Phase I Study of ZD6474 and Temozolomide in Patients With Advanced Cancer
Phase I Study of ZD6474 and Temozolomide in Patients With Advanced Cancer
RATIONALE: Vandetanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vandetanib together with temozolomide may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of vandetanib and temozolomide in treating patients with advanced solid tumors that cannot be removed by surgery.
OBJECTIVES:
OUTLINE: Patients receive escalating doses of oral vandetanib once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and prior to each treatment course for correlative laboratory studies, including evaluation of plasma VEGF levels by ELISA, serum angiogenesis assay, and measurement of circulating endothelial cell populations (CD133, CD34, CD146). Frozen serum and plasma samples are also stored for future research studies.
DISEASE CHARACTERISTICS:
Histologically confirmed solid tumor
Measurable or evaluable disease
No known standard therapy that is potentially curative or definitely capable of extending life expectancy exists
No intracranial metastatic disease, unless it has been radiologically and clinically stable for the past 3 months
PATIENT CHARACTERISTICS:
ECOG performance status 0-2
ANC ≥ 1,500/μL
Absolute lymphocyte count > 1,000/μL
Platelet count ≥ 100,000/μL
Hemoglobin ≥ 8.0 g/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST ≤ 3 times ULN (≤ 5 times ULN if liver involvement)
Creatinine ≤ 1.5 times ULN OR creatinine clearance > 50 mL/min
Potassium normal
Serum calcium (ionized or adjusted for albumin) normal
Magnesium normal
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No uncontrolled infection
No currently active diarrhea that results in an ongoing need for IV fluids and/or that may affect the ability of the patient to absorb vandetanib or tolerate diarrhea
No evidence of severe or uncontrolled systemic disease or any concurrent condition that, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or that would jeopardize compliance with the study
No other malignancies within the past 5 years, except cervical carcinoma in situ or adequately treated basal cell or squamous cell carcinoma of the skin
No clinically significant cardiac event, such as myocardial infarction, NYHA class II-IV heart disease within the past 3 months, or presence of cardiac disease that, in the opinion of the treating physician, increases the risk of ventricular arrhythmia
No history of arrhythmia (i.e., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (CTCAE grade 3)
No asymptomatic sustained ventricular tachycardia
No history of QTc prolongation as a result of other medication that required discontinuation of that medication
No congenital long QT syndrome
No 1st degree relative with unexplained sudden death under 40 years of age
No left bundle branch block
No QTc with Bazett's correction that is unmeasurable
QTc < 480 msec on screening ECG
No hypertension that is uncontrolled by medical therapy (i.e., systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg)
No bleeding diathesis (inherited coagulopathy)
PRIOR CONCURRENT THERAPY:
Recovered from prior therapy
More than 30 days since prior investigational agents
More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
More than 4 weeks since prior immunotherapy or biologic therapy
More than 4 weeks since prior major surgery
More than 4 weeks since prior radiotherapy, except palliative radiotherapy
No prior radiotherapy to > 25% of bone marrow
No prior temozolomide or dacarbazine
No prior enrollment in this study
More than 2 weeks since prior and no concurrent known potent CYP3A4 inducers, such as rifampin, phenytoin, carbamazepine, barbiturates, or St. John's wort
More than 2 weeks since prior and no concurrent drugs associated with an increased risk of causing Torsades de Pointes
No concurrent medication that may cause QTc prolongation
No concurrent anticoagulants
No other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational