Anti-TGF-beta Therapy in Patients With Myelofibrosis

NCT01291784 | Terminated Phase 1 Results DMC

• 2 other identifiers: GCO 10-1450GC1008-JM
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• Safety and Tolerability

  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.

  28 days

Secondary Outcomes (4)

• Bauermeister Scale

  6 months

• European Consensus Fibrosis Grade

  6 months

• Peripheral Blood CD34+

  6 months

• JAK2V617F Allele Burden

  6 months

Study Arms (1)

monoclonal antibody to TGF-beta

EXPERIMENTAL

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

Interventions

monoclonal antibody to TGF-beta BIOLOGICAL

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

Also known as: GC1008

monoclonal antibody to TGF-beta

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Prothrombin Time (PT) \< 1.5 X ULN
• Partial thromboplastin time (aPTT) \< 1.5 X ULN

You may not qualify if:

• 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.
• Other serious non-malignancy-associated medical conditions that may be expected to limit life expectancy or significantly increase the risk of SAEs.
• 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

Sponsors & Collaborators

• John Mascarenhas: lead

Study Sites (1)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Related Publications (1)

• 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.

  PMID: 23682558 RESULT

MeSH Terms

Conditions

Primary Myelofibrosis; Polycythemia Vera

Interventions

fresolimumab

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms

Limitations and Caveats

Early termination when the drug was no longer made available by the pharmaceutical company due to unanticipated management and administrative decisions. Limited patient data (2 evaluable patients), a dose accumulation ratio cannot be determined.

Results Point of Contact

• Title: Dr. John O. Mascarenhas
• Organization: Icahn School of Medicine at Mount Sinai

john.mascarenhas@mssm.edu

212-241-6756

Study Officials

• John Mascarenhas, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

• Ronald Hoffman, MD

  Icahn School of Medicine at Mount Sinai

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 7, 2011
• First Posted: February 8, 2011
• Study Start: February 1, 2011
• Primary Completion: January 1, 2013
• Study Completion: January 1, 2013
• Last Updated: December 8, 2014
• Results First Posted: August 28, 2014

Record last verified: 2014-11

Locations

US (1)