Anti-TGF-beta Therapy in Patients With Myelofibrosis

NCT ID: NCT01291784

Last Updated: 2014-12-08

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-28
• Study Completion Date: 2013-01-31

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.

Conditions

Myelofibrosis; Primary Myelofibrosis; Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase; Post-essential Thrombocythemia Related Myelofibrosis

Keywords

monoclonal antibody

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

monoclonal antibody to TGF-beta

starting dose of 1mg/kg intravenous over approximately 1 hour every 4 weeks for a total of 6 doses

Group Type: EXPERIMENTAL

monoclonal antibody to TGF-beta

Intervention Type: BIOLOGICAL

starting dose of 1mg/kg intravenous over approximately 1 hour every 4 weeks for a total of 6 doses

Interventions

monoclonal antibody to TGF-beta

starting dose of 1mg/kg intravenous over approximately 1 hour every 4 weeks for a total of 6 doses

Intervention Type: BIOLOGICAL

Other Intervention Names

GC1008

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

John Mascarenhas

OTHER

Sponsor Role: lead

Responsible Party

John Mascarenhas

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

John Mascarenhas, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Ronald Hoffman, MD

Role: STUDY_CHAIR

Icahn School of Medicine at Mount Sinai

Locations

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Countries

United States

References

Mascarenhas J, Li T, Sandy L, Newsom C, Petersen B, Godbold J, Hoffman R. Anti-transforming growth factor-beta therapy in patients with myelofibrosis. Leuk Lymphoma. 2014 Feb;55(2):450-2. doi: 10.3109/10428194.2013.805329. Epub 2013 Jun 24. No abstract available.

Reference Type: RESULT

PMID: 23682558 (View on PubMed)

Other Identifiers

GC1008-JM

Identifier Type: -

Identifier Source: secondary_id

GCO 10-1450

Identifier Type: -

Identifier Source: org_study_id