Bevacizumab vs Dacarbazine in Metastatic Melanoma

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

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.

Study Overview

• Status: Terminated
• Conditions: Metastatic Malignant Melanoma; Unresectable Malignant Melanoma
• Intervention / Treatment: Drug: Bevacizumab; Drug: Propranolol; Drug: Enalapril; Drug: Dacarbazine

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Haukeland University Hospital
• Collaborators: Norwegian Cancer Society; The Norwegian Melanoma Group
• Investigators: Principal Investigator: Oddbjorn Straume, MD PhD, Department of Oncology, Haukeland University Hospital, Bergen, Norway; Study Director: Olav Mella, MD PhD, Department of Oncology, Haukeland University Hospital, Bergen, Norway

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2013
• Primary Completion (Actual): February 20, 2017
• Study Completion (Actual): February 20, 2017

Study Registration Dates

• First Submitted: October 8, 2012
• First Submitted That Met QC Criteria: October 11, 2012
• First Posted (Estimate): October 12, 2012

Study Record Updates

• Last Update Posted (Actual): February 24, 2017
• Last Update Submitted That Met QC Criteria: February 23, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Antineoplastic Agents; Protease Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Propranolol; Bevacizumab; Enalapril; Dacarbazine
• Other Study ID Numbers: 2012/910