Clinical trial NCT01182285: A Phase II Trial of Valproic Acid in Patients With Advanced Thyroid Cancers of Follicular Cell Origin
Official title: A Phase II Trial of Valproic Acid in Patients With Advanced Thyroid Cancers of Follicular Origin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Thyroid Neoplasm
Keywords: Depakote
Poorly Differentiated Thyroid Cancer
RAI Uptake
Thyrogen
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2010-08-16
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: RAI (Radioactive Iodine) Uptake and Tg (Thyroglobulin) Level Compared Pre and Post- Valproic Treatment
timeFrame: 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.
measure: Number of Participants With Adverse Events
timeFrame: Date treatment consent signed to date off study, approximately 41 months and 11 days
Secondary outcomes:
measure: Best Overall Response
timeFrame: Week 16
measure: NIS (Na/I-symporter) Expression
timeFrame: Entry to study and after 10 weeks of treatment
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Naris Nilubol, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295.18.2164.
citation: Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer. 1998 Dec 15;83(12):2638-48. doi: 10.1002/(sici)1097-0142(19981215)83:123.0.co;2-1.
citation: Goretzki PE, Simon D, Frilling A, Witte J, Reiners C, Grussendorf M, Horster FA, Roher HD. Surgical reintervention for differentiated thyroid cancer. Br J Surg. 1993 Aug;80(8):1009-12. doi: 10.1002/bjs.1800800826.
citation: Nilubol N, Merkel R, Yang L, Patel D, Reynolds JC, Sadowski SM, Neychev V, Kebebew E. A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin. Clin Endocrinol (Oxf). 2017 Jan;86(1):128-133. doi: 10.1111/cen.13154. Epub 2016 Sep 8.