E6508: A Phase II Study of L-BLP25 and Bevacizumab in Unresectable Stage IIIA and IIIB Non-Squamous Non-Small Cell Lung Cancer after Definitive Chemoradiation

Summary

This is a phase ii study of L-BLP25 and Bevacizuman after difinitive chemoradiation.
The study consists of:

Concomitant Chemoradiation
-Paclitaxel: once per week for 6 weeks
-Carboplatin: infused once per week for 6 weeks (immediately following paclitaxel)
-Definitive Radiation: 5 days a week (Mon-Fri) for 6.5 weeks

Patients will be elavuated. Consolidation chemotherapy will be administered for 2 cycles. Patient must start Consolidation Chemotherapy within 4 weeks of completing Concomitant Chemoradiation or the patient's protocol treatment will be discontinued.


Step 1 x Consolidation Chemotherapy (Cycles 1 and 2)
1 Cycle [?] 21 days.

Consolidation Chemotherapy:
- Paclitaxel 225 mg/m2 iV over 3 hours on day 1.
- Carboplatin auC 6 iV 15-30 minute infusion on day 1, immediately following paclitaxel.

all patients with CR, PR, or SD at evaluation at end of Consolidation Chemotherapy may be
registered to Step 2 (Maintenance Therapy). Patients with progressive disease or whose
response is unevaluable will discontinue protocol treatment.

Step 2 x Maintenance Therapy (Cycles 1, 2, 3,[?]for up to 34 cycles) 1 Cycle [?] 21 days.

Maintenance therapy will continue for a maximum of 34 cycles or until PD or unacceptable toxicity. Patients must be registered to Maintenance Therapy (Step 2) within 7 days of completing Consolidation Chemotherapy (Step 1).

Patients on Step 2 Will Receive the Following:
- Cyclophosphamide 300 mg/m2 (600 mg maximum) iV over 15 -30minutes x 3 days prior to day 1 of Cycle 1 only.
- Bevacizumab 15 mg/kg iV on day 1 of each cycle.
(a urine dipstick should be performed at baseline then prior to every other course of bevacizumab. Treatment may proceed if dipstick result is 0 x1+. if the result of urine protein dipstick is [Greater Than] 1+, 24 hour urine for protein must be
obtained)
- L-BLP25 Vaccine 806 ug subcutaneously:
-Days 1, 8, and 15 of cycles 1 and 2 then
- Day 1 of cycles 4, 6, 8, [?] (every other cycle)

Participant Eligibility

1. Patients must have newly diagnosed histologically confirmed non-squamous nonsmall
cell lung cancer (adeno, large cell undifferentiated, bronchoalveolar, and nonsmall
cell carcinoma NOS).
2. Patients must be without significant pleural effusion and have either unresectable
Stage IIIA disease or Stage IIIB disease (TNM staging system AJCC V7).
-
* Unresectable
* Stage IIIA = Stage IIIA patients with mediastinal lymph node enlargement of > 1 cm but < 2.0 cm on CT scans must have these nodes biopsied (pathologic confirmation) to rule out resectability. These staging procedures are not mandatory for patients with obvious nodal involvement (obvious nodal involvement >= 2cm). Patients with stage IIIA must not have
significant pleural effusion.
- All patients with stage IIIB disease (without significant pleural effusion) will be eligible. This includes patients with metastases to contralateral mediastinal or supraclavicular nodes.
- To be eligible patients with either unresectable Stage IIIA disease or Stage IIIB disease must not have significant pleural effusion. Patients without significant pleural effusion will constitute those in whom:
1) pleural effusion is seen on CT scan only (not seen on CXR) or
2) pleural effusion does not reaccumulate after one thoracentesis and is cytologically negative.
o If pleural effusion is seen on CT scan, a CXR must be done.
- If pleural effusion is seen on CT scan only, and not seen on CXR, patient is eligible.
- If pleural effusion is seen on CT scan, and seen on CXR, thorocentesis must be done.

* If fluid does not reaccumulate within 1 week after thoracentesis, cytology must be done:
- If cytologically negative, patient is eligible.
- If cytologically positive, patient is not eligible.

* If fluid does reaccumulate within 1 week after thorocentesis,
patient is not eligible.

* Does patient have either unresectable Stage IIIA disease or Stage IIIB disease
o If Stage IIIA with mediastinal lymph node enlargement between 1 and 2.0 cm, have nodes been biopsied to rule out resectability?

* Is patient without significant pleural effusion?
o If pleural effusion was seen on CT scan, was pleural effusion seen on CXR?
- If pleural effusion was seen on CT scan and CXR after thorocentesis was done, did fluid reaccumulate within 1 week?
o If, after thorocentesis was done and fluid did not reaccumulate
within 1 week, was cytologic result negative?
3. Patients must have measurable or non-measurable disease, as defined by RECIST
(see Section 6). Baseline measurements/evaluations of all sites of disease must be
obtained within 4 weeks prior to registration.
4. Patients must not have CNS metastases. A head CT or MRI is required within 4
weeks prior to registration for evaluation.
5. Patients must have ECOG performance status of 0-1.
6. Patients must have no other active malignancies.
7. Patients must be > 18 years of age.
8. Required bone marrow function laboratory values (obtained within 4 weeks prior to
registration):
- WBC > 4000/mm3 or ANC > 2000/mm3
- Platelets > 140,000/mm3
- Hemoglobin > 9.0 g/dL
9. Required liver function laboratory values (obtained within 4 weeks prior to
registration):
- Total bilirubin < 1.5 mg/dL
- SGOT (AST) < 2.5 times the Institutional upper limit of normal.
- SGPT (ALT) <= 2.5 times the Institutional upper limit of normal.
10. Required renal function laboratory values (obtained within 4 weeks prior to registration):
- 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.
Urine protein value by urine dipstick <= 0 x 1+ ?
11. Patients may be on a stable regimen of therapeutic anticoagulation or may be receiving prophylactic anticoagulation of venous access devices, provided that coagulation studies met entry criteria. Caution must be exercised for patients requiring anticoagulation, including treatment with low dose heparin or low molecular weight heparin for DVT prophylaxis while on study due to an increased risk of bleeding with bevacizumab.
12. Required Coagulation laboratory values (obtained within 4 weeks prior to registration):
- INR <= 1.5, or, if patient is on therapeutic anticoagulation, INR <= 3.0.
- A PTT no greater than institutional upper limits of normal
3.1.13 Patients must not have had prior chemotherapy or monoclonal antibodies for other cancers within 5 years prior to registration.
14. Patients must not have had prior chemotherapy for lung cancer.
15. Patients must not have had prior chest radiation.
16. Patients must not have ongoing (lasting > 14 days) or active infection, ongoing (lasting > 14 days) fever within 6 months prior to registration.
17. Patients must not have a history of gross hemoptysis (>= grade 2; defined as bright red blood of a [(1/2] teaspoon or more) within 3 months prior to registration. If a patient has hemoptysis, the source of hemoptysis should be confirmed; extrapulmonary hemoptysis is allowable, pulmonary hemoptysis is not.
If patient has hemoptysis, has it been confirmed that the hemoptysis is extrapulmonary?
18. Patients must not have Grade 2 or greater bleeding or any bleeding requiring intervention. Patients must have no history of bleeding diathesis or coagulopathy.
19. Patients must not have any of the following:
- Clinically significant cardiovascular disease
- Previous myocardial infarction within 6 months prior to registration
- New York Heart Association (NYHA) > class II congestive heart failure
- Unstable angina pectoris
- Serious cardiac arrhythmia requiring medication within 4 weeks of registration
- History of stroke within 6 months prior to registration
- Any prior history of hypertensive crisis or hypertensive encephalopathy
- History of TIA within 6 months prior to registration
20. Patients must not have had any of the following within 6 months prior to registration: grade 2 or greater peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess.
21. Patients must not have psychiatric illness/social situations that would limit compliance with study requirements.
22. Patients with a history of hypertension must be well-controlled (< 150/100) on a stable regimen of anti-hypertensive therapy.
23. Patients must not have had any of the following within 4 weeks prior to registration: a significant traumatic injury, a serious non-healing wound, ulcer, bone fracture, open biopsy, or major surgical procedure.
24. Patients must not have any anticipated major surgical procedure(s) during the course of the study.
25. Patients receiving daily treatment with aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory agents (NSAIDS) known to inhibit platelet function are not eligible. Treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal) is also not allowed.
26. Patient must not have a recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia, or presence of hereditary or congenital immunodeficiencies.
27. Patient must not have any preexisting medical condition requiring chronic steroid or immunosuppressive therapy.
28. Patient must not have any autoimmune disease.
29. Patient must not have known Hepatitis B or C.
30. Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk from bevacizumab. It is also unknown if these agents are excreted into breast milk.
-All females of childbearing potential must have a blood or urine test within 2 weeks prior to Step 1 registration to rule out pregnancy.
31. Women of childbearing potential and sexually active males must agree to use an accepted and effective method of contraception (hormonal or barrier methods, abstinence) prior to study entry, during study treatment and for at least 6 months after completion of bevacizumab.
32. Patients who received immunotherapy (e.g. interferon, interleukins, GM-CSF, G-CSF) within 28 days prior to registration are not eligible for this study.
33. No prior splenectomy allowed.
34. Patients must not have any known hypersensitivity to any component of bevacizumab.
35. Patient must not have a core biopsy or any other minor surgical procedure, excluding the placement of a vascular access device, <= 7 days prior to registration.