dose of 10 milligrams (mg) BI 836845, administered thrice every 3 weeks. Dose levels evaluated were: 10 mg, 20 mg, 40 mg, 60 mg, 90 mg, 135 mg, 200 mg, 300 mg, 450 mg, 600 mg, 800 mg, 1050 mg, 1400 mg and 1800 mg. The BI 836845 dose which could achieve a plateau in total Insulin-like growth factor 1 (IGF-1) plasma concentrations was considered the RBD.

Time frame: During the first course of treatment, up to 21 days

Population: Treated set (TS) restricted to the part 1 (dose escalation) of the trial: All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment in the dose escalation part of the trial.

Number of participants with DLTs occurring during the first treatment course of the dose escalation part. DLT was defined as drug-related adverse events meeting the criteria summarized below: * Common terminology criteria for adverse events (CTCAE) grade 4 neutropenia for ≥ 7 days (d) * Febrile neutropenia with single temperature of \> 38.3°C/ ≥ 38°C more than 1 hour (h) * Documented infection with high neutrophile count * CTCAE grade 4 thrombocytopenia/CTCAE grade 3 thrombocytopenia associated with bleeding requiring transfusion * AST (Aspartate Amino Transferase)/ALT (Alanine Amino Transferase) \> 5x normal * CTCAE grade 3/4 non-hematologic toxicity * CTCAE grade ≥2 infusion reaction * CTCAE grade ≥2 nausea and/or vomiting for ≥7 d * CTCAE grade ≥3 skin toxicity * CTCAE grade ≥3 hyperglycemia * Any electrolyte grade 3 AE * No recovery from non-DLT CTCAE grade \>2 * Sustained fatigue/asthenia grade 3 for longer than 96 h * Other event qualified as DLT by the investigator

Time frame: During the first course of treatment, up to 21 days

Population: TS restricted to the part 1 (dose escalation) of the trial: All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment in the dose escalation part of the trial. Three patients (two patients at the 450 mg and one patient at 800 mg) were replaced thus not included in the analysis of primary endpoint.

Area under the plasma concentration-time curve from time 0 to 168 hours (AUC 0-168) of the BI 836845. As defined in the CTP, PK data is presented by BI 836845 dose level and was not collected for Course 4 part 2. For Course 1 of part 1 and part 2, Course 2 part 1 and part 2, Course 3 part 2, Course 4 part 1 the following timeframe applies : At 0.083 hour before and 0.5, 1, 2, 4, 7, 24, 72\*, 168, 169, 336 and 337 hours after infusion. \* applies only to part 1 administration courses. In Course 3 of part 1 the following timeframe applies: At 0.083 hour before and 0.5, 1, 168, 169, 336 and 337 hours after infusion. In the arm BI 836845 450 mg, data from 3 participants was available (15800, 20400 and 12700); as these 3 subjects represented less than 2/3 of the participants included in this course and this dose group, no descriptive statistics were presented in the Clinical Trial Report. The gMean and gCV values were calculated post hoc for ClinicalTrials.gov disclosure purpose only.

Time frame: Up to 337 hours. Detailed timeframe is in the description.

Population: Pharmacokinetic (PK) set: All patients in the treated set who were documented to have received at least one dose of BI 836845 and who had at least one valid PK parameter concentration available. Participants with no available blood samples were excluded from the analysis.

Number of patients with best overall response. Best overall response represented the best response (complete response - CR, partial response - PR, stable disease -SD, progressive disease - PD) a patient had during their time in the study from first administration of trial medication until the earliest date of progression, or the last evaluable assessment in the absence of progression or the start of subsequent anti-cancer therapy. CR was defined by the disappearance of all target lesions and PR was defined by a decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Time frame: First treatment administration until disease progression or last evaluable assessment in absence of progression; Up to 72 weeks

Population: Treated set (TS): All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment.

Number of patients with Disease control. Disease control was defined as best overall response of CR, PR or SD \>24 week, with no confirmation required.

Time frame: First treatment administration until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy. Up to 72 weeks.

Population: Treated set (TS): All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment.

Duration of objective response (days), defined as time from first objective response to the time to progression or death and was only calculated for patients with an objective response (with no confirmation required).

Time frame: First treatment administration until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy. Up to 72 weeks.

Population: Treated set (TS): All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment. Only two subjects experienced event or were eligible for censoring.

Number of patients with adverse events (AEs) according to the grading as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The intensity of AEs was defined based on: * Grade 1 - Mild AE; awareness of sign(s) or symptom(s) which is/are easily tolerated. * Grade 2 - Moderate AE; enough discomfort to cause interference with usual activity. * Grade 3 - Severe AE; incapacitating or causing inability to work or to perform usual activities. * Grade 4 - Life-threatening or disabling AE. * Grade 5 - Death related to AE.

Time frame: First treatment administration until end of treatment plus residual effect period; Up to 74 weeks

Population: Treated set (TS): All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment.

Maximum measured concentration of the BI 836845 in plasma (Cmax). Geometric mean (gMean) and Geometric coefficient of variation (gCV) is presented for each course. As defined in the CTP, PK data is presented by BI 836845 dose level and was not collected for Course 4 part 2. For Course 1 of part 1 and part 2, Course 2 part 1 and part 2, Course 3 part 2, Course 4 part 1 the following timeframe applies : At 0.083 hour before and 0.5, 1, 2, 4, 7, 24, 72\*, 168, 169, 336 and 337 hours after infusion. \* applies only to part 1 administration courses. In Course 3 of part 1 the following timeframe applies: At 0.083 hour before and 0.5, 1, 168, 169, 336 and 337 hours after infusion.

Time frame: Up to 337 hours. Detailed timeframe is in the description.

Population: Pharmacokinetic (PK) set: All patients in the treated set who were documented to have received at least one dose of BI 836845 and who had at least one valid PK parameter concentration available. Participants with no available blood samples were excluded from the analysis.

Number of patients with the objective response (OR). Objective response was defined as best overall response of complete response (CR) or partial response (PR) (with no confirmation required) based on Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. CR was defined by the disappearance of all target lesions and PR was defined by a decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. The best overall response was recorded since first administration of the trial medication and until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy.

Time frame: First treatment administration until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy. Up to 72 weeks.

Population: Treated set (TS): All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment.

PFS was evaluated only for cohort 2 (Biopsiable tumors) in expansion phase of the study. PFS was defined as the time from first treatment administration until tumour progression according to RECIST 1.1 or death from any cause, whichever occurred earlier. Median duration along with 95% confidence interval is based on Kaplan-Meier method.

Time frame: First treatment administration until tumour progression or death. Up to 72 weeks

Population: TS restricted to the part 2 - biopsiable tumours cohort (dose expansion) of the trial: All enrolled patients who gave informed consent and who were documented to have taken at least one dose of investigational treatment in the biopsiable tumours cohort of the dose escalation part of the trial.

Time to maximum measured concentration of the BI 836845 in plasma (tmax). As defined in the CTP, PK data is presented by BI 836845 dose level and was not collected for Course 4 part 2. For Course 1 of part 1 and part 2, Course 2 part 1 and part 2, Course 3 part 2, Course 4 part 1 the following timeframe applies : At 0.083 hour before and 0.5, 1, 2, 4, 7, 24, 72\*, 168, 169, 336 and 337 hours after infusion. \* applies only to part 1 administration courses. In Course 3 of part 1 the following timeframe applies: At 0.083 hour before and 0.5, 1, 168, 169, 336 and 337 hours after infusion.

Time frame: Up to 337 hours. Detailed timeframe is in the description.

Population: Pharmacokinetic (PK) set: All patients in the treated set who were documented to have received at least one dose of BI 836845 and who had at least one valid PK parameter concentration available. Participants with no available blood samples were excluded from the analysis.