Carboplatin and Etoposide in Combination With Vorinostat for Patients With Extensive Stage Small Cell Lung Cancer

Vorinostat inhibits growth and induces apoptosis in various human carcinoma cells.
Furthermore, it affects the expression of various genes that are necessary for proliferation
of cancer cells. Vorinostat also appears to block angiogenic signaling. Pre-treating four
human cancer cell lines (including a brain tumor line) with vorinostat increased the killing
efficiency of etoposide, ellipticine, doxorubicin, or cisplatin, but not of the topoisomerase
I inhibitor camptothecin 13. Topoisomerase II is a ubiquitous nuclear enzyme that is involved
in DNA replication, transcription, chromosome segregation, and apoptosis. It is the target
for several anti-cancer drugs including etoposide. Treatment with HDAC inhibitors induces
expression of topoisomerase II in cancer cells and enhances the sensitivity to etoposide 14.

Early phase clinical trials have demonstrated single agent anti-cancer activity with
vorinostat. In our study, combination of vorinostat with carboplatin and paclitaxel,
demonstrated promising anticancer activity against NSCLC, including histological subsets of
patients whose tumors demonstrated neuroendocrine differentiation 8. For all these reasons,
vorinostat is a rational choice to combine with the regimen of carboplatin and etoposide for
evaluation in patients with SCLC-ED.

Inclusion Criteria:

- Histologically or cytologically confirmed small cell lung cancer.

- 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 CT scan.

- Patients must be chemotherapy naive.

- Previous radiotherapy is allowed only if < 30% of marrow bearing bones were irradiated
and if radiotherapy was completed at least 2 weeks prior to enrollment and the patient
has recovered from all adverse effects of prior radiotherapy.

- Age >18 years.

- Life expectancy of greater than 3 months.

- ECOG performance status <2 (Karnofsky >60%).

- Adequate organ and marrow function.

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or double barrier method of birth control) prior to study entry and for the
duration of study participation.

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

- Both men and women of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

- Patients who have had chemotherapy or any other investigational agent for any
indication within 30 days of study enrollment.

- Patients who have had radiotherapy within 2 weeks, prior to entering the study or
those who have not recovered from adverse events due to these therapies.

- Patients with known brain metastases are excluded.

- Patients who have been previously treated with an HDAC inhibitor (use of valproic acid
is allowed with a 30-day washout).

- Patients with peripheral neuropathy CTC grade >2 are excluded.

- 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.

- Any major surgery within 2 weeks prior to enrollment. Minimally invasive procedures
for the purpose of diagnosis or staging of the disease are permitted.

- History of another malignancy in the last 5 years. Patients with prior history of in
situ cancer, basal or squamous cell skin cancer are eligible. Patients with other
malignancies are eligible if they were cured by surgery alone and have been
continuously disease free for at least 5 years.

- Pregnant women are excluded from this study because irinotecan and paclitaxel are
antineoplastic agents with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with agents used in this trial, breastfeeding
should be discontinued if the mother is treated with these agents.

- Patients with known HIV, Hepatitis B, Hepatitis C or active Hepatitis A are excluded.

- Patients on any systemic steroids for any indication, with doses that have not been
stabilized to the equivalent of < 10 mg/day prednisone during the 30 days prior to
study enrollment. This does not include short courses of steroids administered at high
doses.

- Patients with the inability to absorb oral vorinostat.

- Patients with known allergy or hypersensitivity to any component of any of the study
therapies.