Warfarin and Vatalanib in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

Primary

• Determine the acute and chronic changes in INR in patients with advanced solid tumors treated with low-dose warfarin and vatalanib.

Secondary

• Determine the steady-state pharmacokinetics of this regimen in these patients.
• Determine the safety and tolerability of this regimen in these patients.

OUTLINE: This is a nonrandomized, open-label, multicenter study.

• Pharmacokinetic (PK) phase: Patients receive oral low-dose warfarin once daily on days 1-14 and oral vatalanib once daily, 1 hour before warfarin administration, on days 2-14 in the absence of disease progression or unacceptable toxicity.
• Continuation phase: Patients not experiencing a drug interaction in the PK phase continue to receive oral vatalanib and oral low-dose warfarin once daily. Patients experiencing a drug interaction (INR > 2.0) in the PK phase receive oral vatalanib alone once daily. Continuation therapy continues indefinitely in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Inclusion criteria

• Histologically confirmed advanced solid tumor
• Progressed despite standard therapy OR no known standard therapy exists

-- Currently receiving OR a candidate for prophylactic low-dose warfarin (1 mg/day)

• INR ≤ 1.4
• Must be an extensive metabolizer of CYP2C9 (at least 1 wild type allelle: *1)
• 18 and over
• Hemoglobin ≥ 9 g/dL
• AST and ALT ≤ 3 times upper limit of normal (ULN)

• Bilirubin ≤ 1.5 times ULN
• Albumin ≥ 3.0 g/dL
• Hepatitis B surface antigen negative
• Hepatitis C antibody negative
• Creatinine ≤ 1.5 ULN OR
• Creatinine clearance > 50 mL/min
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• More than 14 days since prior anticancer chemotherapy
• More than 14 days since prior anticancer hormonal therapy
• More than 14 days since prior anticancer radiotherapy
• More than 14 days since other prior anticancer therapy
• More than 30 days since prior investigational drugs
• No ethanol for 2 days prior to and for the first 17 days of study treatment

Exclusion criteria

• No poor metabolizers of CYP2C9 (2 alleles of either *2 or *3)
• brain metastases
• history of or active coagulation disorders
• significant risk for bleeding
• uncontrolled high blood pressure (BP), defined as diastolic BP > 90 mm Hg or systolic BP > 140 mm Hg
• history of cerebral or aortic aneurysm
• pregnant or nursing
• recent history or evidence of drug or alcohol abuse
• active peptic ulcer disease or gastrointestinal bleeding
• contraindication or allergy to warfarin or related compounds
• risk for adverse events related to prolonged PT/PTT due to warfarin administration
• other medical condition that would preclude study participation
• concurrent chemotherapy
• concurrent hormonal therapy
• concurrent radiotherapy
• other concurrent CYP2C9 substrates or inhibitors
• concurrent CYP3A4 inducers or inhibitors
• concurrent food or dietary supplement known to alter the metabolism of CYP3A4 (e.g., grapefruit or Hypericum perforatum [St. John's wort])