Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: A virus called Seneca Valley virus-001 (NTX-010) may be able to kill tumor cells without damaging normal cells. It is not yet known whether NTX-010 is more effective than a placebo in treating small cell lung cancer. PURPOSE: This randomized phase II trial is studying NTX-010 to see how well it works compared with a placebo when given after chemotherapy in treating patients with extensive-stage small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary To compare the progression-free survival (PFS) of patients with extensive-stage small cell lung cancer treated with Seneca Valley virus-001 (NTX-010) vs placebo. Secondary To compare the overall survival (OS) of patients treated with NTX-010 vs placebo. To describe the adverse events profile and safety of NTX-010 in this patient population. To determine the antitumor response rate, as assessed by RECIST criteria, and duration of tumor response in this patient population. To assess the quality of life of this patient population. Exploratory To determine the relationship between the presence of neutralizing antibodies and PFS. To assess whether or not a slow viral clearance is associated with better response as determined by PFS. To determine any potential impact of the presence of one or several neuroendocrine markers in the tumor sample (synaptophysin, chromogranin, or CD56) on PFS and OS. To determine any potential relationship between presence of cell surface determinants of NTX-010 tropism in the tumor tissue and clinical outcomes such as improved PFS and OS. To determine any potential relationship between the loss of integrity of IFN signaling in the tumor tissue and clinical outcomes such as improved PFS and OS. To assess whether or not the presence of circulating tumor cells permissive to NTX-010 is associated with better clinical outcomes as determined by PFS and OS. OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0 vs 1), tumor response to standard chemotherapy (partial response vs stable disease vs complete response), and time between completion of chemotherapy to randomization 1 month (≤1 month) vs 2 months (>1 month but ≤ 2 months) vs 3 months (> 2 months but ≤ 3 months). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive a single dose of Seneca Valley virus-001 (NTX-010) IV over 1 hour on day 1. Arm II: Patients receive a single dose of placebo IV over 1 hour on day 1. In both arms, patients may also undergo prophylactic cranial irradiation (PCI) daily on days 22-35 if they have not previously undergone PCI or whole-brain radiotherapy. Quality of life is assessed at baseline and then periodically during the study. Blood samples are collected periodically for viral clearance and antiviral neutralizing antibody levels, circulating tumor cells, and other biomarker laboratory studies. After completion of study therapy, patients are followed up periodically for up to 5 years.

Official Title
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A Randomized Double-Blinded Phase II Study of NTX-010, a Replication-Competent Picornavirus, After Standard Platinum-Containing Cytoreductive Induction Chemotherapy in Patients With Extensive Stage Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Biological: Seneca Valley virus-001
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of extensive-stage small cell lung cancer (SCLC) No mixed histology Presence of ≥ 1 neuroendocrine marker (synaptophysin, chromogranin, or CD56) in tumor tissue Achieved partial response (PR), complete response (CR), or stable disease (SD) ≤ 12 weeks of completing 4-6 courses of platinum-based chemotherapy regimen for extensive-stage SCLC Patients with PR or SD must have measurable disease, defined as ≥ 1 lesion whose longest diameter can be accurately measured as ≥ 2.0 cm but < 10 cm by chest x-ray OR as ≥ 1.0 cm but < 10 cm by CT scan, CT component of a PET/CT scan, or MRI If CT scan is used, it must be used for both pre- and post-treatment tumor assessments Measurable disease is not required for patients with CR Brain metastases allowed provided they have been stable for ≥ 4 weeks after completion of prior radiotherapy PATIENT CHARACTERISTICS: ECOG performance status 0 or 1 Life expectancy of ≥ 8 weeks ANC ≥ 1,500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal AST ≤ 3 times ULN (≤ 5 times ULN if liver has tumor involvement) Not pregnant or nursing Negative pregnancy test Fertile patients must use adequate contraception Able to comply with study procedures to minimize virus exposure to others Willing to provide required biologic specimens Willing to return to NCCTG/CTSU enrolling institution for follow-up Adequate lung function (i.e., not oxygen dependent) The patient is eligible if not on a 24-hour oxygen schedule No second primary malignancy within the past 5 years, except for the following: Carcinoma in situ of the cervix Non-melanomatous skin cancer History of low-grade (Gleason score ≤ 6) localized prostate cancer (even if diagnosed < 5 years prior to study entry) Stage I breast cancer that was treated ≥ 5 years before study entry Transitional cell carcinoma of the bladder (in situ) No active hepatitis B or hepatitis C No clinically significant infection No significant traumatic injury within the past 4 weeks No concurrent uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 4 weeks since prior radiotherapy (2 weeks for palliative radiotherapy to skeletal metastases) Other