A Phase II Trial of Valproic Acid in Patients With Advanced Thyroid Cancers of Follicular Cell Origin
Condition: Thyroid Neoplasm
MeSH terms: Thyroid Neoplasms; Thyroid Diseases
Intervention: Valproic Acid; Liothyronine Sodium
Intervention description: Week 1:
(Days 1-3): Valproic acid - 500 mg every evening (Day 4-7): Valproic acid - 500 mg twice daily (morning and evening) Weeks 2 through 10: Valproic acid 500 mg every morning and 1000 mg every evening; Patients who exhibit an increased radioiodine uptake on Thyrogen scan post valproic acid therapy at week 10. Begin Cytomel for 4 weeks (25 micrograms twice a day)
Intervention MeSH terms: Valproic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Depakote; Poorly Differentiated Thyroid Cancer; RAI Uptake; Thyrogen

Summary:

      Background:

        -  Patients who have advanced thyroid cancer have a low long-term survival rate. These
           types of thyroid cancer do not respond well to conventional surgery or radiation, or to
           specific thyroid cancer treatments such as radioactive iodine treatment and thyroid
           hormone for thyroid stimulating hormone (TSH) suppression.

        -  Valproic acid has long been approved as an anticonvulsant to treat seizures in patients
           with epilepsy. It has also been used to treat bipolar disorder. Recent studies have
           shown that valproic acid has promising effects in thyroid cancer treatment because it
           may help destroy cancer cells and help conventional treatments be more effective.
           However, valproic acid is not approved for thyroid cancer and is therefore an
           investigational drug.

      Objectives:

        -  To determine whether valproic acid can inhibit tumor growth or induce tumor cell death.

        -  To determine whether valproic acid can make tumor cells increase their uptake of
           radioiodine.

      Eligibility:

      - Individuals at least 18 years of age who have advanced-stage thyroid cancer that is either
      unresponsive to conventional treatments or fails to absorb radioiodine.

      Design:

        -  Eligible participants will continue on the standard thyroid hormone suppression therapy
           and begin receiving valproic acid for a total of 10 weeks. Participants will keep a
           study diary to record doses and side effects, and will have regular clinic visits to
           provide blood samples and receive additional valproic acid.

        -  After 10 weeks, participants will have a Thyrogen scan to measure radioiodine uptake
           after valproic acid therapy. Tumor biopsies and blood samples will be taken at this
           time.

        -  If there is increased radioiodine uptake on the scan, participants will have additional
           radioiodine therapy.

        -  If there is no increased uptake on the scan, participants will continue on valproic acid
           for 7 more weeks. After 16 total weeks of treatment, additional blood samples and scans
           will be taken. Participants may continue to take valproic acid if the thyroid cancer
           appears to be responding to the treatment.

        -  Follow-up visits will be scheduled at 3, 6, 9 (for patients continuing on valproic acid
           only), and 12 months.
    

Eligibility criteria:

        -  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.