High-Dose or Low-Dose Vorinostat in Combination With Carboplatin or Paclitaxel in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To determine whether high dose, short course vorinostat achieves higher peak serum
concentrations than standard dosing.

SECONDARY OBJECTIVES:

I. To determine the toxicity profiles of two different escalated intermittent dosing
schedules of vorinostat combined with carboplatin at an area under curve (AUC) of 5.

II. To describe the response rate in patients with advanced solid tumors treated with these
regimens.

III. To develop pharmacodynamic markers for vorinostat. IV. To determine the toxicity
profiles of escalated intermittent dosing schedule of vorinostat at 1200 mg combined with
paclitaxel at 175 mg/m^2 and to describe the response rate in patients with advanced solid
tumors treated with this regimen.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive high-dose vorinostat orally (PO) once daily (QD) on days 1-3 and
low-dose vorinostat PO QD on days 8-10 (course 1). After 5 days, patients receive high-dose
vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3 of all subsequent
courses.

ARM II: Patients receive high-dose vorinostat and low-dose vorinostat as in arm I. After 5
days, patients receive lower-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30
minutes on day 3 of all subsequent courses.

ARM III: Patients receive low-dose vorinostat PO QD on days 1-3 and high-dose vorinostat PO
QD on days 8-10 (course 0). After 5 days, patients receive vorinostat and carboplatin as in
Arm I.

ARM IV: Patients receive low-dose vorinostat and high-dose vorinostat as in Arm III. After 5
days, patients receive vorinostat and carboplatin as in Arm II.

ARM V: Patients receive low-dose vorinostat PO QD on days 1-3 and mid-dose vorinostat PO QD
on days 8-10 (course 0). After 5 days, patients receive mid-dose vorinostat PO QD on days 1-3
and paclitaxel IV over 3 hours on day 3.

ARM VI: Patients receive mid-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD
on days 8-10 (course 0). After 5 days, patients receive vorinostat and paclitaxel as in Arm
V.

In all arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study therapy, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which no superior curative or palliative measures are known

- At least 4 weeks must have passed since prior chemotherapy or radiation therapy; 6
weeks if the last regimen included BCNU or mitomycin C

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Life expectancy of greater than 3 months

- Leukocytes > 3,000/mcL

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Total bilirubin < institutional upper limits of normal

- Potassium < institutional upper limits of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal, or < 5 x ULN if liver metastases are
present

- 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 within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier
(except alopecia, lymphopenia, hyperglycemia, hypoalbuminemia and elevated serum
alkaline phosphatase); all other toxicities should have resolved to grade 1 or less
prior to beginning treatment

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases that are untreated or have progressed after
definitive therapy should be excluded from this clinical trial; patients with treated
brain metastases, who are no longer receiving steroids for at least 14 days, are not
receiving enzyme-inducing anti-epileptic drugs, and have no unstable neurologic
symptoms may be enrolled at the discretion and joint decision of the principal
investigator and treating physician

- Prior or current use of valproic acid, a histone deacetylase (HDAC) inhibitor

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to paclitaxel, vorinostat or carboplatin

- Inability to swallow oral medications

- 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

- Women that are pregnant or breastfeeding are excluded from this study; all women of
child-bearing potential must have a negative pregnancy test before receiving
vorinostat; women of child-bearing potential and men must agree to use adequate
contraception for the duration of the study; breastfeeding should be discontinued if
the mother is treated with vorinostat; these potential risks may also apply to other
agents used in this study; subjects that become pregnant or think they may be pregnant
while taking part in this study should notify their treating physician immediately

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated