Sunitinib in Treating Patients With Recurrent or Persistent Leiomyosarcoma of the Uterus

PRIMARY OBJECTIVES:

I. Assess the activity of sunitinib malate, in terms of rate of progression-free survival for ≥ 6 months and objective tumor response, in patients with recurrent or persistent leiomyosarcoma of the uterus who have received 1 or 2 prior cytotoxic therapies.

II. Determine the frequency and severity of adverse events.

SECONDARY OBJECTIVES:

I. Determine the duration of progression-free survival and overall survival.

OUTLINE: This is a multicenter study. Patients receive oral sunitinib malate once daily on days 1-28. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

Inclusion criteria

• Histologically confirmed leiomyosarcoma of the uterus

• Recurrent or persistent disease
• Refractory to curative therapy or established treatments
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan

• Ascites and pleural effusions are not considered measurable disease
• Must have ≥ 1 target lesion to assess response

• Tumors in a previously irradiated field are considered non-target lesions unless there is documented progression or biopsy-confirmed persistence ≥ 90 days after completion of radiotherapy
• Received at least 1 but no more than 2 prior cytotoxic regimens

• Initial treatment may have included high-dose chemotherapy, consolidation, or extended therapy administered after surgery or nonsurgical assessment
• Cytotoxic regimens may have included any agent that targets the genetic and/or mitotic apparatus of dividing cells, resulting in dose-limiting toxicity to the bone marrow and/or gastrointestinal mucosa
• Not a candidate for a higher priority GOG protocol
• No known brain metastases
• GOG performance status 0-2 (for patients who have received 1 prior regimen) OR GOG 0-1 (for patients who have received 2 prior regimens)
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• SGOT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 1.5 times ULN
• QTc < 500 msec
• LVEF normal by echocardiogram
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 1 month after completion of study treatment
• Patients with a pre-existing thyroid abnormality unable to maintain normal thyroid function with medication are not eligible
• No significant EKG abnormalities (i.e., no history of serious ventricular arrhythmia OR EKG with ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
• No sensory or motor neuropathy > grade 1
• No NYHA class III-IV congestive heart failure

• NYHA class II cardiac dysfunction allowed
• History of NYHA class II heart failure that is asymptomatic on treatment allowed
• No active infection requiring antibiotics
• No other invasive malignancies within the past 5 years except for nonmelanoma skin cancer
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib malate
• No poorly controlled hypertension (i.e., systolic blood pressure [BP] ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg)
• No gastrointestinal tract disease resulting in an inability to take oral medication
• No requirement for IV alimentation
• No active peptic ulcer disease
• No other condition that would impair ability to swallow and retain study drug
• No serious or nonhealing wound, ulcer, or bone fracture
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
• No cerebrovascular accident or transient ischemic attack within the past year
• No myocardial infarction, cardiac arrhythmia, stable or unstable angina, or symptomatic congestive heart failure within the past year
• No pulmonary embolism within the past year
• No uncontrolled illness including, but not limited to, any of the following:

• Ongoing or active infections
• Psychiatric illness or social situations that would preclude study compliance
• Recovered from prior surgery, chemotherapy, or radiotherapy
• Prior anthracycline exposure and central thoracic radiation that included the heart allowed provided patient has New York Heart Association (NYHA) class II cardiac function
• At least 1 week since prior hormonal therapy
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin C) or radiotherapy
• At least 4 weeks since prior major surgery
• At least 3 years since prior radiotherapy for localized cancer of the breast, head and neck, or skin and no recurrent or metastatic disease
• At least 3 years since prior adjuvant chemotherapy for localized cancer of the breast and no recurrent or metastatic disease
• No prior radiotherapy to any portion of the abdominal cavity or pelvis unless for treatment of leiomyosarcoma
• No prior chemotherapy to any portion of the abdominal cavity or pelvis unless for treatment of leiomyosarcoma
• No prior noncytotoxic chemotherapy for recurrent or persistent disease
• No prior surgical procedures affecting absorption
• No coronary or peripheral artery bypass graft or stenting within the past year
• No other prior antiangiogenic agents (e.g., bevacizumab, sorafenib, pazopanib, AZD2171, vatalanib, or vascular endothelial growth factor [VEGF] Trap)
• No other prior cancer treatment that would preclude study treatment
• At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following:

• Azole fungals (e.g., ketoconazole or itraconazole)
• Clarithromycin
• Erythromycin
• Diltiazem
• Verapamil
• HIV protease inhibitors (e.g., indinavir, saquinavir, ritonavir, atazanavir, or nelfinavir)
• Delavirdine
• At least 12 days since prior and no concurrent CYP3A4 inducers, including any of the following:

• Rifampin
• Rifabutin
• Carbamazepine
• Phenobarbital
• Phenytoin
• Hypericum perforatum (St. John's wort)
• Efavirenz
• Tipranavir
• No concurrent proarrhythmic potential agent, including any of the following:

• Terfenadine
• Quinidine
• Procainamide
• Disopyramide
• Sotalol
• Probucol
• Bepridil
• Haloperidol
• Risperidone
• Indapamide
• Flecainide
• No concurrent therapeutic coumarin-derivative anticoagulants, such as warfarin

• Doses ≤ 2 mg daily allowed for prophylaxis of thrombosis
• Low molecular weight heparin allowed provided PT INR ≤ 1.5
• No concurrent amifostine or other protective agents
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies