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

NCT01182285 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 10004110-C-0041
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Thyroid Neoplasm

Keywords

Depakote; Poorly Differentiated Thyroid Cancer; RAI Uptake; Thyrogen

Outcome Measures

Primary Outcomes (2)

• RAI (Radioactive Iodine) Uptake and Tg (Thyroglobulin) Level Compared Pre and Post- Valproic Treatment

  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.

  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.

• Number of Participants With Adverse Events

  Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

  Date treatment consent signed to date off study, approximately 41 months and 11 days

Secondary Outcomes (2)

• Best Overall Response

  Week 16

• NIS (Na/I-symporter) Expression

  Entry to study and after 10 weeks of treatment

Study Arms (3)

A - Phase I Radioiodine-Resistant

EXPERIMENTAL

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

Drug: Valproic Acid

B1 - Phase 2 Schedule 1

ACTIVE COMPARATOR

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)

Drug: Valproic Acid; Drug: Liothyronine Sodium

B2 - Phase 2 Schedule 2

ACTIVE COMPARATOR

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.

Drug: Valproic Acid

Interventions

Valproic Acid DRUG

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

A - Phase I Radioiodine-Resistant; B1 - Phase 2 Schedule 1; B2 - Phase 2 Schedule 2

Liothyronine Sodium DRUG

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)

Also known as: Cytomel

B1 - Phase 2 Schedule 1

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Extensive (invasive) loco-regional tumor mass and/or metastatic spread, rendering patient inoperable.
• 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.).
• 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%).
• Initial therapy must have included total/near-total thyroidectomy and RAI ablation therapy.
• 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.
• Greater than or equal to 18 years of age.
• Must be able to understand and sign the Informed Consent Document.
• Clinical performance status of Eastern Oncology Cooperative Group (ECOG) less than or equal to 1.
• Life expectancy of greater than three months.
• 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.
• 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)

You may not qualify if:

• Allergy to valproic acid.
• Current coexisting malignancy other than basal cell carcinoma.
• 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.
• Active systemic infections, coagulation disorders or other major medical illnesses.
• Patients taking tolbutamide, warfarin, zidovudine, benzodiazepines, clonazepam, diazepam.
• Seizure disorder.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 16684987 BACKGROUND

• 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.

  PMID: 9874472 BACKGROUND

• 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.

  PMID: 8402050 BACKGROUND

• 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.

  PMID: 27392538 RESULT

MeSH Terms

Conditions

Thyroid Neoplasms

Interventions

Valproic Acid; Triiodothyronine

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Thyronines; Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Thyroxine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Naris Nilubol
• Organization: National Cancer Institute

niluboln@nih.gov

301-451-2355

Study Officials

• Naris Nilubol, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 13, 2010
• First Posted: August 16, 2010
• Study Start: September 24, 2010
• Primary Completion: September 28, 2015
• Study Completion: April 28, 2016
• Last Updated: May 16, 2018
• Results First Posted: December 14, 2016

Record last verified: 2018-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)