Trial to Determine MTD of BI 836845 Administered Intravenously Once Every Three Weeks in Patients With Advanced Solid Tumours and Later a Weekly Dosing Schedule in Selected Tumour Types

To determine the MTD or relevant biological dose (RBD) of BI 836845 during the first treatment course of the dose escalation phase. The MTD was defined as the highest dose level of BI 836845 below the maximum dose administered at which no more than 1 out of 6 patients experienced a drug-related DLT during the first course of treatment. Starting dose of 10 mg BI 836845, administered once every 3 weeks. Dose levels evaluated were: 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, 640 mg, 1280 mg, 1800 mg, 2400 mg, and 3600 mg. In the absence of the MTD, the RBD, where a plateau in total Insulin-like growth factor 1 (IGF-1) level and total neutralisation of IGF activity is predicted, is reported.

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

Population: Treated set (TS) restricted to part 1 - dose escalation phase: 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 phase.

DLTs defined as drug related: CTCAE Grade 4 neutropenia lasting ≥7 days; febrile neutropenia and/or documented infection with Absolute Neutrophil Count \<1.0x109/L; Grade 4 thrombocytopaenia or Grade 3 associated with bleeding needing platelet transfusion; Grade ≥3 increased hepatic enzymes; Grade 3 or 4 non-haematologic toxicity with exceptions; Grade ≥2 infusion reaction despite adequate pre-medication; Grade ≥2 nausea and/or vomiting persisting for ≥7 days despite antiemetic treatment; Grade ≥3 skin toxicity despite adequate supportive care measures for up to 2 weeks if it does not reach an improvement to grade ≤2; Grade ≥3 hyperglycaemia resistant to treatment with anti-diabetic agents; any electrolyte grade 3 AE refractory to optimal correction therapy; no recovery from a non-DLT grade \>2 toxicity to grade 1 within 14 days of administered dose; sustained fatigue/asthenia grade 3 for \>96 h associated with deterioration of Performance score (Eastern Cooperative Oncology Group).

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

Population: Treated set (TS) restricted to part 1 - dose escalation phase: 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 phase.

Area under the plasma concentration-time curve (AUC) of the analyte (BI 836845); AUC(0-504) in part 1 using 3- weekly dosing and AUC(0-168) in part 2 using weekly dosing.

Time frame: Part 1: 5 minutes before and 0.5, 1, 2, 4, 7, 24, 72, 168 and 336 h after infusion for Course 1. Part 2: 5 minutes before and 1, 2, 4, 7, 24, 168, 169, 336, 337 h after infusion for Course 1, 2 and 3.

Population: PK set. Only participants with available PK data are included in the analysis. PK data are reported based on the dosage administered to patients.

Best overall response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) based on RECIST criteria version 1.1: CR for target lesions: Disappearance of all target lesions. CR for non-target lesions: Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10 millimeters \[mm\] short axis). PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study. PD: At least a 20% increase in the sum of the diameters (SoD) of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm; Appearance of 1 or more new lesions; Unequivocal progression of existing non-target lesions.

Time frame: First treatment administration, up to 246 days.

Population: TS

Disease control was defined as best overall response of CR, PR (confirmation was not required for CR or PR) or confirmed SD (i.e. lasting for at least 24 weeks).

Time frame: First treatment administration, up to 246 days.

Population: TS

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, up to 246 days.

Population: TS. Only participants with objective response were included in the endpoint.

Percentage 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, 14 June 2010 are presented. When no CTCAE grading was available for a specific event, the intensity of the AE was judged based on the following: * Grade 1 - Mild AE; awareness of sign(s) or symptom(s) which were 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: From first drug administration, until 21 days after last drug administration, up to 253 days.

Population: TS

Maximum measured concentration of the analyte in plasma (Cmax) in the first cycle of treatment (dose escalation phase, part 1) and in the first 3 cycles of treatment (dose expansion phase, part 2).

Time frame: Part 1: 5 minutes before and 0.5, 1, 2, 4, 7, 24, 72, 168 and 336 h after infusion for Course 1. Part 2: 5 minutes before and 1, 2, 4, 7, 24, 168, 169, 336, 337 h after infusion for Course 1, 2 and 3.

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. PK data are reported based on the dosage administered to patients.

Objective response was defined as best overall response of CR or PR (with no confirmation required).

Time frame: First treatment administration, up to 246 days.

Population: TS

PFS was evaluated 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.

Time frame: First treatment administration until tumour progression or death, up to 162 days.

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

Time to maximum measured concentration of the analyte in plasma (tmax) in the first cycle of treatment (dose escalation phase, part 1) and in the first 3 cycles of treatment (dose expansion phase, part 2).

Time frame: Part 1: 5 minutes before and 0.5, 1, 2, 4, 7, 24, 72, 168 and 336 h after infusion for Course 1. Part 2: 5 minutes before and 1, 2, 4, 7, 24, 168, 169, 336, 337 h after infusion for Course 1, 2 and 3.

Population: PK set. PK data are reported based on the dosage administered to patients.