Temozolomide Combined With Bevacizumab in Metastatic Melanoma. A Multicenter Phase II Trial
Temozolomide Combined With Bevacizumab in Metastatic Melanoma. A Multicenter Phase II Trial
RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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 temozolomide together with bevacizumab may kill more tumor cells.
PURPOSE: This phase II trial is studying how well giving temozolomide together with bevacizumab works in treating patients with stage IV melanoma that cannot be removed by surgery.
OBJECTIVES:
Primary
Secondary
Tertiary
OUTLINE: This is a multicenter study.
Patients receive oral temozolomide once daily on days 1-7 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Blood is collected at baseline and on day 1 of course 2. Samples are analyzed for circulating endothelial cells and endothelial progenitor cells by flow cytometry and pro- and anti-angiogenic serum factors by ELISA. Paraffin-embedded tumor tissue is analyzed for MGMT promoter methylation status by methylation-specific PCR; MGMT protein expression by IHC; and MSH2, MSH6, and MLH-1 expression (DNA repair enzymes).
After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for 1 year.
DISEASE CHARACTERISTICS:
Histologically confirmed melanoma
Measurable disease, defined as at least one lesion that can be measured in at least one dimension as ≥ 20 mm (or as ≥ 10 mm if the CT slice thickness is ≤ 5 mm)
Must have 1 paraffin block of primary tumor and/or metastatic tissue available for analysis of MGMT
No ocular melanoma
No bleeding skin metastases
No CNS metastases (even if previously treated) by brain MRI
PATIENT CHARACTERISTICS:
WHO performance status 0-2
ANC ≥ 1.5 x 10^9/L
Platelet count ≥ 100 x 10^9/L
Hemoglobin ≥ 90 g/L (transfusion allowed)
Serum total bilirubin ≤ 1.5 times upper limit of normal (ULN)
ALT and alkaline phosphatase ≤ 2.5 times ULN (5 times ULN in patients with liver metastases)
Serum creatinine < 177 μmol/L
Proteinuria < 2+ by urine dipstick OR urine protein ≤ 1 g by 24-hour urine collection
INR ≤ 1.5
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 12 months after completion of study treatment
No other primary tumors within the past 5 years, except adequately controlled limited basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
No history or evidence of CNS disease unrelated to cancer (e.g., uncontrolled seizures) by physical/neurological examination, unless adequately treated with standard medical therapy
No frequent vomiting or any other pre-existing medical condition that would preclude swallowing and/or absorption of oral medication
No history or evidence of inherited bleeding diathesis or coagulopathy with risk of bleeding
No uncontrolled hypertension (i.e., systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg, measured repeatedly, despite adequate treatment with at least two different antihypertensive drugs)
No clinically significant (i.e., active) cardiovascular disease, including any of the following:
No serious non-healing wound, active peptic ulcer, or non-healing bone fracture
No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
No significant traumatic injury within the past 30 days
No uncontrolled active infection
No known HIV infection
No known hypersensitivity to any of the study drugs or excipients
No evidence of any other disease, metabolic or psychological dysfunction, psychiatric disorder, 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 may affect patient compliance with study routines, or places the patient at high risk from treatment-related complications
PRIOR CONCURRENT THERAPY:
At least 4 weeks since prior adjuvant cytokine therapy (e.g., interleukin, interferon) or vaccine therapy and recovered
Prior perfusion therapy (limb and liver) for loco-regional disease allowed
No prior chemotherapy for metastatic disease
No prior bevacizumab or other angiogenic inhibitors
No prior radiotherapy to lesion(s) selected for measurement
More than 30 days since prior treatment in a clinical trial
More than 30 days since prior major surgery with high risk of bleeding
More than 24 hours since prior minor surgery
More than 10 days since prior and no concurrent full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes
More than 10 days since prior and no concurrent acetylsalicylic acid (> 325 mg/day) or clopidogrel (> 75 mg/day)
No other concurrent non-steroidal anti-inflammatory drugs (NSAIDs)
No concurrent dipyridamole
No concurrent major surgery
No concurrent radiotherapy to the target lesions
No other concurrent experimental drugs or anticancer therapy