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

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.

• bevacizumab (Biological), also known as NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal Bevacizumab Antibody: IV
• Tecemotide (Biological), also known as L-BLP25
• carboplatin (Drug), also known as CBDCA, paraplatin, JM-8, NSC 241240: IV
• cyclophosphamide (Drug), also known as Cytoxan, Neosar, CTX, CPM: IV
• paclitaxel (Drug), also known as taxol, NSC #673089: IV
• radiotherapy (Radiation): radiotherapy is given 5 days a week for 6½ weeks during concomitant chemoradiotherapy

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 18 Years to any

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 Exclusion Criteria:

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

Participant flow

Outcome results

• Proportion of Patients With Target Adverse Events for the Step 2 Treatment (Primary), Number, proportion of participants: Step 2 - Maintenance Therapy 0.03 (0.003 to 0.113)
• Overall Survival (Secondary), Median, months: Step 2 - Maintenance Therapy 42.7 (21.7 to 63.3)
• Progression-free Survival (Secondary), Median, months: Step 2 - Maintenance Therapy 14.9 (11.0 to 20.9)

Adverse events

Time frame: Assessed every 3 weeks while on treatment and for 30 days after the end of treatment, up to 5 years

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2014-12-08)

• Jyoti D. Patel, Study chair, Robert H. Lurie Cancer Center

NIH grants: U10CA180794