S0802 - Topotecan With or Without Aflibercept in Treating Patients With Extensive-Stage 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

• Progressive or recurrent disease following one (and only one) standard first-line platinum-containing regimen (cisplatin or carboplatin)
• Measurable or non-measurable disease per RECIST criteria

• Disease must be outside a previously irradiated field OR a new lesion must be inside the irradiated field
• Disease must be outside a previously resected area OR a new lesion must be present
• 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:

• Myocardial infarction
• Cerebrovascular accident
• Transient ischemic attack
• Worsening of pre-existing angina within the past 6 months
• No uncontrolled hypertension (systolic BP > 150 mm Hg or diastolic BP > 100 mm Hg)

• History of hypertension allowed provided it is controlled on anti-hypertensive medications
• 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:

• Adequately treated basal cell or squamous cell skin cancer
• In situ cervical cancer
• Adequately treated stage I or II cancer currently in complete remission
• Any other cancer from which the patient been disease-free for 5 years
• 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

• Non-enzyme-inducing anticonvulsant drugs (e.g., Keppra) allowed
• Concurrent chronic oral anticoagulation therapy allowed provided INR is maintained in the therapeutic range (INR 2-3)