Phase II Study of Bevacizumab (Avastin®) in Myelofibrosis
Condition: Myelofibrosis
MeSH terms: Primary Myelofibrosis
Intervention: bevacizumab (Avastin)
Intervention description: 15 mg/kg of bevacizumab by IV infusion once every 3 weeks (1 cycle) for 12 weeks (4 cycles)
Intervention MeSH terms: Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Myelofibrosis; Idiopathic; Bevacizumab; Avastin; bone marrow fibrosis; bone marrow angiogenesis; JAK2

Summary:

      Myelofibrosis is the gradual replacement of bone marrow (place where most new blood cells are
      produced) by fibrous tissue which reduces the body's ability to produce new blood cells and
      results in the development of chronic anemia (low red blood cell count). One of the main
      distinctions of myelofibrosis is "extramedullary hematopoiesis", the migration or traveling
      of the blood-forming cells out of the bones to other parts of the body, such as the liver or
      spleen, resulting in an enlarged spleen and liver.

      There is not a standard treatment for myelofibrosis, therefore there is no medication that is
      specifically used in the treatment of myelofibrosis. Bevacizumab (Avastin®) targets and stops
      a growth factor in the body that helps produce the type of fibrous tissue that is gradually
      replacing the bone marrow in the bones.

      The purpose of this study is to find out how safe and effective bevacizumab is in treating
      myelofibrosis. The investigators also wish to find out important biologic characteristics or
      features of myelofibrosis (how it works and operates) during the time of study participation
      through an additional correlative biomarker study (MPD-RC #107). The purpose of the biomarker
      study is to understand the causes of MPD and to develop improved methods for the diagnosis
      and treatment of these diseases, while the main study is trying to find out how well
      bevacizumab will work in treating the disease.
    

Eligibility criteria:

        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.