A Randomized Phase II Trial of Weekly Topotecan With and Without AVE0005 (Aflibercept; NSC-724770) in Patients With Platinum Treated Extensive Stage Small Cell Lung Cancer (E-SCLC)
A Randomized Phase II Trial of Weekly Topotecan With and Without AVE0005 (Aflibercept; NSC-724770) in Patients With Platinum Treated Extensive Stage Small Cell Lung Cancer (E-SCLC)
This randomized phase II trial is studying topotecan to see how well it works when given with or without aflibercept in treating patients with extensive-stage small cell lung cancer. Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Combinations of biological substances in aflibercept may be able to carry tumor-killing substances directly to small cell lung cancer cells. Aflibercept may also stop the growth of small cell lung cancer by blocking blood flow to the tumor. It is not yet known whether topotecan is more effective with or without aflibercept in treating patients with small cell lung cancer.
PRIMARY OBJECTIVES:
I. Evaluate the efficacy of topotecan hydrochloride with vs without aflibercept (ziv-aflibercept), in terms of progression-free survival at 3 months, in patients with extensive stage small cell lung cancer previously treated with platinum-based therapy.
SECONDARY OBEJCTIVES:
I. Assess the response rate (confirmed and unconfirmed, complete and partial responses) in a subset of patients with measurable disease.
II. Assess the overall survival of these patients. III. Evaluate the frequency and severity of toxicities of these regimens in these patients.
OUTLINE: This is a multicenter study. Patients are stratified according to response to prior platinum-based therapy (platinum-sensitive disease vs platinum-refractory disease). Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive ziv-aflibercept IV over 1 hour on day 1 and topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with responsive or stable disease after 4 courses may then receive ziv-aflibercept IV on day 1 and topotecan hydrochloride IV on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with responsive or stable disease after 4 courses may then receive topotecan hydrochloride IV on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed periodically for up to 2 years.
Inclusion Criteria:
Histologically or cytologically confirmed extensive stage small cell lung cancer
Measurable or non-measurable disease per RECIST criteria
No known brain metastasis unless the metastasis has been treated and is stable for ≥ 3 months prior to study entry
No leptomeningeal involvement or brain stem metastasis
Zubrod performance status 0-1
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 10 g/dL
Serum creatinine ≤ 1.5 times upper limit of normal OR creatinine clearance ≥ 60 mL/min
Urine protein: creatinine ratio < 1 OR urine protein < 500 mg by 24-hour urine collection
Not pregnant or nursing
Fertile patients must use effective contraception
Willing to provide smoking history
No evidence of active infection
No active bleeding
No significant history of bleeding diathesis, including hemoptysis (½ teaspoon of hemoptysis within the past 3 months), or underlying coagulopathy
No history of recent arterial embolic events, including any of the following:
No uncontrolled hypertension (systolic BP > 150 mm Hg or diastolic BP > 100 mm Hg)
No history of congestive heart failure
No history of encephalitis or encephalopathy of any cause
No diverticulitis, gastrointestinal bleeding, or peptic ulcer within the past 3 months
No known AIDS or HIV-1 associated complex
No known history of immune or immunodeficiency disorders
No unstable or pre-existing major medical conditions except for cancer-related abnormalities
No other prior malignancy except for any of the following:
Concurrent chronic therapeutic doses of low molecular weight heparin allowed
At least 21 days since prior and no concurrent radiotherapy and recovered
At least 28 days since prior and no concurrent surgery (e.g., thoracic or other major surgeries) and recovered
No prior bevacizumab or other anti-angiogenic therapies including, but not limited to, small molecule tyrosine kinase inhibitors
No concurrent enzyme-inducing anticonvulsant drugs
Concurrent chronic oral anticoagulation therapy allowed provided INR is maintained in the therapeutic range (INR 2-3)
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