Erlotinib and Bevacizumab in Treating Patients With Stage IV Melanoma

Study Overview
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Brief Summary
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RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving erlotinib together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving erlotinib together with bevacizumab works in treating patients with stage IV melanoma.

Detailed Description
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OBJECTIVES: Primary Determine the overall response rate, response duration, and frequency of progression-free survival at 6 months in patients with stage IV melanoma treated with erlotinib hydrochloride and bevacizumab. Determine objective responses in patients treated with this regimen. Secondary Determine the overall safety and tolerability of this regimen in these patients. Evaluate tissue blocks for EGFR by monoclonal antibody H11 (DAKO) or fluorescence in situ hybridization(FISH)7p12-specific probe-overexpression or amplification in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive oral erlotinib hydrochloride once daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tissue collection to analyze EGFR by monoclonal antibody H11 (DAKO) or fluorescence in situ hybridization (FISH) 7p12-specific probe-overexpression or amplification. Biological markers AKT, MAPK, p27, p21, CD13, CD34, and factor VIII are also measured. After completion of study treatment, patients are followed periodically.

Official Title
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A Phase II Trial of Tarceva (Erlotinib) and Avastin (Bevacizumab) in the Treatment of Patients With Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: bevacizumab
* Drug: erlotinib hydrochloride
* Genetic: fluorescence in situ hybridization
* Genetic: gene expression analysis
* Other: immunologic technique
* Other: laboratory biomarker analysis
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Measurable Stage IV melanoma Easter Cooperative Oncology Group (ECOG) Performance Status must be 0-1 Good organ function as demonstrated by, Creatinine <2.mg/dl, AST or ALT <5 times upper limit of normal for subjects with documented liver metastases; <2.5 times the upper limit of normal (ULN) for subjects without evidence of liver metastases, bilirubin<2.0mg/dl,, absolute neutrophil count (ANC)>1500/ul, platelets>75k/ul, hemoglobin (Hgb)>9 (may be transfused to obtain) Prior therapy: adjuvant interferon (IFN) allowed; no more than one prior regimen for advanced stage IV disease Patients must have a life expectancy of >3 months Patients with brain metastases are eligible only if they fulfill the following: resected or stereotactic treatment a minimum of 3 months previously and no active CNS disease since then; brain metastases treated greater than 6 months ago without evidence of progression or hemorrhage, <1cm in size per lesion (up to 3 lesions), and off all steroids Patients may not have received other agents, either investigational or marketed, which act by either EGFr inhibition or anti-angiogenesis mechanisms. Other epidermal growth factor receptor (EGFR) inhibitors include (but are not limited to): Iressa, erbitux, CI-1033. Angiogenesis inhibitors include (but are not limited to): SU5416, SU6668, SU 0122348, CP547632, VEGF Trap, anti-integrin αVβ3. Recovered from toxicity of major surgery (4 wks), chemotherapy or biologic therapy (4 wks), and/or radiation therapy (2 wks) No active other malignancy within 12 months No active systemic infection Over age of 18 years and signed IRB approved informed consent Exclusion Criteria: Subjects meeting any of the following criteria (3.2.2-3.2.16) are ineligible for study entry Compromised renal or hepatic function as defined by Creatinine >2.0mg/dl, aspartate transaminase (AST) or alanine transaminase (ALT) >5 times upper limit of normal for subjects with documented liver metastases; >2.5 times the upper limit of normal (ULN) for subjects without evidence of liver metastases Patient may not be part of any other investigational studies internationalized normal ratio (INR) > 1.5 Patients with PEG or G-tube are ineligible. Major surgical procedure, open biopsy; or significant traumatic injury within 28 days, or anticipation of need for major surgical procedure during the course of the study Any non-healing wound, ulcer, or bone fracture. Any clinical evidence or history of a bleeding diathesis or coagulopathy. Patients with a history of deep vein thrombosis or thromboembolic disease within the past 6 months. History of acute myocardial infarction within 6 months. In addition, patients are ineligible if they have clinically significant cardiovascular disease ((e.g., uncontrolled hypertension [blood pressure of >160/110 mmHg on medication], New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia requiring medication, or peripheral vascular disease (Grade II or greater) Patients with > 1+ proteinuria will have 24-hour urine collection; for protein. Patients with ≥ 1gm protein/24 hrs will be excluded If child bearing age must not be pregnant or nursing and use methods to prevent pregnancy History or evidence upon physical examination of central nervous system (CNS) disease (e.g., primary brain tumor, seizures not controlled with standard medical therapy, or history of stroke) Inability to comply with study and/or follow-up procedures History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications.

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: Therapeutic Intervention<br>Tarceva and Avastin: Tarceva: 150mg PO, days 1-28 Avastin: 10mg/kg, IV infusion, days 1,15 Regimen will be repeated every 28 days = 1 course | Biological: bevacizumab<br>* 10mg/kg, slow IV infusion, Days 1 and 14<br>* Other names: Avastin;Drug: erlotinib hydrochloride<br>* 150mg PO qd<br>* Other names: Tarceva;Genetic: fluorescence in situ hybridization<br>* Targeting multiple genetic aberrations in isolated tumor cells.<br>Genetic: gene expression analysis<br>* gene expression analysis<br>Other: immunologic technique<br>* immunologic technique<br>Other: laboratory biomarker analysis<br>* laboratory biomarker analysis<br>Procedure: biopsy<br>* biopsy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Response | Per Response Evaluation Criteria in Solid Tumor (RECIST): Progressive disease (PD): >=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): >=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression. | Time from on study date to date of progression in months, if the progression happened in the patient. Disease progression is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions with reference to the smallest sum LD since treatment began or the appearance of one or more new lesions. | up to one year after off-study date | 
| Progression-free Survival at 6 Months | Patients with Progression-free survival at 6 months | 6 months | 
| Number of Patients With Each Worst-grade Toxicity Response | Number of patients with worst-grade toxicity at each of five grades following National Cancer Institute Common Toxicity Criteria with grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening/disabling, 5 = death. | Day 1 of each 28-day cycle for 6 cycles (168 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV melanoma, recurrent melanoma