Phase II Study of Bevacizumab (Avastin®) in Myelofibrosis

• Sponsor: Ronald Hoffman (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00667277
• Collaborator: Myeloproliferative Disorders-Research Consortium (Other), National Cancer Institute (NCI) (NIH)
• Enrollment: 13
• Locations: 5
• Arm: 1
• Duration (Months): 24
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Myelofibrosis is the gradual replacement of bone marrow (place where most new blood cells are produced) by fibrous tissue which reduces the body's ability to produce new blood cells and results in the development of chronic anemia (low red blood cell count). One of the main distinctions of myelofibrosis is "extramedullary hematopoiesis", the migration or traveling of the blood-forming cells out of the bones to other parts of the body, such as the liver or spleen, resulting in an enlarged spleen and liver.

There is not a standard treatment for myelofibrosis, therefore there is no medication that is specifically used in the treatment of myelofibrosis. Bevacizumab (Avastin®) targets and stops a growth factor in the body that helps produce the type of fibrous tissue that is gradually replacing the bone marrow in the bones.

The purpose of this study is to find out how safe and effective bevacizumab is in treating myelofibrosis. The investigators also wish to find out important biologic characteristics or features of myelofibrosis (how it works and operates) during the time of study participation through an additional correlative biomarker study (MPD-RC #107). The purpose of the biomarker study is to understand the causes of MPD and to develop improved methods for the diagnosis and treatment of these diseases, while the main study is trying to find out how well bevacizumab will work in treating the disease.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis	Drug: bevacizumab (Avastin)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Bevacizumab (Avastin®) in Myelofibrosis
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bevacizumab (Avastin) Use of bevacizumab (Avastin) in the treatment of myelofibrosis.	Drug: bevacizumab (Avastin); 15 mg/kg of bevacizumab by IV infusion once every 3 weeks (1 cycle) for 12 weeks (4 cycles); Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Reason for Therapy Discontinuation [2 years]

   Patient outcomes for myelofibrosis patients treated on a single agent bevacizumab. The two subjects who withdrew consent prior to initiation of therapy are included in the "patient refusal" category.

Secondary Outcome Measures

1. Number of Cycles [2 years]

   Number of cycles of bevacizumab received. Patients received bevacizumab as a single agent at a dose of 15 mg/kg intravenously on Day 1 of a 21-day cycle.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of primary myelofibrosis, essential thrombocythemia related myelofibrosis, and polycythemia vera related myelofibrosis requiring therapy, including those previously treated and relapsed or refractory, or, if newly diagnosed, with intermediate or high risk according to Lille scoring system

• Patients not willing to undergo, not a candidate for, or not having a donor for a bone marrow transplant.

• Signed informed consent: Patients must have signed consents for both the bevacizumab protocol and for the mandatory biomarker MDP-RC 107 protocol to be eligible to participate.

• Patients must have been off any IM-directed therapy for 2 weeks prior to entering this study and have recovered from the toxic effects (grade 0-1) of that therapy.

• Serum bilirubin levels less than or equal to 2 times the upper limit of the normal range for the laboratory (ULN). Higher levels are acceptable if these can be attributed by treating physician to active hemolysis or ineffective erythropoiesis due to myelofibrosis;

• Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels less than or equal to 2x ULN.

• Serum creatinine levels less than or equal to 1.5 x ULN.

• Women of childbearing potential must have a negative serum or urine pregnancy test prior to bevacizumab treatment and should be advised to avoid becoming pregnant. Men must be advised to not father a child while receiving treatment with bevacizumab. Both women of childbearing potential and men must practice effective methods of contraception (those generally accepted as standard of care measures). Women of child bearing potential are women who are not menopausal for 12 months or who have not undergone previous surgical sterilization.

• Age > 18 years.

• LVEF >50% by MUGA or ECHO (only in patients with prior exposure to anthracyclines).

Exclusion Criteria:

• Nursing and pregnant females. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

• Inadequately controlled hypertension (defined as systolic blood pressure >140 and/or diastolic blood pressure >90 mmHg on antihypertensive medications) within 4 weeks prior to entering this study

• Any prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• Unstable angina

• History of myocardial infarction within 6 months

• History of stroke or transient ischemic attack within 6 months

• History of Budd-Chiari Syndrome or portal vein thrombosis.

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

• Symptomatic peripheral vascular disease

• Evidence of bleeding diathesis or clinically significant coagulopathy

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days, or anticipation of the need for major surgical procedure during the course of the study

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device or bone marrow biopsy, within 7 days prior to study enrollment

• Proteinuria at screening as demonstrated by either

• Urine protein:creatinine (UPC) ratio greater than or equal to 1.0 at screening OR

• Urinalysis with proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).

• History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months

• Ongoing serious, non-healing wound, ulcer, or bone fracture

• Known hypersensitivity to any component of bevacizumab

• Patients with a history of DVT and/or a CNS thrombotic or hemorrhagic event within the past 6 months.

