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

Study Overview
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Brief Summary
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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).

Official Title
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A Phase I Dose Escalation Trial of BI 836845 Administered Intravenously Once Every Three Weeks in Patients With Advanced Solid Tumours During Escalation and Weekly in Selected Tumour Types During Expansion, With Repeated Administrations in Patients Showing Clinical Benefit.

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BI 836845


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients with cytologically or histologically confirmed solid tumours that are refractory to standard therapy or that have no standard therapy. Patients should have evaluable disease, or at least one measurable lesion according to Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1 Age, equal, or more than, 18 years old. Life expectancy of at least 3 months. Written informed consent that is consistent with ICH-GCP guidelines. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2. Patients must have recovered from any previous surgery and no major surgery within the last 28 days prior to start of trial medication. Cardiac left ventricular function with resting ejection fraction >50% as determined by Echocardiography (ECHO) or Multiple Gated Acquisition scan (MUGA). Absolute neutrophil count equal, or more than, 1,500/µl. Platelets equal, or more than, 100,000/µl. Total bilirubin equal, or less than 1.5 x institution upper limit of normal. 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). Creatinine equal, or less than, 1.5 x institution upper limit of normal. Haemoglobin equal, or more than, 9g/dL. Haemoglobin A1c less than 8% and fasting glucose, equal, or less than, 8.9 mmol/L (= 160 mg/dL). 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. Patients entering part II of the study should have cytologically or histologically confirmed disease from the Ewing's family of tumours/PNET (cohort 1), or solid tumours suitable for biopsy (cohort 2), that are refractory to standard therapy or that have no standard therapy. Patients eligible to undergo biospy should have normal coagulation parameters (INR and PTT within normal ranges) and platelet count (equal, or more than, 100,000/µl) prior to biospy tissue collection. Exclusion criteria: Active infectious disease. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol. History of thrombosis within 1 year of study or if concurrent anticoagulation required. 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. 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. 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. Use of any investigational drug within 4 weeks before start of therapy or concomitantly with this trial. Patients unable to comply with the protocol. Active alcohol abuse or active drug abuse (at the discretion of the investigator). Patients with unstable arrhythmias or unstable angina or severe obstructive pulmonary disease within the last year. For patients entering part II of the study, prior use of any insulin growth factor (IGF) inhibitor. Patients with a history of diabetes mellitus. Pregnancy or breast feeding. Patients that are to undergo biospy should not have a history of a hereditary bleeding disorder as judged by the investigator. Patients that are to undergo biospy should pause acetylsalicylic acid treatment for at least 7 days prior to biospy tissue collection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy<br>BI 836845 dose escalation, infusion, once every three weeks, monotherapy | Drug: BI 836845<br>* Intravenous infusion once every three weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurence of drug related dose limiting toxicities for determination of Maximum Tolerated Dose (MTD) (Part I) |  | 12 months | 
| Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Part I) |  | 12 months | 
| Response rate (CR/PR/SD) according to RECIST criteria 1.1 (Part II). |  | up to 44 months | 
| Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Part II) |  | up to 44 months | 
| Intensity of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Part I) |  | 12 months | 
| Duration of objective response (CR/PR), defined as time from first objective response to the time to progression or death (Part II). |  | up to 44 months | 
| Intensity of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Part II) |  | up to 44 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum measured plasma concentration (Cmax). (Part I and II) |  | up to 336 | 
| Time from dosing to the maximum plasma concentration (tmax). (Part I and II) |  | up to 336 hours | 
| Area under the plasma concentration-time curve over the time interval of one week (AUC0-168). (Part I and II) |  | up to 168 hours | 
| Area under the plasma concentration-time curve over one dosing interval (AUC0-t). (Part I and II) |  | up to 168 hours | 
| Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC0-inf). (Part I and II) |  | up to 336 hours | 
| Terminal half-life (t1/2). (Part I and II) |  | up to 336 hours | 
| Mean residence time after intravenous infusion (MRT). (Part I and II) |  | up to 336 hours | 
| Total plasma clearance (CL). (Part I and II) |  | up to 336 hours | 
| Apparent volume of distribution during the terminal phase (Vz). (Part I and II) |  | up to 336 hours | 
| Volume of distribution after intravenous infusion at steady state (Vss). (Part II) |  | up to 336 hours |