Bortezomib (PS-341) in Combination With Carboplatin and Docetaxel for Patients With Advanced Non-Small Cell Lung Cancer

A chemotherapy efficacy plateau' has been reached for the treatment of patients with advanced
or metastatic non-small cell lung cancer. Platinum-based two-drug combination is considered
the current standard of care for the treatment of advanced NSCLC. There is a need to develop
novel regimens to improve the outcome for patients with advanced NSCLC. The combination of
carboplatin and docetaxel is effective for therapy of advanced NSCLC. This combination
results in improved survival and quality of life for patients with advanced NSCLC. Docetaxel
exhibits preclinical synergy with bortezomib. Hence we plan to perform a phase I/II study to
define the maximum tolerated dose of bortezomib that can be administered in combination with
docetaxel and carboplatin and subsequently evaluate the efficacy of the regimen for patients
with advanced NSCLC.

Inclusion Criteria:

- Histologically/cytologically confirmed stage IIIB (pleural or pericardial effusion) or
stage IV NSCLC

- Age > 18 years

- ECOG PS < 2

- No prior chemotherapy

- Measurable disease

- Signed informed consent

- Adequate bone marrow function

- Adequate renal function

- Adequate hepatic function

Exclusion Criteria:

- Untreated clinically active brain metastasis

- Radiotherapy within 2 weeks prior to initiation of protocol therapy

- Treatment with any investigational therapy within 4 weeks prior to enrollment

- History of any cancer other than NSCLC (except non-melanoma skin cancer or carcinoma
on situ of the cervix) within the last 5 years

- Patients in their reproductive age group should use an effective method of birth
control. Men and women of childbearing potential must be willing to consent to using
effective contraception while on treatment and for at least 3 months thereafter.
Patients who are breast-feeding will be excluded from the study. Women of childbearing
potential must have a negative pregnancy test.

- Major surgery within 3 weeks prior to enrollment

- Use of immunosuppressive agents including systemic corticosteroids within 4 weeks
prior to enrollment (corticosteroids are permitted as physiological replacement
therapy or as supportive care for nausea and emesis)

- Known history of Human immunodeficiency virus infection

- Any co-morbidity or condition of sufficient severity to limit full compliance with the
protocol per assessment by the investigator

- Concurrent serious medical infection or illness, or psychiatric illness likely to
interfere with participation in this clinical study.

- History of known hypersensitivity to docetaxel or other drugs formulated with
polysorbate 80, bortezomib, boron or mannitol

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

- Myocardial infarction within 6 months prior to enrollment or has New York Hospital
Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
of acute ischemia or active conduction system abnormalities. Prior to study entry, any
ECG abnormality at Screening has to be documented by the investigator as not medically
relevant.