Tanespimycin in Treating Patients With Inoperable Locoregionally Advanced or Metastatic Thyroid Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well tanespimycin works in treating patients with inoperable locoregionally advanced or metastatic thyroid cancer. Drugs used in chemotherapy, such as tanespimycin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the 1-year treatment failure rate in patients with inoperable locoregionally advanced or metastatic medullary or differentiated thyroid carcinoma treated with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (tanespimycin). SECONDARY OBJECTIVES: I. Determine the toxicity of this drug in these patients. Determine the 1-year progression-free rate in patients treated with this drug. II. Determine the response rate and duration of response in patients treated with this drug. III. Determine the time to treatment failure and time to subsequent therapy in patients treated with this drug. IV. Determine the time to disease progression and overall survival of patients treated with this drug. V. Correlate the incidence rate of RAS, RAF, and RET mutations with clinical outcome in patients treated with this drug. OUTLINE: This is a multicenter study. Patients are stratified according to type of thyroid carcinoma (medullary vs differentiated). Patients receive tanespimycin intravenously (IV) over 2-6 hours on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 3 years from study entry.

Official Title
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A Phase II Trial of 17-Allylaminogeldanamycin (17AAG) in Advanced Medullary and Differentiated Thyroid Carcinoma

Conditions
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Recurrent Thyroid Cancer, Stage IV Follicular Thyroid Cancer, Stage IV Papillary Thyroid Cancer, Thyroid Gland Medullary Carcinoma

Intervention / Treatment
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* Drug: tanespimycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of thyroid carcinoma of 1 of the following types: Medullary Differentiated Iodine I 131-resistant disease, defined as failure to incorporate and/or progression of measurable disease after treatment with iodine I 131 Inoperable locoregionally advanced or metastatic disease Measurable disease, defined as ≥ 1 lesion ≥ 2.0 cm by conventional techniques OR ≥ 1.0 cm by spiral CT scan No active CNS metastases Performance status - ECOG 0-2 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9.0 g/dL Bilirubin ≤ normal Alkaline phosphatase ≤ 2.5 times upper limit of normal (ULN) AST ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN QTc < 450 msec for male patients (470 msec for female patients) LVEF > 40% by MUGA DLCO ≥ 80% No cardiac symptoms ≥ grade 2 No active ischemic heart disease within the past year No congenital long QT syndrome No left bundle branch block No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row) No myocardial infarction within the past year No New York Heart Association class III or IV congestive heart failure No poorly controlled angina No history of angina (of any sort) within the past 6 months No history of uncontrolled dysrhythmias or requiring antiarrhythmic drugs No history of cardiac toxicity after treatment with anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine) No other significant cardiac disease No uncontrolled infection No history of serious allergic reaction to eggs No pulmonary symptoms ≥ grade 2 No symptomatic pulmonary disease requiring medication including the following: Dyspnea on or off exertion Paroxysmal nocturnal dyspnea Oxygen requirement Significant pulmonary disease (e.g., chronic obstructive/restrictive pulmonary disease) No home oxygen need meeting the Medicare criteria No history of pulmonary toxicity after treatment with anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or noninvasive carcinoma No active seizure disorder More than 4 weeks since prior and no concurrent immunotherapy More than 4 weeks since prior biologic therapy No concurrent routine or prophylactic colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) More than 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered No other concurrent chemotherapy See Disease Characteristics More than 4 weeks since prior and no concurrent radiotherapy More than 4 weeks since prior radiopharmaceuticals No prior radiotherapy to > 25% of bone marrow No prior radiotherapy that potentially included the heart in the field (i.e., mantle) or chest More than 4 weeks since prior therapeutic surgery for the tumor More than 3 months since prior sublingual nitroglycerin No other concurrent investigational ancillary therapy Concurrent CYP3A4 inhibitors allowed No concurrent medications that prolong or may prolong QTc interval

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 (chemotherapy)<br>Patients receive tanespimycin IV over 2-6 hours on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: tanespimycin<br>* Given IV<br>* Other names: 17-AAG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Have Remained on Treatment and Progression-free at Least One Year After Start of 17-AAG (Tanespimycin) | The one-year treatment failure free rate is 100% times the proportion of eligible patients who remain on treatment and are progression-free at least one year after treatment start. A 90% confidence interval for the one year treatment failure free rate was constructed using the properties of the binomial confidence interval. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Patients that are not classified as having a progression are termed progression-free. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response | The number of responses were categorized and summarized independently within each of the patient groups. Participants were evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.0. Complete Response (CR): Disappearance of all lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest dimension (LD) of target lesions taking as reference the baseline sum LD. | Baseline, every 3 courses, and at the end of treatment study | 
| Progression-Free Survival | Defined as the time from registration to the date of progression or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Patients that are not classified as having a progression are termed progression-free. Estimated using the Kaplan-Meier method. | Every 3 months for up to 3 years | 
| Overall Survival | Defined as the time from registration to date of last follow-up or death due to any cause. Estimated using the Kaplan-Meier method. | Every 3 months until progression, and then every 6 months up to 3 years | 
| Toxicity | Defined as the number of participants reporting grade 3 or higher adverse events that are classified as either possibly, probably, or definitely related to study treatment. Determined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. | Every 3 courses during treatment (median cycle number was 5 with a maximum of 38 cycles) |