Phase II Study of Bevacizumab (Avastin®) in Myelofibrosis

Inclusion Criteria:

• Diagnosis of primary myelofibrosis, essential thrombocythemia related myelofibrosis, and polycythemia vera related myelofibrosis requiring therapy, including those previously treated and relapsed or refractory, or, if newly diagnosed, with intermediate or high risk according to Lille scoring system
• Patients not willing to undergo, not a candidate for, or not having a donor for a bone marrow transplant.
• Signed informed consent: Patients must have signed consents for both the bevacizumab protocol and for the mandatory biomarker MDP-RC 107 protocol to be eligible to participate.
• Patients must have been off any IM-directed therapy for 2 weeks prior to entering this study and have recovered from the toxic effects (grade 0-1) of that therapy.
• Serum bilirubin levels less than or equal to 2 times the upper limit of the normal range for the laboratory (ULN). Higher levels are acceptable if these can be attributed by treating physician to active hemolysis or ineffective erythropoiesis due to myelofibrosis;
• Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels less than or equal to 2x ULN.
• Serum creatinine levels less than or equal to 1.5 x ULN.
• Women of childbearing potential must have a negative serum or urine pregnancy test prior to bevacizumab treatment and should be advised to avoid becoming pregnant. Men must be advised to not father a child while receiving treatment with bevacizumab. Both women of childbearing potential and men must practice effective methods of contraception (those generally accepted as standard of care measures). Women of child bearing potential are women who are not menopausal for 12 months or who have not undergone previous surgical sterilization.
• Age > 18 years.
• LVEF >50% by MUGA or ECHO (only in patients with prior exposure to anthracyclines).

Exclusion Criteria:

• Nursing and pregnant females. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Inadequately controlled hypertension (defined as systolic blood pressure >140 and/or diastolic blood pressure >90 mmHg on antihypertensive medications) within 4 weeks prior to entering this study
• Any prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• Unstable angina
• History of myocardial infarction within 6 months
• History of stroke or transient ischemic attack within 6 months
• History of Budd-Chiari Syndrome or portal vein thrombosis.
• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
• Symptomatic peripheral vascular disease
• Evidence of bleeding diathesis or clinically significant coagulopathy
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days, or anticipation of the need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device or bone marrow biopsy, within 7 days prior to study enrollment

• Proteinuria at screening as demonstrated by either

  • Urine protein:creatinine (UPC) ratio greater than or equal to 1.0 at screening OR
  • Urinalysis with proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
• History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months
• Ongoing serious, non-healing wound, ulcer, or bone fracture
• Known hypersensitivity to any component of bevacizumab
• Patients with a history of DVT and/or a CNS thrombotic or hemorrhagic event within the past 6 months.
• Patients on anticoagulation therapy for a variety of conditions such as prosthetic heart valves or chronic atrial fibrillation.