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Thyroid Diseases

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Valproic Acid

Enzyme Inhibitors

Neurotransmitter Agents

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 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 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.

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)

Liothyronine Sodium

Naris Nilubol, M.D.

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.

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.

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

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

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.

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

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.

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.

National Cancer Institute (NCI)

Principal Investigator

Adverse events are not reported per Arm. All adverse events were reported to include phases 1 and 2 since it is analyzed throughout the whole study. No adverse events were recorded for participants at University of California San Francisco (UCSF).

A - Phase 1 Radioiodine Resistant Thyroid Cancer 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 B2 - Phase 2 Schedule 2 (No Increased Radioiodine Uptake) 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 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.

All Participants (Phase 1 and Phase 2 Schedule 2)

A- Phase 1 Radioiodine-Resistant 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

B2 - Phase 2 Schedule 2 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 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.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Five and eight participants were enrolled from University of California San Francisco (UCSF), and the National Institutes of Health, respectively.

Dr. Naris Nilubol

Tg start - >900 ng/ml

Tg start - 707 ng/ml

Tg start - 661 ng/ml

Tg start - 362 ng/ml

Tg start - 289 ng/ml

Tg start - 183 ng/ml

Tg start - 154 ng/ml

Tg start - 101 ng/ml

Tg start - 99 ng/ml

Tg start - 15.7 ng/ml

antiTg start - 142 IU/ml

antiTg start - 220 IU/ml

antiTg start - <20 IU/ml

Tg end - >900 ng/ml

Tg end - 749 ng/ml

Tg end - 702 ng/ml

Tg end - 630 ng/ml

Tg end - 480 ng/ml

Tg end - 362 ng/ml

Tg end - 204 ng/ml

Tg end - 184 ng/ml

Tg end - 183 ng/ml

Tg end - 128 ng/ml

Tg end - 61 ng/ml

Tg end - 10.8 ng/ml

Tg end - none

antiTg end - 338 IU/ml

anti Tg end - 220 IU/ml

antiTg end - 83 IU/ml

antiTg end - 80 IU/ml

anti Tg end - <20 IU/ml

antiTg end - none

RAI uptake pre-treatment - none

RAI uptake post treatment - none

A - Phase 1 Radioiodine Resistant Thyroid Cancer

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 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.

B2 - Phase 2 Schedule 2 (No Increased Radioiodine Uptake)

13 participants were enrolled in phase 1 and 8/13 (5 from University of California San Francisco (UCSF) moved on from phase 1 to the phase 2 schedule 2 portion. However, Tg data from UCSF is unavailable for 5 of the participant, thus only 3 were analyzed in the phase 2 portion.

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

All Participants

Adverse events are not reported per Arm. All adverse events were reported to include phases 1 and 2 since it is analyzed throughout the whole study.

Number of Participants With Adverse Events

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Unknown

B2 - Phase 2 Schedule 2 (No Increased Radiiodine Uptake)

Best overall response was not assessed for the phase 1 portion.

Best Overall Response

Pre-treatment NIS expression (relative to GAPDH)

Post-treatment NIS expression (relative to GAPDH)

There is no standard of error to report. The acronym GAPDH expanded is glyceraldehyde 3-phosphate dehydrogenase. Only 1 participant was analyzed because biopsies were not performed in 12 subjects.

NIS (Na/I-symporter) Expression

B1 - Phase 2 Schedule 1 (Increased Radioiodine Uptake)

First Intervention Week 1-10

Second Intervention Week 11-17

Third Intervention Week 11-52

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Recurrence

Adenocarcinoma

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Micronutrients

Anti-Infective Agents

Iodine

Cadexomer iodine

Ad5-CMV-NIS

liothyronine sodium

reverse transcriptase-polymerase chain reaction

laboratory biomarker analysis

iodine I 131

Brian J. Davis, M.D.

RATIONALE: Radioactive drugs, such as radioactive iodine, may carry radiation directly to tumor cells and not harm normal cells. Placing a gene called Ad5CMV-NIS in prostate cancer cells may help the prostate cells take in more radioactive iodine and thus kill the cancer cells. Drugs, such as liothyronine sodium, may protect the thyroid from the side effects of radioactive iodine.

PURPOSE: This phase I trial is studying the side effects and best dose of gene therapy given together with radioactive iodine in treating patients with locally recurrent prostate cancer that did not respond to external-beam radiation therapy.

OBJECTIVES:

Primary

* To determine the safety and tolerance of Ad5CMV-NIS administered intraprostatically followed by radioiodine treatment in patients with locally recurrent adenocarcinoma of the prostate following external beam radiotherapy.
* To determine the maximum tolerated dose of Ad5CMV-NIS in these patients.

