Phase I Trial of BI 836845 for Various Solid Cancer

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) or the relevant biological dose (RBD) in the absence if a MTD of a new drug BI 836845 which blocks the insulin-like 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 Weekly Intravenous Administrations of BI 836845 in Patients With Advanced Solid Cancers 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: Patients with histologically or cytologically confirmed diagnosis of advanced, non resectable and / or metastatic solid cancer, who have failed conventional treatment, or for whom no therapy of proven efficacy exists, or who are not amenable to established forms of treatment. Patients should have evaluable disease, or at least one measurable lesion according to RECIST criteria version 1.1. Age 18 years or older. Life expectancy of at least 3 months in the opinion of the investigator. Written informed consent that is consistent with ICH-GCP guidelines and local legislation. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2. Patients must have recovered from any previous surgery and have had no major surgery within the last 28 days prior to start of trial medication in the opinion of the investigator. Cardiac left ventricular function with resting ejection fraction > 50% as determined by ECHO or MUGA. Absolute neutrophil count = 1,500/µL. Platelets =100,000/µL. Total bilirubin = 1.5x institution ULN. AST and ALT = 2.5x institution ULN (in case of hepatic primary cancer or known liver metastases: AST and ALT = 5x ULN). Creatinine =1.5 x institution ULN. Haemoglobin = 9g/dL. Haemoglobin A1c less than 8% and fasting plasma glucose =160 mg/dL (=8.9 mmol/L). 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. Child-Pugh score 5 or 6. (this criterion is limited to HCC patients in Part II only). Patients eligible to undergo tumor biopsy should have normal coagulation parameters (INR and PTT within normal range). (this criterion is limited to patients in Part II only) Exclusion criteria: Active infectious disease considered by the investigator to be incompatible with the protocol. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol. History of thrombosis (except tumor invading great vessel) within 1 year of study or if concurrent anticoagulation required, except low-dose warfarin (up to 1 mg/day). Patients not recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, molecular targeted, or radiotherapies to at least CTCAE = 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, molecular-targeted therapy, biological therapies (including trastuzumab), hormone therapy for breast cancer within 2 weeks of starting trial medication (excluding LHRH agonists in prostate cancer, or bisphosphonates), or treatment with other investigational drugs. Use of any investigational drug within 4 weeks before start of trial medication 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 IGF inhibitor. Pregnancy or breast feeding. Other malignancy requiring active therapy. Patients with a history of diabetes mellitus. For patients that are to undergo tumor biopsy, a history of a hereditary bleeding disorder or clinically relevant major bleeding event in the past 6 months as judged by the investigator (this criterion is limited to patients in Part II only)

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 week, monotherapy | Drug: BI 836845<br>* Intravenous infusion once every week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator defined dose limiting toxicity (DLT) during first treatment course |  | 3 weeks | 
| Maximum tolerated dose (MTD) or relevant biological dose (RBD) in the absence of MTD |  | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) [Days] |  | every 6 weeks for 18 weeks then every 9 weeks until last administration of BI 836845 | 
| Pharmacokinetic (PK) parameters: - Maximum measured plasma concentration (Cmax) - Time from dosing to the maximum plasma concentration (tmax) - Area under the plasma concentration-time curve from 0 hour to the last sampling time point (AUC0-tz) |  | up to 28 days after end of treatment visit | 
| Disease control (Best overall response of complete response (CR), partial response (PR) or confirmed stable disease (SD) > 24 weeks according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1) |  | every 6 weeks for 18 weeks then every 9 weeks until last administration of BI 836845 18 weeks | 
| Maximum grade (severity) of Adverse Events according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |  | up to 4 months after last administration of BI 836845 | 
| Duration of objective response [Days] (Objective response: Best overall response of complete response (CR) or partial response (PR) according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1) |  | every 6 weeks for 18 weeks then every 9 weeks until last administration of BI 836845 18 weeks | 
| Partial response according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 |  | every 6 weeks for 18 weeks then every 9 weeks until last administration of BI 836845 |