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

Phase 2

Completed

Conditions: Thyroid Neoplasm

Interventions: Drug: Valproic Acid
Drug: Liothyronine Sodium

Registration Number: NCT01182285

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
B1 - Phase 2 Schedule 1	Liothyronine Sodium	Drug: Valproic Acid Week 11 - 17 (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 Drug: Cytomel (25 micrograms) Patients who exhibit an increased radioiodine uptake on Thyrogen scan post valproic acid therapy at week 10. Begin Liothyronine Sodium (Cytomel) for 4 weeks (25 micrograms twice a day)
A - Phase I Radioiodine-Resistant	Valproic Acid	Drug: Valproic Acid Week 1 - 10 (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
B1 - Phase 2 Schedule 1	Valproic Acid	Drug: Valproic Acid Week 11 - 17 (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 Drug: Cytomel (25 micrograms) Patients who exhibit an increased radioiodine uptake on Thyrogen scan post valproic acid therapy at week 10. Begin Liothyronine Sodium (Cytomel) for 4 weeks (25 micrograms twice a day)
B2 - Phase 2 Schedule 2	Valproic Acid	Drug: Valproic Acid Week 11 - 52 (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 Weeks 17-52: Patients who show a response by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria or have a decreased thyroglobulin level from Day 1 of the treatment (registered as a partial response to the treatment) will continue on valproic acid at their current dose for a total of 52 weeks.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	Date treatment consent signed to date off study, approximately 41 months and 11 days	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
RAI (Radioactive Iodine) Uptake and Tg (Thyroglobulin) Level Compared Pre and Post- Valproic Treatment	Entry to study and after 10 weeks of treatment for Phase 1, and 10 weeks of treatment to 16 weeks of treatment for phase 2.	Complete response (CR) is increased Rai uptake on post- valproic acid therapy at week 10, AND a decrease in Tg level to less than 2 ng/ml (or a decrease in Tg-Ab level to less than 2.0 IU/ml) at 10 weeks AND disappearance of all lesions at 16 weeks. Partial response (PR) is increased Rai uptake on post-valproic scan at week 10, OR a decreased Tg level (or a decrease in Tg Ab (Tg antibody) level by more than 20%) at 10 weeks AND 30% decrease in target lesion at 16 weeks. Stable disease (SD) is no change in RAI uptake AND Tg levels (or TG-Ab level) AND no significant change of lesions at 16 weeks. Progressive disease (PD) is tumor mass increases OR Tg levels (or Tg-Ab levels) increases over 10 weeks OR at least 20% increase in target lesion at 16 weeks.

Secondary Outcome Measures

Name	Time	Method
NIS (Na/I-symporter) Expression	Entry to study and after 10 weeks of treatment	NIS (Na/I-symporter) Expression is assessed by quantitative reverse transcription (RT) polymerase chain reaction (PCR) and immunohistochemistry (IHC). NIS mRNA expression was measured by quantitative RT PCR from biopsy samples.
Best Overall Response	Week 16	Best overall response was assessed by radioiodine uptake. Complete response (CR) is increased Rai (radioiodine) uptake on post- valproic acid therapy at week 10, AND a decrease in Tg (thyroglobulin ) level to less than 2 ng/ml (or a decrease in Tg-Ab (thyroglobulin antibodies) level to less than 2.0 IU/ml) at 10 weeks AND disappearance of all lesions at 16 weeks. Partial response (PR) is increased Rai uptake on post-valproic scan at week 10, OR a decreased Tg level (or a decrease in Tg Ab (Tg antibody) level by more than 20%) at 10 weeks AND 30% decrease in target lesion at 16 weeks. Stable disease (SD) is no change in RAI uptake AND Tg levels (or TG-Ab level) AND no significant change of lesions at 16 weeks. Progressive disease (PD) is tumor mass increases OR Tg levels (or Tg-Ab levels) increases over 10 weeks OR at least 20% increase in target lesion at 16 weeks.