Bevacizumab vs Dacarbazine in Metastatic Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to compare efficacy of bevacizumab monotherapy with standard chemotherapy (DTIC) in patients with metastatic malignant melanoma. In addition, we want to evaluate the predictive value of a set biomarkers associated with vascular endothelial growth factor (VEGF) dependent angiogenesis. Also, we aim to identify mechanisms causing acquired resistance to treatment with bevacizumab and escape mechanisms caused by other angiogenic growth factors than VEGF. Finally, we want to analyze safety and influence on outcome variables by primary prevention of bevacizumab induced hypertension by low dose beta blockers in comparison with an ACE inhibitor.

Official Title
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A Randomized Phase II Trial Comparing Bevacizumab Monotherapy With Dacarbazine (DTIC) in Treatment of Malignant Melanoma, Focusing on Angiogenic Markers and Prevention of Hypertension.

Conditions
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Metastatic Malignant Melanoma, Unresectable Malignant Melanoma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Propranolol
* Drug: Enalapril
* Drug: Dacarbazine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously treated or untreated, histologically confirmed, metastatic and unresectable melanoma with progressive disease Both BRAF wild type patients as well as BRAF mutated patients are allowed. For BRAF mutated patients, BRAF targeting agents should be considered in first line if otherwise indicated and no contraindications exist. WHO performance status 0-1 Age >18 years, Known BRAF mutation Able to undergo outpatient treatment Patients must have clinically and/or radiographically documented measurable disease according to RECIST. All radiology studies must be performed within 28 days prior to registration (35 days if negative). At least 4 weeks since adjuvant interferon alpha At least 4 weeks since 1st line treatment in case of metastasis Major surgical procedure or significant traumatic injury > 28 days prior to study treatment start. Biopsy or fine needle aspiration > 2 days prior to study treatment start. Central venous line placement must be inserted at least 2 days prior to treatment start. Only patients with irradiated and asymptomatic brain metastases and off dexamethasone are allowed. Hematology: absolute granulocytes > 1.0 x 109/L Platelets > 100 x 109/L Bilirubin < 1.5 x upper normal limit Serum creatinine < 1.5 x upper normal limits LDH < 1.5 x upper normal limit INR < 1.5 Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial Before patient registration/randomization, written informed consent must be given according to national and local regulations. Exclusion Criteria: No previous DTIC No previous anti-VEGF targeted therapies No pregnant or lactating patients can be included No clinical evidence of coagulopathy No unstable angina pectoris No AV-block II or III without pacemaker No severe congestive heart failure No untreated phaeochromocytoma No severe bradycardia No severe hypotension No severe impairment of peripheral arterial circulation No uncontrolled cardiac arrhythmia No severe asthma or COPD No uncontrolled diabetes mellitus No Angioneurotic edema No severe Aortic valve stenosis No severe hypertrophic cardiomyopathy No severe renal dysfunction No patients on beta blockers/ ACE inhibitors by inclusion unable/unwilling to discontinue beta blockers/ ACE inhibitors and convert to other classes of antihypertensive drugs No full-dose oral coumarin-derived anticoagulants (INR>1.5) or heparin, thrombolytic agents, or chronic, daily treatment with aspirin (>325 mg/day). No uncontrolled hypertension

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab plus propranolol<br>Bevacizumab 10mg/kg q2w plus propranolol 80 mg x 1 | Drug: Bevacizumab<br>* Bevacizumab 10 mg/kg q3w<br>* Other names: Avastin;Drug: Propranolol<br>* Propranolol 80 mg x 1<br>* Other names: Inderal retard;|
| Experimental: Bevacizumab plus enalapril<br>Bevacizumab 10mg/kg q2w plus enalapril 5 mg x 1 | Drug: Bevacizumab<br>* Bevacizumab 10 mg/kg q3w<br>* Other names: Avastin;Drug: Enalapril<br>* Enalapril 5 mg x 1<br>* Other names: Vasotec;|
| Active Comparator: Dacarbazine<br>Dacarbazine 1000mg/m2 q3w | Drug: Dacarbazine<br>* dacarbazine 1000 mg/m2 q3w<br>* Other names: DTIC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Participants will be followed for the duration of the treatment and as long as they do not progress, an expected average of 6 months | Average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rates according to RECIST | Participants will be followed for the duration of the treatment with CT scans for response evaluation every 2 months for an expected average of 6 months. | Average 6 months | 
| Disease control rate at 6 months | Number of patient with complete response, partial response or stable disease at 6 months | 6 months | 
| Prevention of hypertension by beta blockers or ACE-inhibitors | Safety and influence on outcome variables by primary prevention of bevacizumab induced hypertension, by low dose beta blockers (propranolol 80 mg x 1), in comparison with an ACE inhibitor (enalapril 5 mg x 1). Patients will be monitored as during active treatment with anti hypertensive drugs and bevacizumab for an average of 6 months. | Average of 6 months | 
| Overall survival | Participants will be followed until death for overall survival data, an expected average of 12 months | Average og 12 months |