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Temozolomide Combined With Bevacizumab in Metastatic Melanoma. A Multicenter Phase II Trial

Phase 2
18 Years
Not Enrolling
Melanoma (Skin)

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Trial Information

Temozolomide Combined With Bevacizumab in Metastatic Melanoma. A Multicenter Phase II Trial



- To evaluate the efficacy of temozolomide in combination with bevacizumab in patients
with unresectable stage IV melanoma.


- To evaluate the safety and tolerability of this regimen.


- To evaluate the prognostic and predictive significance of circulating endothelial cells
and endothelial progenitor cells in patients treated with this regimen.

- To predict tumor response and outcome in patients treated with this regimen by
measuring hypermethylation of the tumor.

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.

Inclusion Criteria


- Histologically confirmed melanoma

- Unresectable stage IV disease

- Mucosal and unknown primary disease allowed

- 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)

- Measurable lesion must be outside a previously treated area

- 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


- 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

- 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

- 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

- Cerebrovascular accident/stroke or myocardial infarction within the past 6

- Unstable angina

- New York Heart Association (NYHA) class II or greater congestive heart failure

- Serious cardiac arrhythmia (i.e., ventricular arrhythmia, high-grade
atrioventricular-block) that requires medication during the study, interferes
with regularity of the study treatment, or is uncontrolled by medication

- 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


- At least 4 weeks since prior adjuvant cytokine therapy (e.g., interleukin,
interferon) or vaccine therapy and recovered

- Prior vaccine therapy for stage IV disease allowed

- 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

- Prophylactic use of anticoagulants is allowed (e.g., maintenance of venous

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical benefit number of patients with complete response [CR], partial response [PR], or stable disease) according to RECIST criteria

Outcome Time Frame:

at 12 weeks

Safety Issue:


Principal Investigator

Roger von Moos, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Kantonsspital Graubuenden


Switzerland: Swissmedic

Study ID:

SAKK 50/07



Start Date:

December 2007

Completion Date:

October 2011

Related Keywords:

  • Melanoma (Skin)
  • stage IV melanoma
  • recurrent melanoma
  • Melanoma