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

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.

• 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)