Lung Cancer
Conditions
Keywords
stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, adenocarcinoma of the lung
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.
Interventions
BIOLOGICALbevacizumab
IV
BIOLOGICALTecemotide
DRUGcarboplatin
IV
DRUGcyclophosphamide
IV
DRUGpaclitaxel
IV
RADIATIONradiotherapy
radiotherapy is given 5 days a week for 6½ weeks during concomitant chemoradiotherapy
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Step 1 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
E6508 was activated on December 22, 2010, accrued its first patient on January 17, 2011, suspended per protocol on January 12, 2012 for interim toxicity analysis. The study was then reactivated on October 9, 2012 to stage 2 accrual and closed to accrual on October 13, 2014.
Participants by arm
| Arm | Count |
|---|---|
| Step 2 - Maintenance Therapy 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. | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Step 1 - Chemo RT/Consolidation Chemo | Adverse Event | 10 |
| Step 1 - Chemo RT/Consolidation Chemo | Complicating disease | 1 |
| Step 1 - Chemo RT/Consolidation Chemo | Death | 2 |
| Step 1 - Chemo RT/Consolidation Chemo | Never started therapy | 2 |
| Step 1 - Chemo RT/Consolidation Chemo | No show/Patient moved | 2 |
| Step 1 - Chemo RT/Consolidation Chemo | Progressive disease | 11 |
| Step 1 - Chemo RT/Consolidation Chemo | Withdrawal by Subject | 3 |
| Step 2 - Maintenance Therapy | Adverse Event | 13 |
| Step 2 - Maintenance Therapy | Complicating disease | 2 |
| Step 2 - Maintenance Therapy | Death | 1 |
| Step 2 - Maintenance Therapy | Other | 1 |
| Step 2 - Maintenance Therapy | Progressive disease | 12 |
| Step 2 - Maintenance Therapy | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Step 2 - Maintenance Therapy |
|---|---|
| Age, Continuous | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 48 / 68 | 21 / 33 |
| other Total, other adverse events | 65 / 68 | 32 / 33 |
| serious Total, serious adverse events | 39 / 68 | 11 / 33 |
Outcome results
Primary
Proportion of Patients With Target Adverse Events for the Step 2 Treatment
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.
Time frame: Assessed every 3 weeks while on treatment and up to 5 years
Population: All patients who received step 2 treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step 2 - Maintenance Therapy | Proportion of Patients With Target Adverse Events for the Step 2 Treatment | 0.03 proportion of participants |
Secondary
Overall Survival
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.
Time frame: 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
Population: Only eligible and treated patients are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step 2 - Maintenance Therapy | Overall Survival | 42.7 months |
Secondary
Progression-free Survival
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.
Time frame: 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
Population: Only eligible and treated patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Step 2 - Maintenance Therapy | Progression-free Survival | 14.9 months |