Vinflunine and Erlotinib or Pemetrexed in Treating Patients With Unresectable or Metastatic Solid Tumors

OBJECTIVES:

Primary

• Define the maximum tolerated dose (MTD) of vinflunine and pemetrexed disodium in patients with unresectable or metastatic solid tumors.
• Define the MTD of vinflunine and erlotinib hydrochloride in these patients.

Secondary

• Determine the preliminary safety and efficacy (reported descriptively per patient response; tumor specific response rate reported if applicable) of these regimens.
• Correlate CYP3A4 activity, as measured by midazolam clearance, with vinflunine plasma clearance.

OUTLINE: This is a nonrandomized, open-label, dose-escalation study. Patients are assigned to 1 of 2 treatment groups.

• Group 1: Patients receive pemetrexed disodium IV over 10 minutes and vinflunine IV over 20 minutes on day 1.

Cohorts of 3-6 patients receive escalating doses of pemetrexed disodium and vinflunine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Additional patients may be treated at the MTD.

• Group 2: Patients receive vinflunine IV over 20 minutes on day 1 and oral erlotinib hydrochloride once daily on days 2-21 of course 1 and on days 1-21 of all subsequent courses.

Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride and vinflunine until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Additional patients may be treated at the MTD.

In both groups, courses repeat every 21 days in the absence of unacceptable toxicity.

Blood samples are collected on day 1 of course 1 for pharmacodynamic studies.

After completion of study treatment, patients are followed for 30-40 days.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumors

• Advanced/unresectable or metastatic disease
• Refractory to standard therapy OR no standard therapy exists
• No lymphoma
• Measurable or evaluable disease

• Measurable disease is defined as at least one target lesion measuring ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan
• Evaluable disease includes ascites, pleural effusion, bone metastases, pulmonary lymphangitic spread, and lesions not meeting above criteria as measurable

• Patients with clinically significant ascites or pleural effusions that cannot be controlled by drainage are not eligible
• Brain metastases allowed if CNS-directed treatment has been given, patient has been off CNS-directed therapy for > 3 months, and CNS disease has been clinically and radiographically stable for at least 8 weeks

PATIENT CHARACTERISTICS:

• Life expectancy > 3 months
• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Creatinine clearance ≥ 60 mL/min

• Patients assigned to group 1 with creatinine clearance 45-80 mL/min must be able to withhold NSAIDS during pemetrexed disodium administration
• Total bilirubin ≤ 1.5 mg/dL
• AST and ALT ≤ 3 times upper limit of normal (ULN) OR ≤ 5 times ULN if due to known liver metastases
• No New York Heart Association class III or IV heart failure
• No unstable angina
• No myocardial infarction within the past 6 months
• No poorly controlled hypertension
• No prior allergic reaction to any vinca alkaloid
• No uncontrolled active infection or severe illness
• Able to receive vitamin B12 and folate supplementation and dexamethasone during chemotherapy
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after last dose of chemotherapy

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since prior chemotherapy, investigational agents, or surgery
• Concurrent cytochrome P450/CYP3A4 inducers or inhibitors are allowed provided patient has been on a stable dose for ≥ 2 weeks prior to study entry
• No concurrent ketoconazole, itraconazole, ritonavir, amprenavir, or indinavir
• No concurrent enzyme-inducing antiepileptic drugs (EIAEDs) (e.g., phenytoin, carbamazepine, phenobarbital, primidone, or oxcarbazepine) for patients assigned to group 2