Trial Evaluating Gleevec in Patients With Anaplastic Thyroid Carcinoma

Phase II Trial Evaluating Gleevec (Imatinib Mesylate Formerly Known as STI571) in Patients With Anaplastic Thyroid Cancer

Anaplastic thyroid cancers are rare, aggressive tumors. Standard treatment options include surgery and chemoradiation. Few treatment options are available once metastases develop. Recent data suggest that Imatinib (Gleevec) may be advantageous in this patient population. Patients who have been treated for anaplastic thyroid cancer with chemoradiation or surgery who develop recurrent or metastatic disease outside of the field of radiation are eligible. Patients will be treated with Imatinib 400 mg two times a day for eight weeks, followed by radiologic assessment. Patients will be treated until disease progression or a complete response is obtained.

Anaplastic thyroid carcinomas (ATC) are high grade neoplasms, which account for approximately 2% to 5% of primary malignant thyroid tumors but more than 50% of thyroid cancer deaths. Because therapies for anaplastic thyroid carcinoma are very limited with even early stage disease, new approaches for treating this devastating cancer are needed. Recently, imatinib mesylate (Gleevec®), formerly known as STI571, has been approved for the treatment of chronic myelogenous leukemia and for treatment of gastrointestinal stromal tumors, expressing the c-Kit tyrosine kinase. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor, c-Kit, and inhibits PDGF- and SCF-mediated cellular events. Recent data suggest that many if not most, anaplastic thyroid cancers express PDGF receptors, and that these receptors are functional. Additional preclinical work from Japan demonstrates that c-Abl is overexpressed in p53 mutated/deficient anaplastic thyroid carcinoma cell lines and that select inhibition of c-Abl activity by STI571 has a dramatic cytostatic effect in these cells.

Additional data suggest that many, if not most, anaplastic thyroid cancers express PDGF receptors, and that these receptors are functional. Since activation of PDGF receptors is associated with the growth of other tumors and c-Abl is overexpressed in p53-mutated anaplastic thyroid carcinoma cell lines, it seems appropriate to test Gleevec as a therapy for patients with anaplastic thyroid cancer. The specific hypothesis to be tested is that anaplastic thyroid cancers that overexpress PDGF receptors or Abl will respond to Gleevec therapy. The lack of any accepted efficacious therapies for anaplastic thyroid cancer, the poor prognosis of this cancer, and the relatively low toxicity of Gleevec justify this proposed trial.

Patients with anaplastic thyroid carcinoma who are status post best local control with surgery/chemoradiation, who have measurable disease outside their previous field of radiation, are eligible.

The Primary Objective of this study is:

1. To determine the overall response (complete and partial response) rates of patients with anaplastic thyroid cancer treated with Gleevec at the first response assessment (i.e. 8 weeks following the start of Gleevec), following best local control with surgery or radiation/chemoradiation.

The Secondary Objectives include:

1. To measure the grade III/IV toxicities experienced by patients with anaplastic thyroid cancer who are treated with Gleevec.
2. To determine the time to obtain complete or partial responses in patients with anaplastic thyroid cancer treated with Gleevec, following best local control with surgery or radiation/chemoradiation.

Treatment Plan:

Patients will be treated with Imatinib (Gleevec) 400 mg two times a day for eight weeks after which radiologic imaging will be obtained to assess response. Patients who attained a complete response will be treated with four additional weeks of Imatinib. Patients who attain a partial response or stable disease will be treated until a complete response is attained, or until disease progression. All patients with progression of disease will be taken off the study. Patients continuing on the study, will undergo radiologic imaging every eight weeks following their initial response assessment. All patients will be followed until death.

Inclusion Criteria:

• Patients with histologically confirmed anaplastic thyroid carcinoma, who have measurable disease.
• Patients with brain metastases are eligible if they have been stable for at least six weeks post-radiation therapy.
• Age 18 years, male or female.
• Karnofsky performance status (KPS) of > 70%.
• Life expectancy of at least 12 weeks.
• Hematologic: ANC 1,500 mm3, hemoglobin 8.0 g/dl, platelets 100,000/mm3
• Normal serum calcium level within normal limits for the institution documented within 14 days prior to registration.
• All patients (including those with liver metastases) must have adequate hepatic function as defined by a serum bilirubin 1.5 x the institutional upper limit of normal (ULN), and ALT and AST <2.5 x ULN, obtained within 14 days prior to registration.
• Patients must have a serum creatinine less than 1.5 x the institutional upper limits of normal (adjusted for age) within 14 days of registration.
• Women of childbearing potential must have a negative pregnancy test at baseline, prior to receiving any study drug. (Pregnant or lactating patients are excluded.)
• Patients of reproductive potential must practice effective contraception while on study and for at least six months after receiving the last dose of study drug.
• All patients must sign an informed consent prior to enrollment.
• No prior history of non-thyroid malignancy, except adequately treated skin cancer or in situ cervical carcinoma or any other cancer in complete remission for at least two years.
• Prior chemotherapy, chemoradiation, radiation therapy, or surgery must have been completed at least 28 days prior to registration, and all toxicities must have resolved. Patients who have been treated with nitrosourea or mitomycin C must be off of these drugs for at least 6 weeks prior to registration.
• Patients must be able to take oral medications.

Exclusion Criteria:

• Anaplastic thyroid cancer that does not overexpress PDGF receptors or c-Abl by immunohistochemistry
• Any medical or psychiatric illness which, in the opinion of the principal investigator, would compromise the patient's ability to tolerate this treatment regimen.
• No concurrent radiotherapy (to the primary tumor) or chemotherapy may be given to the patient during the administration of the study drug.
• Pregnant or lactating women, women of childbearing potential with either a positive pregnancy test (PPT) at baseline, or sexually active females not using reliable contraceptive methods while on study and for at least six months after chemotherapy. (Postmenopausal women must have been amenorrheic for least 12 months to be considered of non-childbearing potential).
• Sexually active males not using reliable contraceptive methods while on the study and for at least six months after chemotherapy.
• Patients with malabsorption syndromes will be excluded.
• Serious concurrent infections.
• Patients who have had previous organ allografts will be excluded.
• Prisoners.
• Patients with chronic liver disease (i.e chronic active hepatitis and cirrhosis).
• Patients with a known diagnosis of human immunodeficiency virus (HIV) infection.
• Patients who have had major surgery within 2 weeks of study entry.
• Patients with grade III/IV cardiac problems as defined by the New York Heart Association Criteria (i.e. congestive heart failure, myocardial infarction within 6 months of study entry).