Vandetanib and Bevacizumab in Treating Patients With Advanced Solid Tumors or Lymphoma

Sponsor

National Institutes of Health Clinical Center (CC) (NIH)

Overall Status

Completed

CT.gov ID

NCT00734890

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

35.1

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Vandetanib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bevacizumab and vandetanib may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving vandetanib together with bevacizumab may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vandetanib and bevacizumab in treating patients with advanced solid tumors or lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer Lymphoma Lymphoproliferative Disorder Small Intestine Cancer Unspecified Adult Solid Tumor, Protocol Specific	Biological: bevacizumab Drug: vandetanib Other: laboratory biomarker analysis Other: pharmacological study	Phase 1

Detailed Description

OBJECTIVES:

Primary

Determine the maximum tolerated dose, safety, and toxicity of vandetanib and bevacizumab in patients with advanced solid tumors or lymphoma.

Secondary

Characterize the pharmacokinetic profile of this regimen in these patients.
Measure changes in VEGF and other angiogenic cytokines in plasma samples from these patients.
Determine the biochemical changes in the EGF signal transduction pathways in tumor biopsy samples from these patients.
Determine the anti-angiogenic effects of this regimen in tumor biopsy samples from these patients.
Evaluate the application of dynamic contrast-enhanced MRI to determine early changes in tumor vascular permeability during treatment.
Evaluate the effects of this regimen on circulating endothelial progenitors and mature circulating endothelial cells in these patients.

OUTLINE: Patients receive oral vandetanib once daily on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for correlative laboratory studies, including pharmacokinetic, biomarker (VEGF and other angiogenic cytokines), and circulating endothelial cell analysis. Patients may also undergo optional tumor biopsies for additional correlative laboratory studies.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2008

Actual Primary Completion Date :

Jun 1, 2010

Actual Study Completion Date :

Feb 1, 2011

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose []
Safety []
Toxicity []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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