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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): Valproic Acid; Liothyronine Sodium
Intervention type(s): Drug; Drug
Intervention description(s): 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)
Other intervention name(s): Cytomel
Intervention MeSH terms: Valproic Acid
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Depakote; Poorly Differentiated Thyroid Cancer; RAI Uptake; Thyrogen