Fostamatinib as a Single Agent or in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis With Severe Thrombocytopenia
Condition: Myelofibrosis; Thrombocytopenia
MeSH terms: Thrombocytopenia; Primary Myelofibrosis
Intervention: Fostamatinib; Ruxolitinib
Intervention description: Fostamatinib will be supplied by Rigel Pharmaceuticals.; Ruxolitinib is commercially available.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Fostamatinib may improve thrombocytopenia in myelofibrosis patients with severe
      thrombocytopenia (platelet <50,000/microL) and allow them to initiate treatment with a JAK2
      inhibitor, ruxolitinib. Additionally, fostamatinib monotherapy may also improve myelofibrosis
      related symptoms and splenomegaly.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/essential
             thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or
             intermediate 1 risk by IPSS.

          -  Severe thrombocytopenia defined as platelet count < 50,000/microL (confirmed on at
             least two measurements over an 8-week period prior to start of study).

          -  At least 18 years of age.

          -  ECOG performance status ≤ 2

          -  Able to swallow pills

          -  Adequate bone marrow and organ function as defined below:

               -  ANC ≥ 1000/microL

               -  Peripheral blood blasts ≤ 10%

               -  Albumin > 2.7 g/dL

               -  Total bilirubin ≤ 1.5 x IULN; patients with Gilbert's syndrome may enroll if
                  direct bilirubin ≤ 1.5 x IULN

               -  AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN

               -  Creatinine clearance > 30 mL/min by Cockcroft-Gault

          -  Female subjects must be either post-menopausal for at least 1 year or surgically
             sterile; or, if of childbearing potential, must not be pregnant or lactating and must
             agree to use a highly effective method of birth control throughout the duration of the
             trial and for 30 days following the last dose. Acceptable methods of birth control are
             defined as: hormonal contraception (pill, injection or implant) used consistently for
             at least 30 days prior to screening, an intrauterine device (IUD), or intrauterine
             hormone-releasing system (IUS), or true abstinence (i.e. abstinence is in line with
             the preferred and usual lifestyle of the subject.). Male subjects do not need to use
             contraception for fostamatinib because human studies showed minimal R406 in sperm.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  History of allogeneic stem cell transplant.

          -  Any solid tumor or hematologic malignancy (other than myelofibrosis) requiring active
             treatment at the time of study entry

          -  Currently receiving any other investigational agents.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to fostamatinib, ruxolitinib, or other agents used in the study.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, or cardiac arrhythmia.

          -  Subject has uncontrolled or poorly controlled hypertension, defined as systolic blood
             pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, whether or not the subject is
             receiving anti-hypertensive treatment.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             pregnancy test within 14 days of study entry and prior to the first dose of
             fostamatinib.

          -  Known positive status for human immunodeficiency virus (HIV)

          -  Chronic, active, or acute viral hepatitis A, B, or C infection, or hepatitis B or C
             carrier.

          -  Treatment with strong CYP3A inhibitors or inducers within 14 days before the first
             dose of study drug. Strong CYP3A inhibitors and CYP3A inducers are not permitted
             during the study.

          -  Ongoing gastrointestinal medical condition such as Crohn's disease, inflammatory bowel
             disease, or chronic diarrhea that is not well controlled and could interfere with
             absorption of oral medication or be exacerbated by study medication

          -  Known hepatic cirrhosis or severe pre-existing hepatic impairment.

          -  Uncontrolled coagulopathy or bleeding disorder.

          -  Female patients who intend to donate eggs and male patients who intend to donate sperm
             during the course of this study or for 4 months after receiving the last dose of study
             treatment.