Carboplatin and Paclitaxel With or Without Vorinostat in Treating Patients With Advanced Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To compare progression-free survival associated with the combination of carboplatin,
paclitaxel and vorinostat versus carboplatin, paclitaxel and placebo for patients with
previously untreated, advanced NSCLC.

SECONDARY OBJECTIVES:

I. To determine the response rate, time to treatment failure, and overall survival for the
two regimens.

II. To assess the safety profile of the regimen of vorinostat, carboplatin and paclitaxel
for patients with advanced NSCLC.

III. To understand the mechanistic aspects of drug effect by conducting correlative science
studies on peripheral blood and archived tumor tissue.

An initial safety run-in study is planned (phase I) before starting the phase II randomized
study as described below. Doses of Vorinostat to be tested during the safety run-in portion
are: Dose Level -1 500 mg QD, Dose Level 1 600 mg QD, Dose Level 2 800 mg QD. Patients will
not be randomized during the safety lead-in period, and no patients treated during the
lead-in will be considered in the primary evaluation of each arm in any comparison. Once the
safety run-in portion is completed, all patients will randomized to receive either placebo
or vorinostat at a fixed dose determined during the run-in portion.

Phase II Portion of Study:

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel IV over 3 hours, and carboplatin IV over 30 minutes on
day 0. Patients also receive vorinostat orally (PO) once daily on days -2 to 2.

ARM II: Patients receive paclitaxel and carboplatin as in arm I. Patients also receive
placebo PO once daily on days -2 to 2.

In both arms, treatment repeats every 21 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, quarterly for 1
year, and then twice a year thereafter.

Inclusion Criteria:

- Patients must have histologically confirmed non-small cell lung cancer

- No prior chemotherapy for advanced or metastatic disease

- ECOG performance status 0 or 1

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral CT scan

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy in a metastatic setting

- Patients may not be receiving any other investigational agents

- Patients with untreated brain metastases should be excluded from this clinical trial;
however, patients who have stable brain disease (should be off corticosteroids) at
least 3 weeks after completion of appropriate therapy are eligible

- Patients who have received any prior HDAC inhibitor (except valproic acid for seizure
control provided that the valproic acid has been stopped at least 30 days before
beginning therapy on this protocol) are excluded from this study

- Peripheral neuropathy of severity greater than grade 1

- Known history of allergic reactions to paclitaxel

- Prior therapy with paclitaxel

- Inability to take oral medications on a continuous basis; patients unable to swallow
the vorinostat capsules whole are ineligible (the capsules cannot be crushed or
broken)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with vorinostat; women of childbearing potential must use an
appropriate double barrier method of birth control (such as female use of a
diaphragm, intrauterine device [IUD], sponge and spermicide, in addition to the male
use of a condom) or a prescribed birth control implant or practice abstinence; both
double barrier contraception and implants must be used for at least one week prior to
the start of the research study and continue for at least two weeks following the
last study visit; please note that birth control pills should not be used while on
this study as they may have a negative interaction with the experimental drug in this
study

- HIV-positive patients receiving combination antiretroviral therapy are ineligible