Anti-TGF-beta Therapy in Patients With Myelofibrosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01291784
Recruitment Status : Terminated (Early termination when the drug was no longer made available by the pharmaceutical company due to unanticipated management and administrative decisions.)
First Posted : February 8, 2011
Results First Posted : August 28, 2014
Last Update Posted : December 8, 2014
Information provided by (Responsible Party):
John Mascarenhas, Icahn School of Medicine at Mount Sinai

Brief 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.

Condition or disease Intervention/treatment Phase
Myelofibrosis Primary Myelofibrosis Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase Post-essential Thrombocythemia Related Myelofibrosis Biological: monoclonal antibody to TGF-beta Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of GC1008 in Patients With Primary Myelofibrosis (PMF), Post-polycythemia Vera/Essential Thrombocythemia Related Myelofibrosis (Post-PV/ET MF)
Study Start Date : February 2011
Actual Primary Completion Date : January 2013
Actual Study Completion Date : January 2013

Arm Intervention/treatment
Experimental: monoclonal antibody to TGF-beta
starting dose of 1mg/kg intravenous over approximately 1 hour every 4 weeks for a total of 6 doses
Biological: monoclonal antibody to TGF-beta
starting dose of 1mg/kg intravenous over approximately 1 hour every 4 weeks for a total of 6 doses
Other Name: GC1008

Primary Outcome Measures :
  1. Safety and Tolerability [ Time Frame: 28 days ]

    To assess the safety and tolerability of GC1008 in patients with primary myelofibrosis (PMF) or post-polycythemia vera/essential thrombocythemia myelofibrosis (Post-PV/ET MF).

    A total of 9 AEs determined by the investigator to be at least possibly related to GC1008 occurred during the study.

Secondary Outcome Measures :
  1. Bauermeister Scale [ Time Frame: 6 months ]

    To assess the clinical response to therapy with GC1008 by International Working Group (IWG) criteria and measure the change in degree of bone marrow fibrosis (BMF) assessed by Bauermeister scale.

    Bauermeister scale: 0, no demonstrable reticulin fibers; 1, occasional fine individual fibers and foci of a fine-fiber network; 2, fine fiber network throughout most of the section, but no coarse fibers; 3, diffuse fiber network with scattered thick coarse fibers, but no mature collagen; and 4, diffuse, often coarse fiber network with areas of collagen.

  2. European Consensus Fibrosis Grade [ Time Frame: 6 months ]

    To assess the clinical response to therapy with GC1008 by International Working Group (IWG) criteria and measure the change in degree of bone marrow fibrosis (BMF) assessed by European consensus grading system.

    This scheme consists of a qualitative (reticulin or collagen) and quantitative evaluation of bone marrow fibrosis and distinguishes four increasing categories, ranging from MF-0, which corresponds to normal bone marrow, to MF-3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis.

  3. Peripheral Blood CD34+ [ Time Frame: 6 months ]
    Investigate exploratory markers for their ability to predict responsiveness to treatment with GC1008.

  4. JAK2V617F Allele Burden [ Time Frame: 6 months ]
    Investigate exploratory markers, hematopoietic cells, for their ability to predict responsiveness to treatment with GC1008. Analysis of percentage of mutant alleles in hematopoietic stem cells.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01291784

United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
Sponsors and Collaborators
John Mascarenhas
Principal Investigator: John Mascarenhas, MD Icahn School of Medicine at Mount Sinai
Study Chair: Ronald Hoffman, MD Icahn School of Medicine at Mount Sinai

Publications of Results:
Responsible Party: John Mascarenhas, Principal Investigator, Icahn School of Medicine at Mount Sinai Identifier: NCT01291784     History of Changes
Other Study ID Numbers: GCO 10-1450
First Posted: February 8, 2011    Key Record Dates
Results First Posted: August 28, 2014
Last Update Posted: December 8, 2014
Last Verified: November 2014

Keywords provided by John Mascarenhas, Icahn School of Medicine at Mount Sinai:
monoclonal antibody

Additional relevant MeSH terms:
Primary Myelofibrosis
Polycythemia Vera
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs