Sunitinib in Treating Patients With Idiopathic Myelofibrosis

A Phase II Study of Sunitinib Malate in Idiopathic Myelofibrosis

This phase II trial is studying how well sunitinib works in treating patients with idiopathic myelofibrosis. Sunitinib may stop the growth of abnormal cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the abnormal cells.

PRIMARY OBJECTIVE:

I. Assess the response rate and the duration of response in patients with idiopathic myelofibrosis treated with sunitinib malate.

SECONDARY OBJECTIVE:

I. Assess the safety of sunitinib malate in these patients.

OUTLINE: This is an open-label, multicenter study.

Patients receive oral sunitinib malate once daily for 6 weeks. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 4 weeks.

Criteria:

• At least 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C)
• At least 4 weeks since prior major surgery
• At least 7 days since prior and no concurrent CYP3A4 inhibitors, including azole antifungals (ketoconazole and itraconazole), clarithromycin, erythromycin, diltiazem, verapamil, HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfinavir), and delavirdine
• At least 12 days since prior and no concurrent CYP3A4 inducers, including rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, Hypericum perforatum (St. John's wort), efavirenz, and tipranavir
• No prior antiangiogenic agents (e.g., bevacizumab, sorafenib, pazopanib, AZD2171, vatalanib, VEGF Trap)
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies
• No concurrent therapeutic doses of coumarin-derivative anticoagulants (e.g., warfarin) (Warfarin =< 2 mg/day for prophylaxis of thrombosis and low molecular weight heparin allowed provided INR =< 1.5)
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent agents with proarrhythmic potential (e.g., terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and flecainide)

Inclusion Criteria:

• Diagnosis of MF (histologically confirmed) requiring therapy, including those previously treated and relapsed or refractory (no more than one prior standard acute leukemia-type chemotherapy regimen; no limit on prior MF - directed therapies) or if newly diagnosed, with intermediate or high risk according to Lille scoring system (adverse prognostic factors are: Hb < 10 g/dl, WBC < 4 or > 30 x 10^9/L; risk group: 0 = low, 1 = intermediate, 2 = high), or with symptomatic organomegaly.
• Serum bilirubin levels </= 2x upper limit of the normal (ULN). Higher levels are acceptable if these can be attributed to active hemolysis or MF
• Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels </= 2x ULN. Higher levels are acceptable if these can be attributed to MF.
• Serum creatinine levels </= 2x ULN.
• Eighteen years of age or older.
• ECOG performance status 0-1 (Karnofsky </= 70%).
• Patients must have QTc < 500 msec
• Women of childbearing potential and men must agree to use adequate contraception (e.g. hormonal or barrier method of birth control; abstinence) for the duration of study participation. All women of childbearing potential must have a negative pregnancy test prior to receiving sunitinib. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document
• Both men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to beginning treatment or those who have not recovered from treatment-limiting adverse events (to grade 1 or better) due to agents administered more than 4 weeks earlier. At least 4 weeks must have elapsed since any major surgery prior to study enrollment. Continuous use of supportive care medications (i. e. growth factors, anagrelide, or hydroxyurea) is allowed.
• Patients may not be receiving any other investigational agents.
• Patients who have received prior treatment with any other specific antiangiogenic agent (e.g., bevacizumab, sorafenib, pazopanib, AZD2171, PTK787, VEGF Trap, etc.) targeting VEGF/VEGFR system. Other agents that may have some antiangiogenic effects are allowed). (i.e. thalidomide)
• Patients with abnormal QTc prolongation (defined as a QTc interval equal to or greater than 500 msec) or patients who have a history of serious ventricular arrhythmia (VT or VF>/= 3 beats in a row or other significant (as judged by treating physician) ECG abnormalities.Patients with consistently poorly controlled (during the month prior to study screening) hypertension (systolic blood pressure of 140 mmHg or higher or diastolic blood pressure of 90 mmHg or higher) despite appropriate medical management of the hypertension.
• Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such as warfarin. Exceptions include: patients using warfarin of up to 2 mg daily for prophylaxis of thrombosis, and patients using low molecular weight heparin provided the patient's INR is </= 1.5.
• Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain sunitinib tablets.
• Patients with any of the following conditions:·Serious or non-healing wound, ulcer, or bone fracture, history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of treatment,·cerebrovascular accident (CVA) or transient ischemic attack, myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting, or pulmonary embolism within 12 months prior to study,·Class III or IV heart failure as defined by the NYHA functional classification system.
• Because sunitinib is metabolized primarily by the CYP3A4 liver enzyme, the eligibility of patients taking medications that are potent inducers or inhibitors of that enzyme will be determined following a review of their case by the Principal Investigator. Every effort should be made to switch patients taking such agents or substances to other medications.
• Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid function in the normal range with medications.
• Patients with uncontrolled intercurrent illness (as judged by treating physician) including, but not limited to, ongoing or active infections requiring IV antibiotics.
• Pregnant women are excluded from this study because sunitinib is an antiangiogenic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with sunitinib, breastfeeding should be discontinued if the mother is treated with sunitinib malate.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with sunitinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.