Trial to Determine MTD of BI 836845 Administered Intravenously Once Every Three Weeks in Patients With Advanced Solid Tumours

• To determine the Maximum Tolerated Dose (MTD) in patients with metastatic or advanced solid tumours (Part I study). [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• To determine the Dose Limiting Toxicities (DLT) (Part I study). [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• To determine the safety and tolerability profiles of BI 836845 according to the number and intensity of adverse events as defined in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Part I study). [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• To determine anti-tumour activity in patients with metastatic or advanced solid tumours at MTD according to the Response Evaluation Criteria in Solid Tumours (RECIST) criteria 1.1 (Part II study). [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• To further evaluate the safety profile in patients according to the number and intensity of adverse events in patients with metastatic or advanced solid tumours at MTD (Part II study). [ Time Frame: 6 months ] [ Designated as safety issue: No ]

• To determine pharmacokinetic (PK) parameters of BI 836845 (Part I and Part II study). [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• To determine pharmacodynamic (PD) biomarker parameters of BI 836845 (Part I and Part II study). [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• To determine pharmacogenomic parameters of BI 836845 (Part I and Part II study). [ Time Frame: 18 months ] [ Designated as safety issue: No ]

This study is a phase I, open-label, dose escalation trial to determine the maximum tolerated dose (MTD) of a new drug BI 836845 which blocks the insulin growth factor (IGF) pathway believed to be involved in cancer growth. BI 836845 will be administered for the very first time into cancer patients.

The study will also look at the overall safety of the drug, and examine the drug levels in the body at specific timepoints during the trial (pharmacokinetic profile); the effect the drug may have on tumours will also be examined (pharmacodynamics).

Inclusion criteria:

1. Male or female patients with cytologically or histologically confirmed solid tumours that are refractory to standard therapy or that have no standard therapy.
2. Patients should have evaluable disease, or at least one measurable lesion according to Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1
3. Age, equal, or more than, 18 years old.
4. Life expectancy of at least 3 months.
5. Written informed consent that is consistent with ICH-GCP guidelines.
6. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2.
7. Patients must have recovered from any previous surgery and no major surgery within the last 28 days prior to start of trial medication.
8. Cardiac left ventricular function with resting ejection fraction >50% as determined by Echocardiography (ECHO) or Multiple Gated Acquisition scan (MUGA).
9. Absolute neutrophil count equal, or more than, 1,500/µl.
10. Platelets equal, or more than, 100,000/µl.
11. Total bilirubin equal, or less than 1.5 x institution upper limit of normal.
12. Aspartate Amino Transferas (AST) (Serum glutamic oxaloacetic transaminase (SGOT)) / Alanine Amino Transferase (ALT) (Serum glutamic pyruvic transaminase (SGPT )) equal, or less than, 2.5 x upper limit of normal (in case of known liver metastases AST and/or ALT, equal, or less than, 5 x upper limit of normal).
13. Creatinine equal, or less than, 1.5 x institution upper limit of normal.
14. Haemoglobin equal, or more than, 9g/dL.
15. Haemoglobin A1c less than 8% and fasting glucose, equal, or less than, 8.9 mmol/L (= 160 mg/dL).
16. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment.

Exclusion criteria:

1. Active infectious disease.
2. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.
3. History of thrombosis within 1 year of study or if concurrent anticoagulation required, except low-dose warfarin (up to 1mg/day).
4. Patients not recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, molecular targeted, or radiotherapies to at least Common Terminology Criteria for Adverse Events (CTCAE) equal, or less than, Grade 1. Prior chemotherapy is allowed if completed at least 4 weeks prior to first trial treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from the acute toxicities of that therapy.
5. Patients with untreated or symptomatic brain metastases. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least 4 weeks before starting trial medication, no history of cerebral oedema or bleeding in the past 4 weeks before starting trial medication and must be on a stable or reducing dose of dexamethasone. Anti-epileptic therapy will be allowed if the patient is stable on antiepileptic treatment for 4 weeks, or more, without adjustments before starting trial medication.
6. Patients who have been treated with any of the following within 4 weeks of starting trial medication: chemotherapy, immunotherapy, radiotherapy, biological therapies (including trastuzumab), molecular targeted, hormone therapy for breast cancer within 2 weeks of starting trial medication (excluding Luteinizing-hormone-releasing hormone (LHRH) agonists in prostate cancer, or bisphosphonates), or treatment with other investigational drugs.
7. Participation in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial.
8. Patients unable to comply with the protocol.
9. Active alcohol abuse or active drug abuse (at the discretion of the investigator).
10. Patients with unstable arrhythmias or unstable angina or severe obstructive pulmonary disease within the last year.
11. For patients entering part II of the study, prior use of any insulin growth factor (IGF) inhibitor.
12. Patients with a history of diabetes mellitus.
13. Pregnancy or breast feeding.