Secondary

* To evaluate the PSA response rates, duration, and time to PSA progression in these patients.
* To evaluate the immune response to Ad5CMV-NIS.

OUTLINE: This is a dose-escalation study of Ad5CMV-NIS.

Patients receive intraprostate Ad5CMV-NIS, via transperineal injection under anesthesia, on day 1. They receive dosimetry oral iodine I 123 on day 4 and undergo image studies periodically for the next 24 hours for measurement of radioiodine uptake. Patients receive therapeutic oral iodine I 131 on day 5.

All patients with intact thyroid glands (i.e., not previously surgically removed or ablated) receive TSH suppressive doses of oral liothyronine sodium 3 times daily for 10 days prior and for 15 days post administration of iodine I 123.

Blood samples are collected periodically for measurement of PSA, fT4, and TSH; and peripheral blood cells are monitored for evidence of virus DNA via quantitative reverse-transcriptase-PCR.

After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 8 years. A transrectal tumor biopsy is to be performed at 3 months and 1 year post-treatment.

Gene Therapy and Radioactive Iodine in Treating Patients With Locally Recurrent Prostate Cancer That Did Not Respond to External-Beam Radiation Therapy

Phase I Trial of In Situ Gene Therapy for Locally Recurrent Prostate Cancer Following Radiation Therapy Failure Using Sodium/Iodide Symporter and Radioiodine

Mayo Clinic

Rare Diseases

Carcinoma

Thyroid Cancer, Papillary

Adenocarcinoma, Follicular

Papillary Thyroid Carcinoma

Thyroid Cancer, Follicular

Antineoplastic Agents

Azacitidine

Antimetabolites

azacitidine

Kenneth Ain, MD

RATIONALE: Azacitidine may help thyroid cancer cells regain the ability to take up iodine. This would allow the cancer to be detected and treated by radioactive iodine.

PURPOSE: Phase I trial to study the effectiveness of azacitidine to restore thyroid function in treating patients who have persistent or metastatic thyroid cancer.

OBJECTIVES: I. Determine the ability of azacitidine to restore iodine uptake by dedifferentiated thyroid cancer, enabling detection and treatment with iodine I 131 in patients with metastatic follicular or papillary thyroid cancer. II. Evaluate different doses and schedules of azacitidine administration to determine an optimally effective combination for restoration of iodine I 131 uptake with acceptable toxicity in this patient population. III. Determine the efficacy of azacitidine plus iodine I 131 in this patient population.

OUTLINE: This is a dose escalation study of azacitidine. Patients undergo a control phase consisting of oral liothyronine sodium twice daily on weeks 1-4 and a low iodine diet on weeks 4-7. At week 6, patients receive a scan dose of iodine I 131 followed by whole body scanning over 5 days. Beginning at week 7, patients undergo a treatment phase consisting of oral liothyronine sodium twice daily for 3 weeks, azacitidine subcutaneously daily for 10 or 20 days (weeks 7-11) and a low iodine diet on weeks 8-11. During week 11, patients undergo additional whole body scanning over 5 days followed by a therapeutic dose of iodine I 131. Patients achieving successful therapy receive 5 additional doses of azacitidine. Cohorts of 4 patients receive escalating doses of azacitidine until demonstrable radioiodine uptake is seen or the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 8 patients experience dose limiting toxicity. Patients are followed weekly for 8 weeks.

PROJECTED ACCRUAL: A total of 38 patients will be accrued for this study.

Azacitidine to Restore Thyroid Function in Patients With Persistent or Metastatic Thyroid Cancer

Restoration of Radioiodine Uptake in Thyroid Carcinoma: A Clinical Trial

Lucille P. Markey Cancer Center at University of Kentucky

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II Trial of Valproic Acid in Patients With Advanced Thyroid Cancers of Follicular Cell Origin	NCT01182285	Thyroid Neoplas...	Valproic Acid Liothyronine So...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Gene Therapy and Radioactive Iodine in Treating Patients With Locally Recurrent Prostate Cancer That Did Not Respond to External-Beam Radiation Therapy	NCT00788307	Prostate Cancer	Ad5-CMV-NIS liothyronine so... reverse transcr... laboratory biom... iodine I 131	18 Years - 120 Years	Mayo Clinic
Azacitidine to Restore Thyroid Function in Patients With Persistent or Metastatic Thyroid Cancer	NCT00004062	Head and Neck C...	azacitidine liothyronine so... iodine I 131	-	National Cancer Institute (NCI)

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