S0802 - Topotecan With or Without Aflibercept in Treating Patients With Extensive-Stage Small Cell Lung Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Extensive Stage Small Cell Lung Cancer, Recurrent Small Cell Lung Cancer

Intervention / Treatment
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* Biological: ziv-aflibercept
* Drug: topotecan hydrochloride


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (ziv-aflibercept, topotecan hydrochloride)<br>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. | Biological: ziv-aflibercept<br>* Given IV<br>* Other names: Zaltrap;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: TOPO;|
| Active Comparator: Arm II (topotecan hydrochloride)<br>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. | Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: TOPO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | From the date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Progression is defined as 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Appearance of any new lesion/site. Death due to disease without prior documentation of progression and without symptomatic deterioration. | Disease assessments were performed every 6 weeks, up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated to within at least 15% (95% confidence interval). | Weekly, up to 2 years. | 
| Response Rate (Confirmed and Unconfirmed, Complete and Partial Responses) | The number of confirmed and unconfirmed complete and partial responses in the subset of patients with measurable disease per RECIST 1.0. Estimated to within at least 17% (95% confidence interval). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Disease assessment for response were performed every 6 weeks, up to 2 years. | 
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 3.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. The events listed here are not necessary to be included in Serious Adverse Event. A serious event could be death, life-threatening, hospitalization, disability or permanent damage, congenital anomaly...Grade 3 through 5 adverse event may not meet the criterion of serious adverse event. | Toxicity assessment was evaluated after each cycle (21 days), up to 2 years. |