Inolitazone Dihydrochloride and Paclitaxel in Treating Patients With Advanced Anaplastic Thyroid Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well inolitazone dihydrochloride (efatutazone dihydrochloride) and paclitaxel work in treating patients with anaplastic thyroid cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Drugs used in chemotherapy, such as efatutazone dihydrochloride and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if the combination of paclitaxel and efatutazone (efatutazone dihydrochloride) improves the confirmed response rate in patients with advanced anaplastic thyroid cancer. SECONDARY OBJECTIVES: I. To estimate the overall survival (OS), duration of response, progression-free survival (PFS), and adverse event rates for the combination of paclitaxel and efatutazone. TERTIARY OBJECTIVES: I. The association of biomarkers with clinical outcome data will be assessed in an exploratory translational analysis. OUTLINE: Patients receive paclitaxel intravenously (IV) over 3 hours on day 1 and efatutazone dihydrochloride orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 28 days, every 8 weeks until disease progression, and then every 6 months for 5 years.

Official Title
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A Phase 2 Study of Efatutazone, an Oral PPAR Agonist, In Combination With Paclitaxel in Patients With Advanced Anaplastic Thyroid Cancer

Conditions
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Anaplastic Thyroid Cancer, Recurrent Thyroid Cancer

Intervention / Treatment
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* Drug: efatutazone
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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Patients must have histologically or cytologically diagnosed advanced anaplastic thyroid cancer (ATC) Patients must have measurable disease Patients must have either metastatic (stage IVC) or locally advanced unresectable disease (stage IVB) Patients should have resolution of any toxic effects of prior therapy (except alopecia) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, grade 1 There is no limit to the number of prior lines of treatment a patient has received No treatment with chemotherapy, radiation therapy, immunotherapy, biological therapy, hormonal therapy, or other thiazolidinediones (TZDs) =< 21 days before study registration No prior taxane therapy =< 6 months, except as a radiosensitizer No history of the following: Class III or IV congestive heart failure (CHF) Grade 3 or 4 thromboembolic event =< 6 months Pericardial effusion =< 12 months (any grade) Pericardial involvement with tumor Grade 2 or higher pleural effusion =< 6 months No current symptomatic, untreated, or uncontrolled brain metastases present No major surgery =< 14 days prior to registration No grade 2 or higher neuropathy No known history of severe hypersensitivity reactions to any of the components of efatutazone or paclitaxel formulations Not pregnant and not nursing; women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required Patients with diabetes mellitus requiring concurrent treatment with insulin or thiazolidinedione (TZD) oral agents are not eligible Patients with known hypersensitivity to any TZD oral agents are not eligible Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Creatinine =< 1.5 x upper limit of normal (ULN) mg/dL OR calculated (calc.) creatinine clearance >= 60 mL/min Bilirubin =< 1.5 x ULN Aspartate aminotransferase (AST) =< 2.5 x ULN Although they will not be considered formal eligibility (exclusion) criteria, physicians should recognize that the following may seriously increase the risk to the patient entering this protocol: Psychiatric illness which would prevent the patient from giving informed consent Medical condition such as uncontrolled infection (including human immunodeficiency virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient Patients with a currently active second malignancy other than non-melanoma skin cancers; patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for >= 3 years; there is an exception for patients with a history of well differentiated thyroid cancer that has progressed to anaplastic thyroid cancer Patients who cannot swallow oral formulations of the agent(s) Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study ; appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom) Efatutazone is metabolized by cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), and inhibits CYP2C8, 2C9, 2C19, and 3A4, and is a substrate of P-glycoprotein (PgP) and breast cancer resistance protein (BCRP)

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: efatutazone dihydrochloride, paclitaxel<br>Patients receive paclitaxel IV over 3 hours on day 1 and efatutazone dihydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: efatutazone<br>* Given PO<br>* Other names: CS-7017;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate (Partial Response [PR] or Complete Response [CR]) Per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 Criteria | The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. | Time from study entry to death from any cause, assessed up to 5 years | 
| Duration of Confirmed Response | Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression (PD) is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by ≥50% of previously involved sites from nadir). | The time from the first documented date of confirmed response (CR or PR) to date at which progression is first documented, assessed up to 5 years | 
| PFS Determined Based on RECIST 1.1 Criteria | Progression free survival (PFS) is defined as the time from the date of registration to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1), 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. | The time from study entry to the first of either disease progression or death from any cause, assessed up to 5 years | 
| Number of Patients Experiencing at Least One Grade 3+ Adverse Event Using CTCAE Version 4.0 | The number of patients who experienced at least one grade 3 or higher adverse event is reported below. | Up to 5 years |