Capecitabine and Vorinostat in Treating Patients With Recurrent and/or Metastatic Head and Neck Cancer

PRIMARY OBJECTIVES:

I. To determine the objective response rate (complete and partial) and duration of response
of the combination of vorinostat and capecitabine in patients with recurrent and/or
metastatic squamous cell carcinoma of the head and neck (SCCHN). (SCCHN) II. To determine
the objective response rate (complete and partial) and duration of response of the
combination of vorinostat and capecitabine in patients with recurrent and/or metastatic
nasopharyngeal carcinoma (NPC). (NPC)

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of the combination of vorinostat and capecitabine
in patients with recurrent and/or metastatic SCCHN. (SCCHN) II. To determine the rate of
progression-free survival (PFS) at 6 months. (SCCHN) III. To determine the rate and duration
of stable disease (SD). (SCCHN) IV. To determine the median PFS, and the rate of PFS at 1
year. (SCCHN) V. To determine the median overall survival (OS), and rates of overall
survival at 6 months and at 1 year. (SCCHN) VI. To evaluate the safety and tolerability of
the combination of vorinostat and capecitabine in patients with recurrent and/or metastatic
NPC. (NPC) VII. To determine the duration of objective response. (NPC) VIII. To determine
the rate and duration of stable disease (SD). (NPC) IX. To determine the median PFS, and the
rate of PFS at 1 year. (NPC) X. To determine the median overall survival (OS), and rates of
overall survival at 6 months and at 1 year. (NPC)

OUTLINE: This is a non-randomized, open-label study of patients with SCCHN and NPC (Stage
I), followed by a randomized study of patients with NPC (Stage II).

STAGE I: Patients receive capecitabine orally (PO) twice daily (BID) and vorinostat PO daily
on days 1-14. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

STAGE II: Patients with NPC are randomized to 1 of 2 treatment arms.

ARM I: Patients receive capecitabine PO BID and vorinostat PO daily on days 1-14. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive capecitabine PO BID on days 1-14. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients will be followed up at 3-4 weeks and then
every 6 months for 1 year.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed SCCHN or NPC that is
recurrent and/or metastatic and that is not amendable to curative therapy by surgery
or radiation; SCCHN originating from the following sites are eligible: oral cavity,
oropharynx, larynx, hypopharynx and paranasal sinus are eligible; for patients with a
diagnosis of SCCHN of unknown origin, their eligibility must be reviewed and approved
by the principal investigator

- For patients with SCCHN, they may have received one prior targeted therapy for
recurrent or metastatic disease (excluding histone deacetylase [HDAC] inhibitors)
provided treatment is completed > 4 weeks prior to enrollment; they may have received
prior systemic chemotherapy (ie, induction, concurrent or adjuvant) for SCCHN as part
of the initial multimodality treatment for locally advanced disease if the
chemotherapy is completed > 6 months prior to enrollment; patients are not eligible
if they received fluorouracil (5-FU) or capecitabine previously as part of the
initial multimodality treatment

- Patients with NPC must have completed one prior chemotherapy regimen for recurrent or
metastatic disease at least 4 weeks prior to enrollment; in addition, they may have
received prior systemic chemotherapy (ie, induction, concurrent or adjuvant) for NPC
as part of the initial multimodality treatment for locally advanced disease if the
chemotherapy is completed > 6 months prior to enrollment; patients are eligible if
they received 5-FU as part of the initial multimodality treatment; patients are not
eligible if they received capecitabine previously

- 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 computed tomography (CT)
scan; indicator lesions must not have been previously treated with surgery, radiation
therapy or radiofrequency ablation unless there is documented progression after
therapy

- Patients must have completed any previous surgery or radiotherapy >= 4 weeks prior to
enrollment

- Previously treated patients must have evidence of progressive disease, either
clinically or radiographically, as assessed by the investigator

- Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%)

- Life expectancy of greater than 12 weeks

- Absolute neutrophil count >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Total bilirubin =< 1.25 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x ULN or =< 5 x ULN with documented liver metastases

- Creatinine =< 1.25 x ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients
with creatinine levels above 1.25 x ULN

- 12-lead electrocardiogram (ECG) with normal tracing, or non-clinically significant
changes that do not require medical intervention; corrected QT (QTc) interval < 470
msec, and without history of Torsades de Pointes or other symptomatic QTc abnormality

- Eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity of vorinostat will be determined following
review of their case by the principal investigator

- Women of childbearing potential and men must be surgically sterilized, practicing
abstinence, or agree to use 2 birth control methods prior to study entry and for the
duration of study participation; the 2 birth control methods can be either be 2
barrier methods or a barrier method plus a hormonal method to prevent pregnancy; the
following are considered adequate barrier methods of contraception: diaphragm or
sponge, and condom; other methods of contraception such as copper intrauterine device
or spermicide may be used; appropriate hormonal contraceptives will include any
registered and marketed contraceptive agent that contains an estrogen and/or a
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular
agents); 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 must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests and other study procedures

- Willingness to discontinue taking any medications that are generally accepted to have
a risk causing Torsades de Pointes during the study

Exclusion Criteria:

- Past or current malignancy other than SCCHN or NPC, except for:

- Cervical carcinoma Stage 1B or less

- Non-invasive basal cell and squamous cell skin carcinoma

- Malignant melanoma with a complete response of a duration of > 10 years

- Radically treated prostate cancer (prostatectomy or radiotherapy) with normal
prostate specific antigen (PSA), and not requiring ongoing anti-androgen
hormonal therapy

- Other cancer diagnosis with a complete response of duration of > 5 years

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- Prior use of capecitabine is not allowed

- Prior and concomitant treatment with HDAC inhibitors (such as valproic acid) are not
allowed

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat or other agents used in study

- Patients who are unable to take oral medications and / or who have a clinical or
radiological diagnosis of bowel obstruction are ineligible

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, active peptic ulcer disease, myocardial infarction within 6 months prior
to entry, congestive heart failure, symptomatic congestive heart failure, active
cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, uncontrolled
hypertension 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

- Human immunodeficiency virus (HIV)-positive patients are ineligible

- Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency are excluded