Study of Combretastatin and Paclitaxel/Carboplatin in the Treatment of Anaplastic Thyroid Cancer

A Phase II/III Study to Evaluate the Safety and Efficacy of Combretastatin A-4 Phosphate in Combination With Paclitaxel and Carboplatin in Comparison With Paclitaxel and Carboplatin Against Anaplastic Thyroid Carcinoma [FACT]

The purpose of the study is to determine the safety and efficacy of combretastatin combined with paclitaxel and carboplatin in the treatment of anaplastic thyroid cancer (ATC).

Anaplastic thyroid carcinoma (ATC) is a high-grade neoplasm, characterized by an aggressive clinical course with brief survival, and refractoriness to currently available local and systemic modalities of treatment. There is no standard therapy for ATC, and no randomized comparative trials have been known to be conducted in this disease. One potential strategy is to combine the anti-tumor activity of the vascular disrupting agent combretastatin with conventional cytotoxic agents. This study will compare the overall survival of ATC patients treated with the triplet combination of combretastatin, paclitaxel, and carboplatin compared with the doublet treatment of paclitaxel and carboplatin.

Inclusion Criteria:

• Anaplastic thyroid carcinoma histologically or cytologically confirmed by a pathology review
• Refractory to or progressed during or after therapy, or relapsed within 6 months following initial combined modality therapy (usually including systemic chemotherapy and radiation) for regionally advanced disease
• Systemic therapy is limited to one chemotherapy regimen that is clearly administered contiguously, (i.e., in an uninterrupted primary therapeutic approach)
• Prior radiation: 3 weeks must have elapsed since radiation and disease must be present beyond radiation ports
• Minimum of 3 weeks must have elapsed from the time of last chemotherapy prior to the first dose of study drug
• Patients with bulky thyroid/neck masses and/or suspicion of airway obstruction must undergo screening (indirect and direct laryngoscopy) to ensure patency of the trachea/airway prior to study enrollment and treatment
• ECOG Performance Score less than or equal to 2
• Adequate bone marrow reserve as evidenced by absolute neutrophil count (ANC) greater than 1,500/microL, platelet count greater than 75,000/microL.
• Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 mg/dL (less than 177 micromol/L)
• Adequate hepatic function as evidenced by serum total bilirubin less than 2X greater than the upper limit of normal (ULN) (less than3X ULN in patients with liver metastases), AST (aspartate aminotransferase)/ALT (alanine aminotransferase) less than or equal to 3X the ULN for the local reference lab (less than or equal to 5X the ULN for patients with liver metastases)
• No clinically important sequelae from any prior surgery or radiotherapy.

Exclusion Criteria:

• Tumors confined to the thyroid.
• Clinically evident brain metastasis, including symptomatic involvement, evidence of cerebral edema by CT or MRI, radiographic evidence of progression of brain metastasis since definitive therapy, or continued requirement for corticosteroids
• Patients who receive chemotherapy for metastatic disease after completion of a combined modality approach.
• History of malignancies other than ATC except curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current PSA of less than 4.0 mg/dL or microg/L
• Known hypersensitivity to CA4P, paclitaxel or carboplatin, or any of their components
• Receiving concurrent investigational therapy or who have received investigational therapy for any indication within 28 days of the first scheduled day of dosing
• Greater than Grade 2 peripheral neuropathy
• History of prior cerebrovascular event, including transient ischemic attack
• Uncontrolled hypertension (blood pressure greater than 150/100 mm Hg despite medication)
• Symptomatic vascular disease (e.g. intermittent claudication)
• History of unstable angina pectoris pattern, myocardial infarction (including non-Q wave MI) within the past 6 months, or NYHA Class III and IV congestive heart failure
• History of torsade de pointes
• Bradycardia (less than 60 b/m), heart block (excluding 1st degree block, being PR interval prolongation only), and congenital long QT syndrome
• Any ventricular arrhythmias, or new ST segment elevation or depression or Q wave on ECG
• Ejection fractions less than normal (i.e. less than 45%)
• QTc prolongation greater than 450 ms
• Requirement of any drugs known to prolong the QTc interval, including anti-arrhythmic medications
• Potassium concentrations below 4.0 mEq/dL and magnesium concentrations below 1.8 mg/dL despite being on an electrolyte supplement
• Requirement of any drugs known to prolong the QTc interval
• History of solid organ transplant or bone marrow transplant