Phase I-II Study of Avastin®+ Bortezomib for Patients With Recurrent or Refractory Non-Squamous NSCLC

Inclusion Criteria:

1. Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

2. Female subject is either post-menopausal (Postmenopausal women must be amenorrheic
for at least 12 months to be considered of non-childbearing potential) or surgically
sterilized or willing to use an acceptable method of birth control (i.e. a hormonal
contraceptive, intra-uterine device, diaphragm with spermicide, condom with
spermicide, or abstinence) for the duration of the study. Male subject agrees to use
an acceptable method for contraception for the duration of the study.

3. All patients must have an Eastern Cooperative Oncology Group (ECOG)Performance Status
of 0 - 2

4. Patients must have histologically or cytologically proven selected Stage IIIB (T4
lesion due to malignant pleural or pericardial effusion) or Stage IV advanced
non-small cell lung cancer or recurrent disease after previous surgery and/or
radiation.

5. No history of or active brain metastases

6. Patients must have measurable disease documented by computed tomography (CT) or
magnetic resonance imaging (MRI). Measurable disease must be assessed within 28 days
prior to registration. Pleural effusions, ascites and laboratory parameters are not
acceptable as the only evidence of disease.

7. Recurrent or progressive cancer can be within a previously radiated site

8. Patients must have received one or two prior systemic therapies, one of which
contained a platinum compound. No prior Bortezomib or antiangiogenic agent is
permitted. Prior radiation is permitted; however, at least two weeks must have
elapsed since the completion of prior radiation therapy and patients must have
recovered from all associated toxicities at the time of registration. At least two
weeks must have elapsed since surgery (thoracic or other major surgeries) and
patients must have recovered from all associated toxicities at the time of
registration.

9. Patients must have a serum creatinine (i.e. 1.5 mg/dL) AND a creatinine clearance >/= 40 cc/min determined by either urine
collection and testing or calculation using the following formula: Calculated
Creatinine Clearance = (140 - age) * Weight(kg) * (0.85 if female)/ 72 * creatinine
(mg/dL)

10. Patients must have an Absolute neutrophil count (ANC)>/= 2,000/µl and platelet count
>/= 100,000/µl obtained within 28 days prior to registration. Hemoglobin: >9.0 *
10^9/L

11. Patients must have adequate hepatic function documented by a serum bilirubin institutional upper limit of normal (1.0) and liver enzymes (serum glutamic
oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT)) 3.0 * the institutional upper limit of normal obtained within 28 days prior to
registration

12. Peripheral neuropathy, if present, must be < Grade 2 (NCI Common Terminology Criteria
for Adverse Events Version 3.0).

13. Patients known to be HIV-positive and taking HAART therapy are not eligible due to
possible pharmacokinetic interactions

14. Patients must not be planning to receive any other concomitant anticancer treatment
including chemotherapy, radiation therapy, biologic agents or any other
investigational drugs

15. Patient must be >/= 18 years of age.

16. Patients must be informed of the investigation nature of this study and must sign and
give written informed consent in accordance with institutional and federal
guidelines.

Exclusion Criteria:

1. Patients meeting any of the following exclusion criteria are not to be enrolled in
the study. Participation in an experimental drug study within 4 weeks of the first
treatment on this trial: Blood pressure > 140/90 mm Hg, History of stroke within 6
months, Clinically significant peripheral vascular disease, Evidence of bleeding
diathesis or coagulopathy, Presence of central nervous system or brain metastases

2. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 0, or anticipation of need for major surgical procedure during the
course of the study.

3. Minor surgical procedures such as fine needle aspirations or core biopsies within 7
days prior to Day 0

4. Urine protein: creatinine ratio >/= 1.0 at screening

5. Serious non-healing wound, ulcer, or bone fracture

6. Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class II or heart failure, unstable angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities. Prior to study entry, and ECG abnormality at
Screening has to be documented by the investigator as not medically relevant

7. Patients with squamous histology

8. Patients with hematemesis or more than ½ teaspoon of hemoptysis within 6 months of
study entry.

9. Patients requiring full dose oral or parenteral anticoagulation.

10. Abdominal fistula, GI perforation, or abdominal abscess within the last 6 months

11. Patient has hypersensitivity to boron or mannitol

12. Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum beta-human chorionic gonadotropin
(beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
required for post-menopausal or surgically sterilized women. Patient has received
other investigational drugs within 28 days before enrollment

13. Serious medical or psychiatric illness likely to interfere with participation in this
clinical study

14. No other prior or concurrent malignancy is allowed except for: non-melanoma skin
cancers, in situ cervical cancer, and any cancer from which the patient has been
disease-free for 3 years or more.

15. Pregnant or nursing women may not participate in this trial because of the increased
risk of fetal harm including fetal death from the chemotherapeutic agents. Women/men
of reproductive potential may not participate unless they have agreed to use an
effective contraceptive method.

16. Patients requiring treatment with Nonsteroidal anti-inflammatory drugs (NSAIDS),
antiplatelet agents, or aspirin > 325 mg/day