Anti-TGF-beta Therapy in Patients With Myelofibrosis
Condition: Myelofibrosis; Primary Myelofibrosis; Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase; Post-essential Thrombocythemia Related Myelofibrosis
MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential
Intervention: monoclonal antibody to TGF-beta
Intervention description: starting dose of 1mg/kg intravenous over approximately 1 hour every 4 weeks for a total of 6 doses
Intervention MeSH terms: Antibodies; Antibodies, Monoclonal
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: monoclonal antibody

Summary:

      TGF-β is a cytokine that is found to be upregulated in the bone marrow of patients with
      myelofibrosis. This cytokine likely plays a dual role in promoting myelofibrosis and
      myeloproliferation, both of which are the bone marrow morphologic hallmark of MF. The
      investigators propose that inhibiting the TGF-β signaling pathway in MF will decrease the
      fibrogenic stimuli leading to myelofibrosis and concomitantly interrupt myeloproliferation.
      This is a novel approach to the treatment of patients with myelofibrosis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age >18

          -  ECOG 0-2

          -  Intermediate-1 or higher by IWG-MRT Post PV/ET MF patients OR intermediate-1 or higher
             JAK2V617F negative PMF

          -  Bone marrow MF-2 or higher as assessed by the European consensus grading score AND
             grade 3 or higher by modified Bauermeister scale.

          -  Patients must be able to give written informed consent to participate. Patients may
             not be consented by a durable power of attorney.

          -  Male and female patients of child-producing potential must agree to use effective
             contraception while enrolled on study and receiving the investigational agent, and for
             at least 3 months after the last treatment.

          -  At the time of enrollment, patients must be >4 weeks since major surgery,
             radiotherapy, chemotherapy (except hydroxyurea) immunotherapy, or biotherapy/targeted
             therapies and recovered from the toxicity of prior treatment to < Grade 1, exclusive
             of alopecia. Concurrent cancer therapy is not permitted for the exception of
             hydroxyurea if already being used at a stable dose for 3 weeks prior to screening.

          -  Patients must have negative tests for human immunodeficiency virus (HIV) and for
             hepatitis viruses B and C (antibody and/or antigen) unless the result is consistent
             with prior vaccination or prior infection with full recovery.

          -  Marrow: Absolute neutrophil count ≥ 500/mm3, and platelet count ≥50,000/mm3 without
             the need for platelet transfusion within 4 weeks

          -  Hepatic: Serum total bilirubin >1.5 X upper limit of normal (ULN) (Patients with
             Gilbert's Disease may be included if their total bilirubin is >3.0 mg/dL); alanine
             aminotransferase (ALT), and aspartate aminotransferase (AST) >2.5 X ULN.

          -  Renal: Serum creatinine of < 1.5 x upper limit of normal (ULN) or, if higher,
             estimated or measured creatinine clearance >45 mL/min.

          -  Coagulation:

               1. Prothrombin Time (PT) < 1.5 X ULN

               2. Partial thromboplastin time (aPTT) < 1.5 X ULN

        Exclusion Criteria:

          -  Central nervous system (CNS) cancer or metastases, meningeal carcinomatosis, malignant
             seizures, or a disease that either causes or threatens neurologic compromise (e.g.,
             unstable vertebral metastases).

          -  Pregnant or nursing women, due to the unknown effects of GC1008 on the developing
             fetus or newborn infant.

          -  Patients with known bleeding diathesis or signs of uncontrolled active bleeding
             (hematuria, GI bleeding) other than self-limited causes of benign etiology that have
             been adequately investigated at the discretion of the investigator.

          -  Patients requiring anticoagulation with aspirin > 81mg daily, unfractionated heparin,
             low molecular weight heparin (LMWH), direct anti-thrombin inhibitors, or vitamin K
             antagonists (e.g. warfarin). This does not apply to patients actively receiving
             aspirin at a dose of ≤ 81mg a day.

          -  Patients diagnosed with another malignancy - unless following curative intent therapy,
             the patient has been disease free for at least 5 years and the probability of
             recurrence of the prior malignancy is >5%. Patients with curatively treated early
             stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or
             cervical intraepithelial neoplasia (CIN) are eligible for this study.

          -  Patients with an organ transplant, including those that have received an allogeneic
             bone marrow transplant.

          -  Use of investigational agents within 4 weeks prior to study enrollment (within 6 weeks
             if the treatment was with a long-acting agent such as a monoclonal antibody).

          -  Significant or uncontrolled medical illness, such as congestive heart failure (CHF),
             myocardial infarction, symptomatic coronary artery disease, significant ventricular
             arrhythmias within the last 6 months, or significant pulmonary dysfunction. Patients
             with a remote history of asthma or active mild asthma may participate.

          -  Active autoimmune disorders or concurrent immunosuppressive medications such as
             prednisone, interferon, cyclosporine, methotrexate or azathioprine.

          -  Active infection requiring antibiotics.

          -  A known allergy to any component of GC1008.

          -  Patients who, in the opinion of the Investigator, have significant medical or
             psychosocial problems that warrant exclusion. Examples of significant problems
             include, but are not limited to:

               1. Other serious non-malignancy-associated medical conditions that may be expected
                  to limit life expectancy or significantly increase the risk of SAEs.

               2. Any condition, psychiatric, substance abuse, or otherwise, that, in the opinion
                  of the Investigator, would preclude informed consent, consistent follow-up, or
                  compliance with any aspect of the study