GW786034 in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

• Determine the safety and tolerability of GW786034 in patients with advanced solid tumors.
• Determine the maximum tolerated dose of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Determine the clinical response in patients treated with this drug.
• Evaluate the effect of this drug on biomarkers of angiogenesis activity in order to estimate activity and to determine the minimum biologically active dose in these patients.

OUTLINE: This is an open-label, nonrandomized, dose-escalation, multicenter study.

Patients receive oral GW786034 twice daily. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 2-6 patients receive escalating doses of GW786034 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 21 days.

PROJECTED ACCRUAL: Approximately 30-50 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed advanced solid tumor
• Refractory to standard therapy or for which no standard therapy exists
• No untreated leptomeningeal or brain metastases

• Previously treated brain metastases are allowed if currently asymptomatic and patient is off steroids and antiseizure medications for more than 3 months before study entry

PATIENT CHARACTERISTICS:

Age

• 21 and over

Performance status

• Karnofsky 70-100%

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL

Hepatic

• Bilirubin no greater than 1.5 mg/dL
• AST and ALT no greater than 2 times upper limit of normal (ULN) (5 times ULN if tumor involvement)

Renal

• Creatinine clearance at least 60 mL/min

Cardiovascular

• No uncontrolled hypertension (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg on 2 consecutive measurements separated by 1 week)
• No arterial or venous thrombosis (including cerebrovascular accident) within the past 3 months
• No myocardial infarction within the past 3 months
• No unstable angina within the past 3 months
• No cardiac angiopathy or stenting within the past 3 months
• No cardiac pacemaker

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 21 days after study treatment
• Able to swallow and retain oral medication
• Good venous access
• No prior or concurrent gastrointestinal disease
• No prior or concurrent condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs
• No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug
• No other unstable, pre-existing major medical condition
• No orthopedic pins or rods or other embedded metal that would preclude undergoing an MRI
• No psychological, familial, sociological, or geographical condition that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 4 weeks since prior immunotherapy
• Concurrent epoetin alfa allowed
• No concurrent anticancer biologic therapy

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No concurrent anticancer cytotoxic chemotherapy

Endocrine therapy

• See Disease Characteristics
• More than 4 weeks since prior hormonal or steroid therapy (other than replacement)
• No concurrent anticancer hormonal therapy (except for replacement)
• No concurrent dexamethasone or prednisone

Radiotherapy

• More than 4 weeks since prior radiotherapy
• No concurrent anticancer radiotherapy

Surgery

• More than 4 weeks since prior major surgery
• No concurrent surgery for cancer

Other

• Recovered from prior therapy
• More than 4 weeks since prior investigational agents
• More then 28 days since prior alteration of antihypertensive medications
• Concurrent bisphosphonates allowed
• No other concurrent anticancer therapy
• No concurrent antidepressants (e.g., amitriptyline, fluoxetine, or fluvoxamine)
• No concurrent oral hypoglycemics (e.g., glipizide, glyburide, rosiglitazone, or tolbutamide)
• No concurrent therapeutic anticoagulation (e.g., warfarin at therapeutic doses)

• Low-dose anticoagulation for prophylaxis allowed
• No concurrent cyclosporine
• No concurrent grapefruit juice
• No concurrent amiodarone, mibefradil, phenobarbital, or pioglitazone
• No concurrent Hypericum perforatum (St. John's Wort)
• No concurrent rifabutin or diethyldithiocarbamate
• No concurrent gestodene, mifepristone, or modafinil
• No concurrent herbal supplements, vitamins, or non-traditional compounds