AZD2171 in Treating Patients With Malignant Mesothelioma That Cannot Be Removed By Surgery

Objective response rate (complete or partial response) [ Designated as safety issue: No ]

Changes in laboratory correlates [ Designated as safety issue: No ]
Pharmacogenomics by correlating genetic polymorphisms with drug activity and toxicity [ Designated as safety issue: Yes ]

Primary

Determine the objective response rate in patients with malignant pleural, peritoneal, or tunica vaginalis mesothelioma that is not amenable to curative surgery who are treated with AZD2171.

Secondary

Tertiary

Generate preliminary data regarding potential utility of pharmacogenomic and plasma/serum biomarkers of angiogenesis as predictive or prognostic markers for future investigations of this drug in malignant mesothelioma.

This is a multicenter study.

Patients receive oral ADZ2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically during study for biomarker and optional pharmacogenomic correlative studies.

After completion of study treatment, patients are followed for up to 8 weeks.

A total of 50 patients will be accrued for this study.

Disease Characteristics:

Histologically or cytologically confirmed malignant pleural, peritoneal, or tunica vaginalis mesothelioma
- Epithelial, sarcomatoid, or mixed subtype
International Mesothelioma Interest Group stage II-IV disease (for patients with pleural mesothelioma)
Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR > 10 mm by spiral CT scan
- Pleural effusion and ascites are not considered measurable lesions
Disease not amenable to curative surgery
No known brain metastases

Patient Characteristics:

ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%
Life expectancy > 3 months
WBC ≥ 3,000/mm³
Absolute neutrophil count ≥ 1,500/mm³
Hemoglobin ≥ 8 g/dL
Platelets ≥ 100,000/mm³
Total bilirubin normal
AST/ALT ≤ 2.5 times upper limit of normal (ULN)
Creatinine normal OR creatinine clearance > 60 mL/min
Fertile patients must use effective contraception
Not pregnant or nursing
Negative pregnancy test
No history of allergic reactions to compounds of similar chemical or biologic composition to AZD2171
Mean QTc ≤ 500 msec (with Bazett’s correction) by EKG
No history of long QT syndrome
Proteinuria ≤ 1+ on two consecutive dipsticks taken ≥ 1 week apart
No other concurrent malignancy
No New York Heart Association class III or IV cardiac disease
No uncontrolled intercurrent illness including, but not limited to, any of the following:
- Hypertension
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situations that would limit study compliance

Prior Concurrent Therapy:

No more than 1 prior cytotoxic chemotherapy
- Prior intrapleural cytotoxic agents (including bleomycin) do not count towards prior cytotoxic chemotherapy
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
No prior radiotherapy to the only site of measurable disease
At least 4 weeks since prior radiotherapy and recovered
At least 4 weeks since prior major surgery and recovered
More than 30 days since prior participation in an investigational trial
No prior treatment with a vascular endothelial growth factor (VEGF) inhibitor
No other concurrent investigational agents
No concurrent commercial agents for the malignancy
No concurrent medication that may markedly affect renal function (e.g., vancomycin, amphotericin, or pentamidine)
No concurrent hematopoietic growth factors except epoetin alfa
No concurrent palliative radiotherapy
No combination antiretroviral therapy for HIV-positive patients
No concurrent drugs or biologics with proarrhythmic potential

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