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)