Decitabine in Treating Patients With Metastatic Papillary Thyroid Cancer or Follicular Thyroid Cancer Unresponsive to Iodine I 131

Study Overview
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Brief Summary
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This phase II trial is studying how well decitabine works in treating patients with metastatic papillary thyroid cancer or follicular thyroid cancer that has stopped responding to radioactive iodine. Iodine I 131 (radioactive iodine) kills thyroid cancer cells. Metastatic thyroid cancer cells can lose the ability to be treated with radioactive iodine. Decitabine may help thyroid cancer cells regain the ability to respond to treatment with radioactive iodine.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine whether decitabine can restore iodine I 131 (131I) uptake in patients with metastatic papillary thyroid or follicular thyroid cancer lesions that are undetectable by low-dose iodine 131I scanning. SECONDARY OBJECTIVES: I. Determine the efficacy of 131I therapy, administered after restoration of 131I uptake by decitabine, in these patients. II. Determine the effect of decitabine on clinical and molecular markers of thyroid cancer cell differentiation in these patients. III. Determine the safety and tolerability of decitabine in patients undergoing thyroid hormone withdrawal-induced hypothyroidism and 131I therapy. OUTLINE: This is an open-label, multicenter study. Patients receive decitabine intravenous (IV) over 1 hour on days 1-5 and 8-12 of weeks 1 and 2 (course 1). On week 3, patients undergo iodine I 131 (131I) scanning using thyrotropin alfa injections. Patients whose scan does not demonstrate iodine uptake continue suppressive thyroid hormone therapy but receive no further study therapy. These patients undergo study follow up. Patients whose scan demonstrates iodine uptake undergo thyroid hormone withdrawal on weeks 4-8 and receive a second course of decitabine (as in course 1) on weeks 7 and 8. Patients then receive 131I therapy on week 9. Patients are followed at 3 and 6 months.

Official Title
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Phase II Study of Decitabine in Patients With Metastatic Papillary Thyroid Cancer or Follicular Thyroid Cancer Unresponsive to Radioiodine

Conditions
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Recurrent Thyroid Cancer, Stage IVA Follicular Thyroid Cancer, Stage IVA Papillary Thyroid Cancer, Stage IVB Follicular Thyroid Cancer, Stage IVB Papillary Thyroid Cancer, Stage IVC Follicular Thyroid Cancer, Stage IVC Papillary Thyroid Cancer

