Phase I Study of Vandetanib (ZD 6474) and Bevacizumab Combination Therapy Evaluating the VEGF and EGF Signal Transduction Pathways in Adults With Solid Tumors and Lymphomas
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically confirmed advanced malignancy, including the following:
- Solid tumor that is refractory to standard therapy or for which no standard
therapy exists
- No lung carcinoma of squamous cell or small cell histology (mixed tumors
will be categorized by the predominant cell type)
- Histological confirmation based on sputum cytology alone is not
acceptable
- Lymphoma (Hodgkin or non-Hodgkin lymphoma) that has progressed after standard
therapy AND for which stem cell transplantation is not indicated or has been
refused
- No known CNS disease, except for treated brain metastasis meeting the following
criteria:
- No ongoing requirement for steroids
- No evidence of progression or hemorrhage by clinical examination and brain
imaging (MRI or CT scan) for ≥ 3 months after treatment
- Stable dose of anticonvulsants allowed
- Prior treatment for brain metastases may have included whole-brain radiotherapy,
radiosurgery (gamma knife, linear accelerator, or equivalent), or a combination
of therapy as deemed appropriate by the treating physician
- Neurosurgical resection or brain biopsy for treatment of CNS metastases
allowed provided treatment was completed more than 3 months ago
PATIENT CHARACTERISTICS:
- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
- Life expectancy > 3 months
- Absolute neutrophil count ≥ 1,500/μL
- Platelet count ≥ 100,000/μL
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
- AST and ALT ≤ 2.5 times ULN
- Creatinine < 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
- Urine protein:creatinine ratio ≤ 0.5 OR urine protein < 1,000 mg by 24-hour urine
collection
- Activated partial thromboplastin time ≤ 1.5 times ULN
- Prothrombin time OR INR < 1.5 times ULN
- Potassium between 4 mmol/L and ULN (supplementation allowed)
- Magnesium normal (supplementation allowed)
- Serum calcium (adjusted for albumin) or ionized calcium normal (supplementation
allowed)
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for ≥ 6 months after
completion of study therapy
- HIV-positivity allowed provided the following criteria are met:
- Patient does not require anti-HIV therapy
- CD4 count > 350/mm^3
- HIV viral load < 25,000 copies/mm^3
- No history of opportunistic infections
- No evidence of severe or uncontrolled systemic disease or any concurrent condition
that could compromise participation in the study, including any of the following:
- Active or uncontrolled infection
- Immune deficiencies
- HIV infection requiring anti-HIV therapy
- Hepatitis B
- Hepatitis C
- Uncontrolled diabetes
- Uncontrolled hypertension
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Myocardial infarction within the past 6 months
- Uncontrolled cardiac arrhythmia
- Stroke/cerebrovascular accident within the past 6 months
- Psychiatric illness/social situation that, in the investigator's opinion, would
make it undesirable for the patient to participate in the study or that would
jeopardize study compliance
- No New York Heart Association class III or IV heart disease within the past 6 months
- No history of arrhythmia (i.e., multifocal premature ventricular contractions,
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation)
that is symptomatic or requires treatment
- Atrial fibrillation allowed provided it is controlled with medication
- No asymptomatic sustained ventricular tachycardia
- No other cardiac disease that, in the investigator's opinion, would increase the risk
of ventricular arrhythmia
- QTc < 480 msec (with measurable Bazett correction) by screening ECG
- No history of QTc prolongation as a result of other medications that required
discontinuation
- No congenital long QT syndrome
- No first-degree relative with unexplained sudden death at under 40 years of age
- No left bundle branch block
- No hypertension not controlled by medical therapy, defined as systolic blood pressure
> 150 mm Hg or diastolic blood pressure > 90 mm Hg despite optimal medical management
- No other clinically significant cardiac event
- No thromboembolic disease within the past 6 months
- No significant vascular disease (e.g., aortic aneurysm or aortic dissection) or
clinically significant peripheral vascular disease
- No serious non-healing wounds (including wounds healing by secondary intention)
- No acute or non-healing ulcers
- No bone fractures within the past 3 months
- No abdominal fistula, gastointestinal perforation, or intra-abdominal abscess within
the past 28 days
- No currently active diarrhea that may affect the ability of the patient to absorb or
tolerate vandetanib
- No hemoptysis (bright red blood of ≥ ½ teaspoon per episode) within the past 3 months
- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Prior anti-VEGF therapy allowed
- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
or radiotherapy and recovered
- More than 4 weeks since prior major surgery and recovered
- At least 2 weeks since prior investigational drugs given in a phase 0 clinical trial
- More than 10 days since prior and no concurrent aspirin (> 325 mg/day) or chronic use
of other NSAIDs
- No concurrent regular, therapeutic anticoagulation
- No concurrent medication that may cause QTc prolongation, induce Torsades de Pointes,
or induce CYP3A4 function, including any of the following:
- Rifampin
- Rifabutin
- Phenytoin
- Carbamazepine
- Phenobarbital
- Hypericum perforatum (St. John's wort)
- No other concurrent antineoplastic therapy, except for gonadotropin-releasing hormone
therapy for prostate cancer