BLP25 Liposome Vaccine and Bevacizumab After Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Stage IIIA or Stage IIIB Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery

Phase 2

Completed

Conditions: Lung Cancer

Interventions: Biological: bevacizumab
Biological: Tecemotide
Drug: carboplatin
Drug: cyclophosphamide
Drug: paclitaxel
Radiation: radiotherapy

Registration Number: NCT00828009

Lead Sponsor: ECOG-ACRIN Cancer Research Group

Brief Summary: RATIONALE: Vaccines may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vaccine therapy together with bevacizumab after chemotherapy and radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying the side effects of giving BLP25 liposome vaccine together with bevacizumab after chemotherapy and radiation therapy in treating patients with newly diagnosed stage IIIA or stage IIIB non-small cell lung cancer that cannot be removed by surgery.

Detailed Description: OBJECTIVES:

Primary

* To determine the safety of BLP25 liposome vaccine (tecemotide) and bevacizumab after definitive chemoradiotherapy and consolidation chemotherapy in patients with newly diagnosed, unresectable stage IIIA or IIIB nonsquamous cell non-small cell lung cancer.

Secondary

* To evaluate the overall survival and progression-free in patients treated with this regimen.

* To evaluate the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study.

Step 1:

* Chemoradiotherapy: Patients receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes once a week for 6 weeks. Patients also undergo concurrent definitive radiotherapy 5 days a week for 6½ weeks. Patients with complete response (CR), partial response (PR), or stable disease (SD) proceed to consolidation chemotherapy.

* Consolidation chemotherapy: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with CR, PR, or SD proceed to maintenance therapy.

Step 2:

* Maintenance therapy: Patients receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and BLP25 liposome vaccine. Patients then receive bevacizumab IV over 30-90 minutes on day 1 and BLP25 liposome vaccine subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 70

Inclusion Criteria

Histologically confirmed newly diagnosed nonsquamous non-small cell lung cancer (NSCLC), including the following subtypes:
- Adenocarcinoma
- Large cell undifferentiated
- Bronchoalveolar cell
- non-small cell carcinoma, not otherwise specified
Unresectable stage IIIA or stage IIIB disease
- Patients with stage IIIA disease with mediastinal lymph node enlargement between 1 cm and 2.0 cm on computerized tomography (CT) scan must have these nodes biopsied (pathologic confirmation) to rule out resectability
- Metastases to contralateral mediastinal or supraclavicular nodes allowed
Measurable or non-measurable disease, as defined by Response Evaluation Criteria in Solid Tumours (RECIST) criteria
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
White blood cell (WBC) ≥ 4,000/mm³ OR Absolute neutrophil count (ANC) ≥ 2,000/mm³
Platelet count ≥ 140,000/mm³
Hemoglobin ≥ 9.0 g/dL
Total bilirubin ≤ 1.5 mg/dL
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT)+ ≤ 2.5 times upper limit of normal
Serum creatinine ≤ 1.5 mg/mL OR creatinine clearance ≥ 45 mL/min
Urine protein:creatinine ratio < 1.0 by urine dipstick OR < 1 g of protein by 24-hour urine collection
INR ≤ 1.5 OR ≤ 3.0 if patient is on therapeutic anticoagulation
PTT normal
Fertile patients must use effective contraception before, during, and for ≥ 6 months after completion of bevacizumab

