Phase I/II Study to Evaluate the Efficacy and Safety of a Combination Chemotherapy

Study design and methodology The study will have two phases.

The phase I will use traditional dose escalation model (3-6 patient per dose level) to
determine the maximum tolerated dose (MTD).

*[In phase II, either level III or (MTD) will be used in the same every 21 day cycle to
evaluate the efficacy and safety of the regimen in first line treatment of advanced NSCLC]*
not conducted.

Treatments administered

In phase I, three dose levels of weekly bortezomib will be studied in conjunction with fixed
dose carboplatin and bevacizumab on a 21 day cycle to define the maximum tolerated dose
(MTD).

A maximum of six cycles will be administered. Patients with complete response, partial
response or stable disease after six cycles will be allowed to continue on single agent
bevacizumab every 3 weeks as maintenance therapy until disease progression.

If no dose limiting toxicity (DLT) is observed in 3 patients during the first cycle, the next
dose level will be accrued. If 1 DLT is observed, 3 additional patients will be accrued to
the dose level. If no additional DLTs are observed, the next dose level will be accrued.
However, if 2 or more DLTs are observed in a given dose level, MTD will be defined. MTD will
be defined as the dose below which ≥2 DLTs were observed.

The following three levels will be studied:

Level I (every 21 day cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.3
mg/m2 D8 : bortezomib 1.3 mg/m2

Level II (every 21 day cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.6
mg/m2 D8 : bortezomib 1.6 mg/m2

Level III(every 21 day cycle):D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.8
mg/m2 D8 : bortezomib 1.8 mg/m2

If 2 or more DLT are observed in Level 1, level -1 will be accrued.

Level -1: (every 21 day cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1
mg/m2 D8: bortezomib 1 mg/m2

*[In phase II, either level III or the MTD dose level will be used in the same every 21 day
cycle to evaluate the efficacy and safety of the regimen in first line treatment of advanced
NSCLC.

Efficacy data collected

The following evaluations will be conducted to assess the efficacy of the combination:

- response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria

- disease free and overall survival, time to progress (TTP) and duration of response
Safety data collected

The following evaluations will be conducted to assess the safety of the combination
chemotherapy:

• toxicity based on National Cancer Institute-Common Terminology Criteria for Adverse Events
(NCI-CTCAE) version 3.0]* Not conducted

Statistical procedures

In phase I portion, 9-18 patients will be enrolled. The patients treated at recommended dose
level for phase II will also be eligible for response evaluation as part of phase II.

*[The primary objective of the phase II study is to estimate the efficacy and safety of the
combination therapy with carboplatin, bortezomib and bevacizumab as the first line therapy in
patients with advanced NSCLC. The primary endpoints are response rate and progression-free
survival (PFS).

(NOT CONDUCTED) In phase II portion, the optimal two-stage design for phase II clinical
trials described by Simon et al. will be utilized.

Overall survival, progression free survival and time to progression will be estimated using
Kaplan-Meier methods. Time to progression, progression free survival and survival will be
calculated from the date of study entry.]* (Phase II not conducted.)

Inclusion Criteria:

- Histologically confirmed SCLC (adeno- and large cell, anaplastic carcinoma and
broncho-alveolar-carcinoma). Patients with squamous-cell histology are eligible with
extra thoracic or peripheral lung lesions only.

- Sputum cytology alone not acceptable evidence of cell type. Cytologic specimens
obtained by brushing, washings, or needle aspiration of defined lesions will be
acceptable. Mixed tumors will be categorized by the predominant cell type unless a
small cell anaplastic elements are present, in which case the patient is ineligible.

- Stage III B because of pleural effusion or Stage IV disease

- Measurable disease.

- Age: 18 years or older

- No history of thrombotic, hemorrhagic, or coagulopathy disorders

- international normalized ratio (INR<1.5) and a prothrombin time (PTT) no greater than
normal limits of normal within 1 week prior to registration. NB: subjects with lung
cancer placed on anticoagulant therapy for a thrombotic event are not eligible for
this study.

- No gross hemoptysis (defined as bright red blood of ½ teaspoon or more)

- No central nervous system (CNS) or brain metastasis

- Laboratory Criteria (completed <2 weeks before enrollment):

- Hematologic: white blood cell (WBC) > 3500/mm3 or absolute neutrophil count (ANC)
> 1500/mm3 and platelet count > 100 000/ mm3;

- Hepatic: Total bilirubin < 1.5 mg/dl

- Renal: Creatinine < 1.5 mg/dl. or calculated

- Creatinine clearance > 45 ml/min (NB: Urine protein:creatinine ratio in exclusion
criteria)

- Eastern Cooperative Oncology Group (ECOG) performance status < 2

- Be free of active infection.

- Be available for active follow up.

- No prior chemotherapy for metastatic disease.

- Be disease free for > 5 years if they had a prior second malignancy other than treated
basal cell carcinoma or squamous cell skin cancer, or carcinoma in situ of the cervix.

- Female subject post-menopausal; surgically sterilized or willing to use an acceptable
method of birth control for the duration of the study. Male subject agrees to use an
acceptable method for contraception for the duration of the study.

Exclusion Criteria:

- CNS or brain metastasis

- Patient has = or greater Grade 2 peripheral neuropathy within 14 days before
enrollment.

- Known previous sensitivity reactions with boron, or mannitol,

- Patients with known HIV positivity

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

- Blood pressure of >150/100 mmHG

- History of myocardial infarction or stroke within 6 months

- Clinically significant peripheral vascular disease

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

- Minor surgical procedure such as fine needle aspirations or core biopsies within 7
days prior to day 0

- Urine protein: Creatinine ratio > 1.0 at screening

- History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess
within 6 months prior to Day 0

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

- Lung carcinoma or any histology in close proximity to a major vessel or cavitation

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant. Pregnancy testing is not required for post-menopausal or surgically
sterilized women.

- Patient has received other investigational drugs with 14 days before enrollment or is
expected to participate in an experiment drug study during this study treatment.

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