Intervention / Treatment
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* Drug: Decitabine
* Radiation: Iodine I 131
* Biological: Recombinant thyrotropin alfa
* Radiation: Fludeoxyglucose F 18
* Procedure: Positron emission tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed papillary thyroid or follicular thyroid carcinoma: Differentiated disease; Metastatic disease documented by ultrasound, computed tomography (CT) scan (without iodinated contrast), or MRI - All metastatic disease foci =< 10 mm in all dimensions Must have been treated with total or near-total thyroidectomy AND at least 1 course of iodine I 131 (131I)(>=29.9 mCi) OR demonstrated negative uptake on a postoperative low-dose131I scan Must have undergone whole body 131I scan 1-3 days after administration of =< 5.5 mCi of 131I demonstrating no visible iodine uptake within the lesions unless demonstrated negative uptake on a postoperative low-dose131I scan within the past 12 weeks: Must have 24-hour urine iodine excretion =< 500 mcg within 1 week of 131I scan Must be receiving thyroid hormone therapy AND have thyroid-stimulating hormone level =< 0.5 mU/L No known brain metastases Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2 OR Karnofsky 60-100% Hematopoietic: Absolute neutrophil count >= 1,500/mm3; Platelet count >= 100,000/mm3; White Blood Count (WBC) >= 3,000/mm3 Hepatic: aspartate aminotransferase-alanine aminotransferase (AST and ALT) =< 2.5 times upper limit of normal; Bilirubin normal Renal: Creatinine not elevated OR Creatinine clearance >= 60 mL/min Cardiovascular: No symptomatic congestive heart failure; No unstable angina pectoris; No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergic reaction attributed to compounds of similar chemical or biological composition to decitabine No concurrent uncontrolled illness No active or ongoing infection No psychiatric illness or social situation that would preclude study compliance No prior cytotoxic chemotherapy for thyroid cancer At least 6 months since prior external beam radiotherapy administered for locoregional disease in the thyroid bed or to the cervical or upper mediastinal lymph node regions (no more than 6,000 cGy) More than 6 months since other prior radiotherapy and recovered More than 6 months since prior therapeutic 131I > 10 mCi More than 18 months since prior cumulative 131I activity of at least 500 mCi More than 12 months since prior amiodarone (Unless 24-hour urinary iodine excretion is =< 500 mcg) No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer therapy No other concurrent investigational agents More than 6 months since prior intrathecal iodinated contrast (Unless 24-hour urinary iodine excretion is =< 500 mcg) More than 3 months since prior IV or oral iodinated contrast for radiographic studies (Unless 24-hour urinary iodine excretion is =< 500 mcg)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Starting dose 6 mg/m^2 Decitabine intravenous (IV) over 1 hour on days 1-5 and 8-12 of weeks 1 and 2 (course 1). Week 3, Iodine I 131 (131I) scanning using thyrotropin alfa injections. Participants whose scan do not demonstrate iodine uptake continue suppressive thyroid hormone therapy but no further study therapy; these participants who do show uptake undergo thyroid hormone withdrawal on weeks 4-8 and second course of decitabine (as in course 1) on weeks 7 and 8, with 131I therapy on week 9. | Drug: Decitabine<br>* Starting dose 6 mg/m^2 intravenously over 1 hour every day for 5 successive days for 2 weeks (10 doses), with possible second course.<br>* Other names: DAC;Radiation: Iodine I 131<br>* Undergo thyrotropin-alfa stimulated radioactive iodine scan<br>* Other names: Iodotrope;Biological: Recombinant thyrotropin alfa<br>* Undergo thyrotropin-alfa stimulated radioactive iodine scan<br>* Other names: Thyrogen;Radiation: Fludeoxyglucose F 18<br>* Optional correlative studies<br>* Other names: FDG;Procedure: Positron emission tomography<br>* Optional correlative studies<br>* Other names: tomography, emission computed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Restoration of Radioiodine Uptake in Metastatic Lesions as Demonstrated by Diagnostic Whole-body Scanning After Decitabine Administration | Number of participants with restoration of radioiodine responsiveness as determined by visible uptake on radioiodine scan in radiographically detectable metastatic foci of papillary or follicular thyroid carcinoma. Response to Decitabine defined as demonstration of radioiodine uptake determined by centralized blinded review of diagnostic scan. All who demonstrated radioiodine uptake in metastatic foci following decitabine therapy would then undergo thyroid hormone withdrawal and a second course of decitabine in preparation for therapeutic administration of radioiodine. Diagnostic radioiodine scans following decitabine therapy (week 3) with a radioiodine scan following thyrotropin alfa stimulation, 0.9 mg intramuscular (IM) injection 24 and 48 hours before administration of the 131I for imaging. Whole body scans (WBS) performed using a gamma camera. | Week 3 following 2 weeks of Decitabine therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Summary of Adverse Events (AEs) by Maximum Grade where Grade 1 AEs >20%, Grade 2 AEs >10%, all Grade 3, Grade 4 and Grade 5 reported. | Up to 6 months | 
| Efficacy of Subsequent Radioiodine Therapy in Terms of CR/PR/SD of Any Radiographic Disease. | Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | 6 months | 
| Change in Fludeoxyglucose (FDG) Uptake Measured by Positron Emission Tomography in Metastatic Tumor Sites Before and After DNA-methyltransferase Inhibitor Therapy (Optional). No Secondary Endpoints Were Measured as no Patient Met the Primary Endpoint. |  | Baseline to 3 weeks | 
| Efficacy of Subsequent Radioiodine Therapy in Terms of Complete Response (CR)/Partial Response (PR)/Stable Disease (SD) of Any Radiographic Disease | Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | 3 months | 
| Efficacy of Subsequent Radioiodine Therapy in Terms of Change in Serum Thyroglobulin Level |  | 6 months | 
| Efficacy of Subsequent Radioiodine Therapy in Terms of Change in Serum Thyroglobulin Level.These Secondary Endpoints Would Only Have Been Assessed if a Patient Had Met the Primary Endpoint, Restoration of Radioiodine Uptake to Justify Radioiodine Therapy. |  | 3 months |