Recurrent Thyroid Cancer, Stage IV Follicular Thyroid Cancer, Stage IV Papillary Thyroid Cancer, Thyroid Gland Medullary Carcinoma
Conditions
Brief summary
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
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.
Interventions
DRUGtanespimycin
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Have Remained on Treatment and Progression-free at Least One Year After Start of 17-AAG (Tanespimycin) | 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | Baseline, every 3 courses, and at the end of treatment study | 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. |
| Progression-Free Survival | Every 3 months for up to 3 years | 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. |
| Overall Survival | Every 3 months until progression, and then every 6 months up to 3 years | Defined as the time from registration to date of last follow-up or death due to any cause. Estimated using the Kaplan-Meier method. |
| Toxicity | Every 3 courses during treatment (median cycle number was 5 with a maximum of 38 cycles) | 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. |
Countries
United States
Participant flow
Recruitment details
From February 2005 thru April 2009, 41 participants were accrued to the this study. The study was closed to enrollment in July, 2009 due to a slow accrual rate.
Pre-assignment details
From February 2005 thru February 2009, 17 participants were accrued to the Advanced Medullary Thyroid Carcinoma group. From February 2008 thru April 2009, 24 participants were accrued to the Differentiated Thyroid Carcinoma group.
Participants by arm
| Arm | Count |
|---|---|
| Advanced Medullary Thyroid Carcinoma Group Patients receive 220 mg/m\^2 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. | 17 |
| Differentiated Thyroid Carcinoma Patients receive 220 mg/m\^2 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. | 24 |
| Total | 41 |
Baseline characteristics
| Characteristic | Advanced Medullary Thyroid Carcinoma Group | Differentiated Thyroid Carcinoma | Total |
|---|---|---|---|
| Age, Continuous | 56 years | 61 years | 60 years |
| Gender Female | 5 Participants | 11 Participants | 16 Participants |
| Gender Male | 12 Participants | 13 Participants | 25 Participants |
| Region of Enrollment United States | 17 participants | 24 participants | 41 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 39 / 41 |
| serious Total, serious adverse events | 13 / 41 |
Outcome results
Primary
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.
Time frame: 1 year
Population: All patients were evaluable for this endpoint in this group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Advanced Medullary Thyroid Carcinoma Group | Proportion of Patients Who Have Remained on Treatment and Progression-free at Least One Year After Start of 17-AAG (Tanespimycin) | 5.9 percentage of participants |
| Differentiated Thyroid Carcinoma | Proportion of Patients Who Have Remained on Treatment and Progression-free at Least One Year After Start of 17-AAG (Tanespimycin) | 12.5 percentage of participants |
Secondary
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.
Time frame: Baseline, every 3 courses, and at the end of treatment study
Population: All participants were evaluated for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Advanced Medullary Thyroid Carcinoma Group | Overall Response | Partial Response (PR) | 1 participants |
| Advanced Medullary Thyroid Carcinoma Group | Overall Response | Complete Response (CR) | 0 participants |
| Differentiated Thyroid Carcinoma | Overall Response | Complete Response (CR) | 0 participants |
| Differentiated Thyroid Carcinoma | Overall Response | Partial Response (PR) | 0 participants |
Secondary
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.
Time frame: Every 3 months until progression, and then every 6 months up to 3 years
Population: All patients were evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Advanced Medullary Thyroid Carcinoma Group | Overall Survival | 2.1 years |
| Differentiated Thyroid Carcinoma | Overall Survival | 1.5 years |
Secondary
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.
Time frame: Every 3 months for up to 3 years
Population: All participants were evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Advanced Medullary Thyroid Carcinoma Group | Progression-Free Survival | 6.4 months |
| Differentiated Thyroid Carcinoma | Progression-Free Survival | 4.1 months |
Secondary
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.
Time frame: Every 3 courses during treatment (median cycle number was 5 with a maximum of 38 cycles)
Population: All participants were evaluable for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Advanced Medullary Thyroid Carcinoma Group | Toxicity | Grade 4 or Higher | 3 participants |
| Advanced Medullary Thyroid Carcinoma Group | Toxicity | Grade 3 or Higher | 4 participants |
| Advanced Medullary Thyroid Carcinoma Group | Toxicity | Grade 5 | 1 participants |
| Differentiated Thyroid Carcinoma | Toxicity | Grade 3 or Higher | 9 participants |
| Differentiated Thyroid Carcinoma | Toxicity | Grade 4 or Higher | 0 participants |
| Differentiated Thyroid Carcinoma | Toxicity | Grade 5 | 0 participants |