Myelofibrosis, Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase, Post-essential Thrombocythemia Related Myelofibrosis, Primary Myelofibrosis
Conditions
Keywords
monoclonal antibody
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.
Interventions
BIOLOGICALmonoclonal antibody to TGF-beta
starting dose of 1mg/kg intravenous over approximately 1 hour every 4 weeks for a total of 6 doses
Sponsors
John Mascarenhas
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | 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
| Measure | Time frame | Description |
|---|---|---|
| Bauermeister Scale | 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. |
| European Consensus Fibrosis Grade | 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. |
| Peripheral Blood CD34+ | 6 months | Investigate exploratory markers for their ability to predict responsiveness to treatment with GC1008. |
| JAK2V617F Allele Burden | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment period from Jan 2011 to Feb 2012 of known patients to the medical clinic.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 MF Subjects 3 subjects were enrolled in the study. The three subjects were treated at a GC1008 dose level of 1 mg/kg given intravenously over approximately 60 minutes and then repeated every 28 days for a total of 6 cycles in the core study period and then an additional 6 cycles in an extension phase. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Phase 1 MF Subjects |
|---|---|
| Age, Continuous | 68.67 years STANDARD_DEVIATION 10.07 |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 1 / 1 | 0 / 1 |
Outcome results
Primary
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.
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sub A | Safety and Tolerability | 4 events |
| Sub B | Safety and Tolerability | 4 events |
| Sub C | Safety and Tolerability | 1 events |
Secondary
Bauermeister Scale
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sub A | Bauermeister Scale | 4 units on a scale |
| Sub B | Bauermeister Scale | 3 units on a scale |
| Sub C | Bauermeister Scale | 4 units on a scale |
Secondary
European Consensus Fibrosis Grade
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sub A | European Consensus Fibrosis Grade | 3 units on a scale |
| Sub B | European Consensus Fibrosis Grade | 2 units on a scale |
| Sub C | European Consensus Fibrosis Grade | 2 units on a scale |
Secondary
JAK2V617F Allele Burden
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sub A | JAK2V617F Allele Burden | 48 percentage of mutant alleles |
| Sub B | JAK2V617F Allele Burden | 95 percentage of mutant alleles |
| Sub C | JAK2V617F Allele Burden | 14 percentage of mutant alleles |
Secondary
Peripheral Blood CD34+
Investigate exploratory markers for their ability to predict responsiveness to treatment with GC1008.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sub A | Peripheral Blood CD34+ | 3 percentage of hematopoietic stem cells |
| Sub B | Peripheral Blood CD34+ | 2 percentage of hematopoietic stem cells |
| Sub C | Peripheral Blood CD34+ | 0 percentage of hematopoietic stem cells |