A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers

BACKGROUND:

- The histone deacetylase (HDAC) inhibitors are a novel class of anticancer agent. These
agents lead to the increased acetylation of both histone and non-histone proteins, which
leads to rapid cell death in many tumor models. It is thought that the cell death
observed with this class of agents may be mediated, in part, through the selective
acetylation of histone proteins resulting in increased expression of specific genes.

- For solid tumors in general, cell death in preclinical models has not translated to
activity in patients. For this reason, studies increasingly have combined chemotherapy
with HDAC inhibitors to achieve additive and potentially synergistic effects on cancer
cells.

- This protocol will study a continuous infusion of the HDAC inhibitor belinostat in
combination with cisplatin and etoposide for patients with advanced cancer.

OBJECTIVES:

- To determine a safe and tolerable phase 2 dose for the combination of belinostat with
cisplatin and etoposide.

- Evaluate molecular markers of HDAC inhibition.

- To explore the results of administering the dose of belinostat based on the patients'
UGT1A1 *28 or *60 genotype, which is a characteristic that may be associated with
toxicity.

ELIGIBILITY:

- The protocol will be open to all patients with recurrent or advanced cancer (small-cell
lung cancer and other advanced cancers) for whom standard therapy offers no curative
potential.

- Age greater than or equal to 18 years

- ECOG Performance Status 0-2

DESIGN:

- The study will begin with belinostat 400 mg/m (2)/24h administered by continuous IV
infusion on days 1 and 2, cisplatin at 60 mg/m(2) IV on day 2, and etoposide at 80 mg/
(2) IV daily times 3 on days 2 - 4. Dose escalation of belinostat will follow according
to traditional 3 patient cohorts.

- With Amendment M, dosing will be based on UGT1A1 status, at either 400 mg/m(2) or

600 mg/m(2)

-INCLUSION CRITERIA:

1. Patients must have histologic or cytologic confirmation of cancer for which there is
no known standard therapy capable of extending life expectancy.

2. Patients must be greater than or equal to 4 weeks from cytotoxic chemotherapy, except
greater than or equal to 6 weeks for mitomycin C or nitrosoureas, and greater than or
equal to 8 weeks from prior UCN01; greater than or equal to 4 weeks from monoclonal
antibody therapy (cetuximab, bevacizumab); greater than or equal to 4 weeks from prior
experimental therapy; greater than or equal 2 weeks from radiation or hormonal
therapy; greater than or equal to 2 weeks from sorafenib, sunitinib or temsirolimus
treatment. Patients with prostate cancer may continue ongoing LhRH agonist therapy.
Patients with bone metastases or hypercalcemia who began intravenous bisphosphonate
treatment prior to study entry may continue this treatment while on study.

3. ECOG performance status 0-2.

4. Life expectancy of 3 months or greater.

5. Patients must have acceptable organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/ mm(3)

- platelets greater than or equal to 100,000/ mm(3)

- total bilirubin less than or equal to 1.2 mg/dL (except patients with Gilbert's
Syndrome)

- AST (SGOT) and ALT(SGPT) less than or equal to 2.5 times institutional upper
limit of normal

- creatinine less than or equal to 1.5 times institutional upper limit of normal

OR

- creatinine clearance >50 mL/min/1.73 m(2) for patients with creatinine levels above
institutional normal.

6. 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, during
the study, and for 3 months after study participation. Should a woman become pregnant
or suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.

7. Age greater than or equal to 18 years.

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

9. Willing to comply with study procedures and follow-up.

EXCLUSION CRITERIA:

1. Patients who have not recovered (CTCAE less than or equal to grade 1) from adverse
events due to prior treatments, except for alopecia or base stable grade 2 tinnitus
(not interfering with ADL s) or stable grade 2 sensory neuropathy without pain or
motor component, and not interfering with ADL s.

2. Patients may not have received more than 2 prior cytotoxic regimens.

3. Patients may not be receiving any other investigational agent with therapeutic
anticancer intent.

4. Patients may not have taken another histone deacetylase inhibitor (i.e. valproic acid,
vorinostat) for at least 2 weeks prior to enrollment.

5. Patients with history of CNS metastasis may not be enrolled on the study, unless
control has been achieved with either radiation or surgical resection at least 3
months prior to enrollment on study.

6. Patients who have had radiation to the pelvis or other bone marrow-bearing sites will
be considered on a case by case basis and may be excluded if the bone marrow reserve
is not considered adequate (>25% of bone marrow).

7. Uncontrolled medical illness including, but not limited to ongoing or active
infection, chronic or acute hepatitis, renal failure, symptomatic congestive heart
failure, myocardial infarction unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements.

8. HIV-positive patients.

9. Patients with acute or chronic hepatitis.

10. Pregnant patients may not receive this experimental therapy.

11. Significant cardiovascular disease, myocardial infarction within the past 6 months,
unstable angina, unstable arrhythmia or a need for anti-arrhythmic therapy (use of
medication to control heart rate in patients with atrial fibrillation is allowed, if
stable medication for at least last month prior to randomization and medication not
listed as causing Torsade de Points), or evidence of acute ischemia on ECG.

12. Baseline prolongation of QT/QTc interval, i.e., defined as an average QTc interval >
450 msec; Long QT Syndrome; or the required use of concomitant medication that may
cause Torsade de Pointes.