prior radiation therapy (including WBRT, PCI, or Gamma Knife) is permitted as long as the following are true: Recovered from prior radiotherapy (alopecia allowed) No prior consolidation radiation therapy to the chest No prior radiotherapy to > 25% of bone marrow For patients without brain metastases, WBRT or standard of care PCI completed ≥ 2 weeks before administration of NTX- 010/placebo More than 365 days since prior immunotherapy or biologic therapy More than 4 weeks since prior major surgery* (i.e., laparotomy) or open biopsy More than 2 weeks since prior minor surgery* No prior exposure to the Seneca Valley virus (NTX-010), as determined by negative serum antibodies No concurrent combination antiretroviral therapy for HIV-positive patients NOTE: *Insertion of a vascular access device is not considered major or minor surgery.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive a single dose of Seneca Valley virus-001 (NTX-010) IV over 1 hour on day 1. | Biological: Seneca Valley virus-001<br>* Given IV<br>|
| Placebo Comparator: Arm II<br>Patients receive a single dose of placebo IV over 1 hour on day 1. | Other: placebo<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | The progression-free survival (PFS) was defined as the time from date of randomization to the documentation of disease progression or death as a result of any cause, whichever comes first. | Time from randomization to the disease progression or death (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from study enrollment (randomization) to the time of death from any cause or last follow-up. | Time from randomization to death or last follow-up (up to 5 years) | 
| Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) | A confirmed tumor response was defined as a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all non-nodal target lesions and each target lymph node must have reduction in short axis to <1.0 cm.; Partial Response (PR), at least a 30% decrease in the sum of the longest diameters of the non-nodal target lesions and the short axes of the target lymph nodes taking as reference the Baseline Sum of Diameters; Overall Response (OR) = CR + PR. | Up to 5 years | 
| Duration of Response | Duration of response was defined as the time from the date at which the patient's earliest best objective status was first noted to be either a CR or PR to the earliest date progression was documented. | Up to 5 years | 
| Number of Participants With at Least One Grade 3 or Above Adverse Events Assessed by NCI CTCAE v4.0 | Adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death. The maximum grade for each type of adverse events were recorded for each patient. | Up to 23 months | 
| Change From Baseline to Day 20-29 in the LASA QOL | Quality of Life (QOL) was measured using the single-item Linear Analogue Self Assessment (LASA) on a 0-10 scale, with 0=as bad as it can be and 10=as good as it can be. The QOL scores was converted to a 100-point scale, with 0=Low QOL and 100=Best QOL. Change from baseline to day 20-29 was calculated by subtracting the baseline scores from the scores at day 20-29. Negative change indicates the QOL decrease and positive change indicates the QOL improvement. | Day 1 Cycle 1 prior to treatment (baseline) and day 20-29 (during the active monitoring phase) | 
| Change From Baseline to Day 30-59 in the LASA QOL | Quality of Life (QOL) was measured using the single-item Linear Analogue Self Assessment (LASA) on a 0-10 scale, with 0=as bad as it can be and 10=as good as it can be. The QOL scores was converted to a 100-point scale, with 0=Low QOL and 100=Best QOL. Change from baseline to day 30-59 was calculated by subtracting the baseline scores from the scores at day 30-59. Negative change indicates the QOL decrease and positive change indicates the QOL improvement. | Day 1 Cycle 1 prior to treatment (baseline) and day 30-59 (during the active monitoring phase) | 
| Clinical Significance Change From Baseline to Day 20-29 in the LASA QOL | Quality of Life (QOL) was measured using the single-item Linear Analogue Self Assessment (LASA) on a 0-10 scale, with 0=as bad as it can be and 10=as good as it can be. The QOL scores was converted to a 100-point scale, with 0=Low QOL and 100=Best QOL. Change from baseline to day 20-29 was calculated by subtracting the baseline scores from the scores at day 20-29. Clinical Significance change over time was determined by the percentage of patients that report an improvement of more than 10 points on the 0-100 point scale. | Day 1 Cycle 1 prior to treatment (baseline) and day 20-29 (during the active monitoring phase) | 
| Clinical Significance Change From Baseline to Day 30-59 in the LASA QOL | Quality of Life (QOL) was measured using the single-item Linear Analogue Self Assessment (LASA) on a 0-10 scale, with 0=as bad as it can be and 10=as good as it can be. The QOL scores was converted to a 100-point scale, with 0=Low QOL and 100=Best QOL. Change from baseline to day 30-59 was calculated by subtracting the baseline scores from the scores at day 30-59. Clinical Significance change over time was determined by the percentage of patients that report an improvement of more than 10 points on the 0-100 point scale. | Day 1 Cycle 1 prior to treatment (baseline) and day 30-59 (during the active monitoring phase) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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extensive stage small cell lung cancer