|A Phase II Trial of Valproic Acid in Patients With Advanced Thyroid Cancers of Follicular Cell Origin
Further Study Information
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.
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.
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).
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.
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 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 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-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:
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, benzodiazapines, clonazepam, diazepam.
6. Seizure disorder.
Trial Lead Organizations/Sponsors
National Cancer Institute
Link to the current ClinicalTrials.gov record.
Note: Information about this trial is from the ClinicalTrials.gov database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the ClinicalTrials.gov record to standardize the names of study sponsors, sites, and contacts. Cancer.gov only lists sites that are recruiting patients for active trials, whereas ClinicalTrials.gov lists all sites for all trials. Questions and comments regarding the presented information should be directed to ClinicalTrials.gov.