Anti-TGF-beta Therapy in Patients With Myelofibrosis

• Sponsor: John Mascarenhas (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01291784
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arm: 1
• Duration (Months): 23
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• 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: Feb 1, 2011
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

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 Names: GC1008

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. Peripheral Blood CD34+ [6 months]

   Investigate exploratory markers for their ability to predict responsiveness to treatment with GC1008.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029

Sponsors and Collaborators

• John Mascarenhas

Investigators

• Principal Investigator: John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai
• Study Chair: Ronald Hoffman, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: John Mascarenhas, Principal Investigator, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01291784
• Other Study ID Numbers: GCO 10-1450; GC1008-JM
• First Posted: Feb 8, 2011
• Last Update Posted: Dec 8, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by John Mascarenhas, Principal Investigator, Icahn School of Medicine at Mount Sinai: monoclonal antibody
• Additional relevant MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential; Antibodies; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	Recruitment period from Jan 2011 to Feb 2012 of known patients to the medical clinic.

Arm/Group Title	Sub A	Sub B	Sub C
Arm/Group Description	Subject A	Subject B	Subject C
Period Title: Overall Study
STARTED	1	1	1
COMPLETED	1	0	1
NOT COMPLETED	0	1	0

Baseline Characteristics

Arm/Group Title	Phase 1 MF Subjects
Arm/Group Description	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.
Overall Participants	3
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.67 (10.07)
Sex: Female, Male (Count of Participants)
Female	2 66.7%
Male	1 33.3%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Safety and Tolerability
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sub A	Sub B	Sub C
Arm/Group Description	Subject A	Subject B	Subject C
Measure Participants	1	1	1
Number [events]	4	4	1

2. Secondary Outcome

Title	Bauermeister Scale
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sub A	Sub B	Sub C
Arm/Group Description	Subject A	Subject B	Subject C
Measure Participants	1	1	1
Number [units on a scale]	4	3	4

3. Secondary Outcome

Title	European Consensus Fibrosis Grade
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sub A	Sub B	Sub C
Arm/Group Description	Subject A	Subject B	Subject C
Measure Participants	1	1	1
Number [units on a scale]	3	2	2

4. Secondary Outcome

Title	Peripheral Blood CD34+
Description	Investigate exploratory markers for their ability to predict responsiveness to treatment with GC1008.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sub A	Sub B	Sub C
Arm/Group Description	Subject A	Subject B	Subject C
Measure Participants	1	1	1
Number [percentage of hematopoietic stem cells]	3	2	0

5. Secondary Outcome

Title	JAK2V617F Allele Burden
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sub A	Sub B	Sub C
Arm/Group Description	Subject A	Subject B	Subject C
Measure Participants	1	1	1
Number [percentage of mutant alleles]	48	95	14

Adverse Events

Arm/Group Title	Sub A		Sub B		Sub C
Arm/Group Description	Subject A		Subject B		Subject C
All Cause Mortality
	Sub A		Sub B		Sub C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sub A		Sub B		Sub C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		1/1 (100%)		0/1 (0%)
Cardiac disorders
Asystole	0/1 (0%)	0	1/1 (100%)	1	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	Sub A		Sub B		Sub C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		1/1 (100%)		1/1 (100%)
Blood and lymphatic system disorders
leukocytosis	0/1 (0%)	0	1/1 (100%)	1	0/1 (0%)	0
leukopenia	1/1 (100%)	1	0/1 (0%)	0	0/1 (0%)	0
General disorders
fatigue	0/1 (0%)	0	1/1 (100%)	1	0/1 (0%)	0
hypoxia	0/1 (0%)	0	1/1 (100%)	1	0/1 (0%)	0
Immune system disorders
herpes zoster	0/1 (0%)	0	0/1 (0%)	0	1/1 (100%)	1
Skin and subcutaneous tissue disorders
skin lesions	1/1 (100%)	3	0/1 (0%)	0	0/1 (0%)	0

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.