Anti-TGF-beta Therapy in Patients With Myelofibrosis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
John Mascarenhas, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT01291784
First received: February 7, 2011
Last updated: March 22, 2013
Last verified: March 2013
  Purpose

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 Intervention Phase
Myelofibrosis
Primary Myelofibrosis
Post-polycythemia Vera Related Myelofibrosis
Post-essential Thrombocythemia Related Myelofibrosis
Biological: monoclonal antibody to TGF-beta
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

Primary Outcome Measures:
  • 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). [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 and European consensus grading system. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Investigate exploratory markers for their ability to predict responsiveness to treatment with GC1008, these include plasma TGF-β level, peripheral blood CD34+ hematopoietic cell number, JAK2V617F allele burden and cytogenetics. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • To assess any impact of GC1008 on myeloproliferative neoplasm associated symptoms with the sequential use of the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and EORTC-QLQ-C30. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 3
Study Start Date: February 2011
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 azathiopurine.
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01291784

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

No publications provided

Responsible Party: John Mascarenhas, Principal Investigator, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT01291784     History of Changes
Other Study ID Numbers: GCO 10-1450, GC1008-JM
Study First Received: February 7, 2011
Last Updated: March 22, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Mount Sinai School of Medicine:
monoclonal antibody

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

ClinicalTrials.gov processed this record on July 24, 2014