A Phase II Trial of Valproic Acid in Patients With Advanced Thyroid Cancers of Follicular Cell Origin

Background:

Patients who have advanced differentiated thyroid cancers (Stage IV) have a five-year
survival of only 25%. Clinically this results in more aggressive growth, metastasis,
decreased or loss of iodine uptake in the tumor, and tumors that may be refractory to
conventional treatment: surgical resection, radioactive iodine treatment and thyroid hormone
for Thyroid Stimulating Hormone (TSH) suppression.

In thyroid cancer, valproic acid, at clinically achievable concentrations, has an
antiproliferative and differentiating effect.

We hypothesize that valproic acid may inhibit proliferation and induce differentiation in
thyroid cancer cells so that 131-I may detect residual disease and be more effective for
radioiodine ablation of thyroid cancer cells of follicular cell origin.

Objectives:

The primary goal of this study is to determine if valproic acid will have an antineoplastic
and differentiation effect in patients with advanced and or metastatic thyroid cancer of
follicular cell origin.

Eligibility:

Unresectable advanced and/or poorly differentiated thyroid cancers of follicular cell origin
(excluding anaplastic and medullary thyroid cancer) that have no uptake (less than 1%) on
radioiodine scan or are unresponsive to radioiodine therapy.

Elevated serum thyroglobulin (Tg) level (greater than 100ng/ml on thyroid hormone; greater
than 10ng/ml off thyroid hormone).

Design:

This will be an open label phase II study to assess the efficacy of valproic acid therapy as
an antiproliferative and differentiation agent in patients with incurable differentiated
thyroid cancer (unresponsive and/or radioiodine negative and unresectable).

Oral valproic acid will be administered to reach a therapeutic serum level (50 to 100
microgram/ml).

The number of patients to be enrolled is 25 with an interim analysis of response once 13
patients are evaluable for response. It is anticipated that five patients may be enrolled per
year.

- INCLUSION CRITERIA:

1. Advanced/poorly differentiated thyroid cancers of follicular cell origin that
have no uptake (less than 1%) on radioiodine scan or are unresponsive to
radioiodine therapy. Unresponsiveness to radioiodine therapy is defined as a
patient s thyroglobulin not falling to less than 2ng/ml within 6 months after
previous radioiodine ablative treatment.

2. Extensive (invasive) loco-regional tumor mass and/or metastatic spread, rendering
patient inoperable.

3. Thyroglobulin (Tg) levels greater than or equal to 100 ng/ml in the absence of Tg
antibodies. Patients who are Tg-antibody (Tg-Ab) positive may be included despite
a lower Tg level if they have detectable disease on cross sectional imaging. (The
presence of Tg-Ab may lead to falsely low Tg levels and therefore render the Tg a
less sensitive marker of disease. However, Tg-Ab has been shown to also act as a
tumor marker, and will be used as an endpoint for the study in patients who are
Tg-Ab positive.).

4. Within 18 months of enrollment, patients must have had an radioactive iodine
(RAI) scan, showing no or therapeutically insignificant RAI uptake (less than or
equal to 1%).

5. Initial therapy must have included total/near-total thyroidectomy and RAI
ablation therapy.

6. Patients must have had no chemotherapy, radiotherapy, or biologic therapy for
their malignancy in the month prior to treatment and must have recovered from all
side effects of therapeutic and diagnostic interventions.

7. Greater than or equal to 18 years of age.

8. Must be able to understand and sign the Informed Consent Document.

9. Clinical performance status of Eastern Oncology Cooperative Group (ECOG) less
than or equal to 1.

10. Life expectancy of greater than three months.

11. Women of childbearing potential must have a negative serum beta-human chorionic
gonadotropin (HCG) within 72 hours prior to study entry and must be willing to
practice effective birth control to prevent pregnancy while receiving treatment
and for three months after treatment is discontinued. All males of child
fathering potential must also be willing to practice effective birth control.

12. Laboratory results must be within the following parameters before entry:

- Absolute Neutrophil Count greater than 750 cells/mm(3)

- Hemoglobin greater than 8.0 gm/dl

- Platelet count greater than 75000/mm(3)

- Creatinine less tha 1.5 times upper limit of normal (ULN)

- Total protein greater than 6.4.

- Total bilirubin should be less than 1.5 times ULN.

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic (SGOT), alanine
aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than 1.5 times
ULN.

- Amylase less than 1.5 times ULN

- Ammonia less than 1.5 times ULN

EXCLUSION CRITERIA:

1. Allergy to valproic acid.

2. Current coexisting malignancy other than basal cell carcinoma.

3. Women of child-bearing potential who are pregnant or breastfeeding.

Valproic acid is a known teratogen, causing primary neural tube defects, facial
abnormalities, and skeletal malformation; therefore pregnant women will be excluded.
Additionally, patients that become pregnant while on study protocol will be
discontinued immediately.

4. Active systemic infections, coagulation disorders or other major medical illnesses.

5. Patients taking tolbutamide, warfarin, zidovudine, benzodiazepines, clonazepam,
diazepam.

6. Seizure disorder.