Temozolomide and Vinorelbine in Treating Patients With Recurrent Brain Metastases

• Maximum tolerated dose (phase I) assessed by NCI CTC at 2 months [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Radiographic response (phase II) assessed by Macdonald criteria every 2 months [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase I/II trial to study the effectiveness of temozolomide and vinorelbine in treating patients who have recurrent brain metastases.

OBJECTIVES:

• Determine the maximum tolerated dose of vinorelbine when administered in combination with temozolomide in patients with recurrent brain metastases (phase I accrual completed).
• Determine the safety and feasibility of this treatment regimen in these patients.
• Determine the efficacy of this treatment regimen, in terms of objective radiographic response and overall and progression-free survival, in these patients.

OUTLINE: This is a dose-escalation study of vinorelbine.

Patients receive vinorelbine IV over 5-10 minutes on days 1 and 8 and oral temozolomide once daily on days 1-7 and 15-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of vinorelbine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 20-35 patients will be treated at that dose level.

Patients are followed every 3-4 months.

PROJECTED ACCRUAL: A minimum of 3 patients will be accrued for the phase I portion of this study and 20-35 patients will be accrued for the phase II portion of this study within 2 years.

• Drug: temozolomide
• Drug: vinorelbine tartrate

INCLUSION CRITERIAL:

• Age > or = 18 years.
• Karnofsky performance score > or = 60.
• Histopathologic confirmation of the diagnosis of a solid tumor malignancy. The brain metastasis diagnosis per se does not have to be pathologically confirmed if the clinical and neuro radiographic picture is typical.
• MRI (or CT if the patient cannot undergo MRI) evidence of evaluable disease in the brain.
• Absolute neutrophil count > or = 1,500/mm³. Platelet count > or = 100,000/mm³.
• Hemoglobin > or = 10 g/dl.
• BUN and serum creatinine both < 1.5 times upper limit of normal.
• Total and direct bilirubin both < 1.5 times upper limit of normal.
• SGOT and SGPT both < or = 3 times upper limit of normal.
• Alkaline phosphatase < or = 2 times upper limit of normal.
• At least two weeks must have elapsed from brain biopsy, craniotomy, or other surgery.
• Life expectancy > or = 8 weeks.
• Patient or their legal guardian or legal next-of-kin must provide written informed consent prior to patient's registration on study.
• At least four weeks must have elapsed from previous external beam radiation therapy, or eight weeks from stereotactic radiosurgery.
• Patients treated with radiosurgery should have evidence of progression at a distant site in the brain, or confirmation of tumor progression by biopsy or PET scan.

EXCLUSION CRITERIA:

• Previous treatment with temozolomide, dacarbazine or vinorelbine.
• Patients who have not recovered from all acute toxicities of prior therapies.
• Patients with evidence of leptomeningeal metastases or primary dural metastases.
• Patients who are poor medical risks because of nonmalignant systemic disease, as well as those with acute infection requiring treatment with intravenous antibiotics.
• Patients whose psychiatric condition would, in the judgment of the principal investigator, make it unlikely that they could adhere to the requirements of the protocol.

• National Cancer Institute (NCI)
• Northwestern Memorial Hospital