Step 1

Exclusion Criteria

Significant pleural effusion
CNS metastases by head CT scan or MRI within the past 4 weeks
Pregnant or breast-feeding
Prior chemotherapy or monoclonal antibodies for other cancers within 5 years prior to registration
Prior chemotherapy for lung cancer
Prior chest radiotherapy
Ongoing (lasting > 14 days) or active infection or ongoing (lasting > 14 days) fever within the past 6 months
Gross hemoptysis ≥ grade 2 (defined as ≥ ½ teaspoon of bright red blood per episode) within the past 3 months
Bleeding ≥ grade 2 or any bleeding requiring intervention
Clinically significant cardiovascular disease
Myocardial infarction within the past 6 months
New York Heart Association class III-IV congestive heart failure
Unstable angina pectoris
Serious cardiac arrhythmia requiring medication within the past 4 weeks
History of hypertensive crisis or hypertensive encephalopathy
Stroke or transient ischemic attack within the past 6 months
Peripheral vascular disease ≥ grade 2 within the past 6 months
Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
Psychiatric illness or social situation that would limit compliance with study requirements
History of uncontrolled hypertension (i.e., blood pressure ≥ 150/100 mm Hg) while on stable regimen of antihypertensive therapy
Significant traumatic injury or serious non-healing wound, ulcer, or bone fracture within the past 4 weeks
Concurrent major surgical procedure
Having anticipated major surgical procedure(s) during the course of the study
Concurrent daily aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory agents (NSAIDs) known to inhibit platelet function
Recognized immunodeficiency disease, including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia, or hereditary or congenital immunodeficiencies
Pre-existing medical condition requiring chronic steroids or immunosuppressive therapy
Autoimmune disease
Known hepatitis B or C
Immunotherapy (e.g., interferon, interleukin, sargramostim [GM-CSF], or filgrastim [G-CSF]) within 28 days prior to registration
Prior splenectomy
Hypersensitivity to any component of bevacizumab
Prior core biopsy or any other minor surgical procedure, excluding the placement of a vascular access device, within 7 days prior to registration

Step 2 Inclusion Criteria:

Serum creatinine ≤ 1.5 mg/ml or calculated creatinine clearance ≥ 45 ml/min
Urine dipstick must be ≤ 0-1+. If urine dipstick results > 1+, 24 hour urine for protein must be obtained. Patients must have < 1g protein/24 hours to participate in the study
Patient must be registered to step 2 within 28 days of completion of consolidation chemotherapy
Patient must have met all eligibility requirements for Step 1
Platelets ≥ 100,000/mm3

Step 2 Exclusion Criteria:

Progressive disease or unevaluable disease per RECIST criteria upon post- consolidation chemotherapy evaluation
Autoimmune disease

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Tecemotide/bevacizumab after chemoradiation	bevacizumab	Concomitant Chemoradiotherapy: Patients (pts) receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes weekly for 6 weeks. Pts also receive radiotherapy 5 days a week for 6½ weeks. Pts with CR, PR, or SD proceed to consolidation chemotherapy. Consolidation chemotherapy: Pts receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression (PD) or unacceptable toxicity. Pts with CR, PR, or SD proceed to maintenance therapy. Maintenance therapy: Pts receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and tecemotide. Pts then receive bevacizumab IV over 30-90 minutes on day 1 and tecemotide subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of PD or unacceptable toxicity.
Tecemotide/bevacizumab after chemoradiation	Tecemotide	Concomitant Chemoradiotherapy: Patients (pts) receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes weekly for 6 weeks. Pts also receive radiotherapy 5 days a week for 6½ weeks. Pts with CR, PR, or SD proceed to consolidation chemotherapy. Consolidation chemotherapy: Pts receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression (PD) or unacceptable toxicity. Pts with CR, PR, or SD proceed to maintenance therapy. Maintenance therapy: Pts receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and tecemotide. Pts then receive bevacizumab IV over 30-90 minutes on day 1 and tecemotide subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of PD or unacceptable toxicity.
Tecemotide/bevacizumab after chemoradiation	radiotherapy	Concomitant Chemoradiotherapy: Patients (pts) receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes weekly for 6 weeks. Pts also receive radiotherapy 5 days a week for 6½ weeks. Pts with CR, PR, or SD proceed to consolidation chemotherapy. Consolidation chemotherapy: Pts receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression (PD) or unacceptable toxicity. Pts with CR, PR, or SD proceed to maintenance therapy. Maintenance therapy: Pts receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and tecemotide. Pts then receive bevacizumab IV over 30-90 minutes on day 1 and tecemotide subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of PD or unacceptable toxicity.
Tecemotide/bevacizumab after chemoradiation	cyclophosphamide	Concomitant Chemoradiotherapy: Patients (pts) receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes weekly for 6 weeks. Pts also receive radiotherapy 5 days a week for 6½ weeks. Pts with CR, PR, or SD proceed to consolidation chemotherapy. Consolidation chemotherapy: Pts receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression (PD) or unacceptable toxicity. Pts with CR, PR, or SD proceed to maintenance therapy. Maintenance therapy: Pts receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and tecemotide. Pts then receive bevacizumab IV over 30-90 minutes on day 1 and tecemotide subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of PD or unacceptable toxicity.
Tecemotide/bevacizumab after chemoradiation	carboplatin	Concomitant Chemoradiotherapy: Patients (pts) receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes weekly for 6 weeks. Pts also receive radiotherapy 5 days a week for 6½ weeks. Pts with CR, PR, or SD proceed to consolidation chemotherapy. Consolidation chemotherapy: Pts receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression (PD) or unacceptable toxicity. Pts with CR, PR, or SD proceed to maintenance therapy. Maintenance therapy: Pts receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and tecemotide. Pts then receive bevacizumab IV over 30-90 minutes on day 1 and tecemotide subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of PD or unacceptable toxicity.
Tecemotide/bevacizumab after chemoradiation	paclitaxel	Concomitant Chemoradiotherapy: Patients (pts) receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 15-30 minutes weekly for 6 weeks. Pts also receive radiotherapy 5 days a week for 6½ weeks. Pts with CR, PR, or SD proceed to consolidation chemotherapy. Consolidation chemotherapy: Pts receive paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for 2 courses in the absence of disease progression (PD) or unacceptable toxicity. Pts with CR, PR, or SD proceed to maintenance therapy. Maintenance therapy: Pts receive a single dose of cyclophosphamide IV over 15-30 minutes 3 days before the first dose of bevacizumab and tecemotide. Pts then receive bevacizumab IV over 30-90 minutes on day 1 and tecemotide subcutaneously on days 1, 8, and 15 of courses 1 and 2 and on day 1 of every other course beginning in course 4. Treatment repeats every 21 days for up to 34 courses in the absence of PD or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Proportion of Patients With Target Adverse Events for the Step 2 Treatment	Assessed every 3 weeks while on treatment and up to 5 years	The study is to evaluate the safety of the combination of tecemotide immunotherapy with bevacizumab. The target adverse events for the combined treatment are as follows: grade 4-5 hemorrhage, esophagitis, fistula, platelet count decrease (thrombocytopenia), encephalitis infection, or hepatic failure episodes.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Every 3 months for patients < 2 years from study entry, and every 6 months if patient is 2-5 years from study entry; up to 5 years	Overall survival was defined as the time from the study registration until death from any cause. Patients who were alive or lost to follow-up at the time of analysis were censored at date last known alive.
Progression-free Survival	Every 3 months for patients < 2 years from study entry, and every 6 months if patient is 2-5 years from study entry; up to 5 years	Progression-free survival was defined as the time from study registration to disease progression or death from any cause, whichever came first. If date of death was greater than 3 months after date of last disease assessment that showed progression-free, the patient was censored at the time of last disease assessment. Patients alive and without documented progression were censored at the date last known progression-free. Progression is defined using Response Evaluation Criteria In Solid Tumors (RECIST) Criteria (version 1.1), as at least 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, the appearance of new lesions, or unequivocal progression of existing non-target lesions.

Trial Locations

Locations (88): Veterans Affairs Medical Center - Palo Alto
🇺🇸
Palo Alto, California, United States
Stanford Cancer Center
🇺🇸
Stanford, California, United States
Medical Center of Central Georgia
🇺🇸
Macon, Georgia, United States
St. Joseph Medical Center
🇺🇸
Bloomington, Illinois, United States
Graham Hospital
🇺🇸
Canton, Illinois, United States
Memorial Hospital
🇺🇸
Carthage, Illinois, United States
Robert H. Lurie Comprehensive Cancer Center at Northwestern University
🇺🇸
Chicago, Illinois, United States
Hematology and Oncology Associates
🇺🇸
Chicago, Illinois, United States
Saint Joseph Hospital
🇺🇸
Chicago, Illinois, United States
Decatur Memorial Hospital Cancer Care Institute
🇺🇸
Decatur, Illinois, United States
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Veterans Affairs Medical Center - Palo Alto
🇺🇸Palo Alto, California, United States