Weekly BI 836880 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase I, multi-centre, non-randomized, uncontrolled, open-label, dose escalating study of BI 836880 administered intravenously once a week. The eligible patient population will be patients with advanced solid tumors. The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for BI 836880 in patients with solid tumors. Preliminary safety data will be evaluated as secondary objectives. Subsequently, pharmacokinetic profile, pharmacodynamic changes in circulating biomarkers and Dynamic Contrast-Enhanced Magnetic Resonance Imaging ( DCE-MRI), anti-tumor activity and the immunogenicity of BI 836880 will be explored up to a total of 40 patients with advanced solid tumors. Dose escalation will be guided by a Bayesian logistic regression model with over dose control (EWOC) using at least 2 patients per dose cohorts. Safety criteria will be followed, including adverse events according to Common Terminology Criteria (CTCAE version 4.03), incidence of dose limiting toxicities, physical examination, vital signs, safety laboratory parameters and Eastern Cooperative Oncology Group (ECOG).

Official Title
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Phase I, Non-randomized, Open-label, Multi-center Dose Escalation Trial of BI 836880 Administered by Weekly Repeated Intravenous Infusions in Patients With Advanced Solid Tumors.

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BI 836880


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 1 Age >=18 years 2. Histologically confirmed malignancy which is locally advanced or metastatic solid tumor, and either refractory after standard therapy for the disease or for which standard therapy is not reliably effective e.g. patients do not tolerate or have contraindications to otherwise available standard therapy and tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-MRI at MTD. 3. ECOG performance status <= 2 4. Adequate hepatic, renal and bone marrow functions as defined by the following criteria: Total bilirubin within normal limits (<= 1.5x upper limit of normal (ULN) for patient with Gilberts syndrome) Alanine amino transferase (ALT) and aspartate amino transferase (AST) <= 1.5x ULN (< 5x upper limit of normal (ULN) for patient known liver metastases) Serum creatinine < 1.5x ULN International normalized Ratio (INR) 0.8-1.2 or partial thromboplastin time (PTT) < 1.5x ULN Absolute neutrophil count (ANC) > 1.5 109/L Platelet count > 100x109/ L. Haemoglobin > 10 g/dl (without transfusion within previous week) 5. Signed and dated written informed consent. 6. Life expectancy >= 3 months in the opinion of the investigator 7. Recovery from all reversible adverse events of previous anti-cancer therapies to baseline or CTCAE grade1, except for alopecia (any grade), sensory peripheral neuropathy CTCAE grade <= 2 or considered by the investigator as clinically not significant. 8. Male or female patients. Women of childbearing potential* must be ready and able to use highly effective methods of birth control per International Conference on Harmonisation [ICH M3(R2)] in combination with male condom as double barrier, during the trial and for at least 6 months after the end of treatment with BI 836880, that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Male patient must always use condoms when sexually active during the trial and for at least 6 months after the end of treatment with BI 836880. *Women of childbearing potential are defined as: Any female who has experienced menarche and does not meet the criteria for women not of childbearing potential as described below. Women not of childbearing potential are defined as: Women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are permanently sterilized (e.g., hysterectomy, bilateral oophorectomy or bilateral salpingectomy). Exclusion criteria: Known hypersensitivity to the trial drugs or their excipients or risk of allergic of anaphylactic reaction to the study drug according to the investigator judgement (e.g. patient with history of anaphylactic reaction or autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs (NSAIDS), inhaled corticosteroids, or the equivalent of < 10 mg/day prednisone) Current or prior treatment with any systemic anti-cancer therapy either within 28 days or a minimum of 5 half-lives, whichever is shorter at the start of study treatment. Serious concomitant disease (based on investigator judgement), especially those affecting compliance with trial requirements or which are considered relevant for the evaluation of the endpoints of the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the investigator would make the patient inappropriate for entry into the trial. Major injuries and/or surgery (as judged by the investigator) or bone fracture within 4 weeks of start of study treatment, or planned surgical procedures during the trial period. Patients with personal or family history of QT prolongation and/or long QT syndrome, or prolonged QT interval corrected for heart rate according to Fridericia's formula (QTcF) at baseline (> 470 ms). QTcF will be calculated by Investigator as the mean of the 3 ECGs taken at screening. Significant cardiovascular/ cerebrovascular disease (i.e uncontrolled hypertension, unstable angina, history of infarction within past 6 months, congestive heart failure > New York heart association ( NYHA II). Uncontrolled hypertension defined as: blood pressure in tested and relaxed condition >= 140 mmHg, systolic or > 90 mmHg diastolic (with or without medication), measured according to Section 5.3.2 and Appendix 10.2. History of severe haemorrhagic or thromboembolic event in the past 12 months (excluding central venous catheter thrombosis and peripheral deep vein thrombosis). Known inherited predisposition to bleeding or to thrombosis in the opinion of the investigator. Patient with brain metastases that are symptomatic and/or require therapy. Patients who require full-dose anticoagulation (according to local guidelines). No vitamin K antagonist and other anticoagulation allowed; low-molecular-weight heparin (LMWH) allowed only for prevention not for curative treatment. Use of alcohol or drug incompatible with patient participation in the study in the investigator opinion Patient unable or unwilling to comply with protocol Women who are pregnant, nursing, or who plan to become pregnant while in the trial Previous enrolment in this trial

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: BI 836880<br> | Drug: BI 836880<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is to determine the maximum tolerated dose (MTD) based on the number of patients presenting dose limiting toxicity (DLT) using CTCAE V4.03, during the first course and judged to be related to the study medication |  | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug related Adverse Events (AEs) leading to dose reduction or discontinuation during treatment period |  | up to 6 months |