Suberoylanilide Hydroxamic Acid in Treating Patients With Stage IIIB, Stage IV, or Recurrent Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To evaluate the response of non-small cell lung cancer to SAHA in the second line setting
by applying RECIST criteria.

SECONDARY OBJECTIVES:

I. To estimate the time to progression and overall survival in this patient population.

II. To examine the toxicity profile of SAHA.

TERTIARY OBJECTIVES:

I. To evaluate the molecular activity of SAHA by evaluating its effect on histone
acetylation, upregulation of target genes, generation of reactive oxygen species, apoptosis
and correlation with P53 status.

II. To explore gene expression profiles that predict response to SAHA.

OUTLINE: This is a multicenter study.

Patients receive oral suberoylanilide hydroxamic acid once daily on days 1-14. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 1 month and then every 3 months
for 1 year or until disease progression.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed non-small cell lung
carcinoma, Stage IV (distant metastases), stage IIIB with malignant pleural effusion,
or recurrent disease

- 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

- Prior therapy: no more than 1 prior cytotoxic chemotherapy regimen for their Stage
IIIB/IV or recurrent disease; no previous irradiation to the only area of measurable
disease, unless that site had subsequent progression of disease; radiation therapy
must be completed at least 3 weeks prior to initiating study drug

- Stage IV patients with brain metastases are eligible providing the brain metastases
are clinically and radiologically stable 4 weeks after treatment with surgery and/or
radiation therapy, and they are not taking steroids

- Life expectancy greater than 3 months

- ECOG performance status 0 or 1 (Karnofsky >= 70%)

- Patients must have normal organ and marrow function as defined below:

- 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

- Peripheral neuropathy =< grade 1

- Caution needs to be exercised when using SAHA with medications or substances known to
affect or with the potential to affect the activity or pharmacokinetics of SAHA; since
grapefruit juice is known to interact with the CYP450 enzymes, it is recommended that
patients abstain from consuming grapefruit, grapefruit juice, and other grapefruit
containing products during this study

- The effects of SAHA on the developing human fetus at the recommended therapeutic dose
are unknown; for this reason and because HDAC inhibitors are known to be teratogenic,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

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

- Patients should not have taken valproic acid, another histone deacetylase inhibitor,
for at least 2 weeks prior to enrollment

Exclusion Criteria:

- Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) or radiotherapy within 3 weeks prior to entering the study

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to SAHA

- Any other active malignancy in the past 5 years except non-melanoma skin cancers

- 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

- Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with SAHA, breastfeeding should be discontinued
if the mother is treated with SAHA

- HIV-positive patients receiving combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with SAHA; in addition,
these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy; appropriate studies will be undertaken in patients
receiving combination anti-retroviral therapy when indicated