• Patients on anticoagulation therapy for a variety of conditions such as prosthetic heart valves or chronic atrial fibrillation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgetown University	Washington	District of Columbia	United States	20057
2	University of Illinois at Chicago	Chicago	Illinois	United States	60612
3	Weill Cornell	Ithaca	New York	United States	14851
4	Mount Sinai Medical Center	New York	New York	United States	10029
5	MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• Ronald Hoffman
• Myeloproliferative Disorders-Research Consortium
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ronald Hoffman, MD, Myeloproliferative Disorders-Research Consortium
• Principal Investigator: Ronald Hoffman, MD, Myeloproliferative Disorders Research Consoritum

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ronald Hoffman, Professor of of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT00667277
• Other Study ID Numbers: GCO 07-0548-00103; P01CA108671-01A2; MPD-RC 103
• First Posted: Apr 28, 2008
• Last Update Posted: Aug 22, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by Ronald Hoffman, Professor of of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai: Myelofibrosis; Idiopathic; Bevacizumab; Avastin; bone marrow fibrosis; bone marrow angiogenesis; JAK2
• Additional relevant MeSH terms: Primary Myelofibrosis; Bevacizumab

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled in this study between May 2008 and March 2009

Arm/Group Title	Bevacizumab (Avastin)
Arm/Group Description	Use of bevacizumab (Avastin) in the treatment of myelofibrosis. bevacizumab (Avastin): 15 mg/kg of bevacizumab by IV infusion once every 3 weeks (1 cycle) for 12 weeks (4 cycles)
Period Title: Overall Study
STARTED	13
COMPLETED	11
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Bevacizumab (Avastin)
Arm/Group Description	Use of bevacizumab (Avastin) in the treatment of myelofibrosis. bevacizumab (Avastin): 15 mg/kg of bevacizumab by IV infusion once every 3 weeks (1 cycle) for 12 weeks (4 cycles)
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.6 (11.0)
Sex: Female, Male (Count of Participants)
Female	3 23.1%
Male	10 76.9%
Diagnosis (participants) [Number]
Primary Myelofibrosis (PMF)	8 61.5%
Post-essential Thrombocythemia Myelofibrosis	3 23.1%
Post-Polycythemia Vera Myelofibrosis (Post PV MF)	2 15.4%

Outcome Measures

1. Primary Outcome

Title	Reason for Therapy Discontinuation
Description	Patient outcomes for myelofibrosis patients treated on a single agent bevacizumab. The two subjects who withdrew consent prior to initiation of therapy are included in the "patient refusal" category.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab (Avastin)
Arm/Group Description	Use of bevacizumab (Avastin) in the treatment of myelofibrosis. bevacizumab (Avastin): 15 mg/kg of bevacizumab by IV infusion once every 3 weeks (1 cycle) for 12 weeks (4 cycles)
Measure Participants	13
Physician decision	6 46.2%
Patient Refusal	5 38.5%
Death	1 7.7%
End of study	1 7.7%

2. Secondary Outcome

Title	Number of Cycles
Description	Number of cycles of bevacizumab received. Patients received bevacizumab as a single agent at a dose of 15 mg/kg intravenously on Day 1 of a 21-day cycle.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab (Avastin)
Arm/Group Description	Use of bevacizumab (Avastin) in the treatment of myelofibrosis. bevacizumab (Avastin): 15 mg/kg of bevacizumab by IV infusion once every 3 weeks (1 cycle) for 12 weeks (4 cycles)
Measure Participants	11
Mean (Standard Deviation) [cycles]	3.1 (2.6)

Adverse Events

Arm/Group Title	Bevacizumab (Avastin)
Arm/Group Description	Use of bevacizumab (Avastin) in the treatment of myelofibrosis. bevacizumab (Avastin): 15 mg/kg of bevacizumab by IV infusion once every 3 weeks (1 cycle) for 12 weeks (4 cycles)
All Cause Mortality
	Bevacizumab (Avastin)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab (Avastin)
	Affected / at Risk (%)	# Events
Total	7/13 (53.8%)
Cardiac disorders
Death	1/13 (7.7%)	1
Left Ventricular Failure	1/13 (7.7%)	1
General disorders
Weight Loss	1/13 (7.7%)	1
Fatigue	1/13 (7.7%)	1
Infections and infestations
Pneumonia	2/13 (15.4%)	2
Nervous system disorders
Peripheral Sensory Neuropathy	1/13 (7.7%)	1
Tremor	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/13 (23.1%)	3
Other (Not Including Serious) Adverse Events
	Bevacizumab (Avastin)
	Affected / at Risk (%)	# Events
Total	7/13 (53.8%)
Blood and lymphatic system disorders
Myelo-suppression	3/13 (23.1%)	7
Edema Limbs	1/13 (7.7%)	1
Gastrointestinal disorders
Diarrhea	1/13 (7.7%)	2
Constipation	2/13 (15.4%)	2
General disorders
General Symptom	1/13 (7.7%)	1
Headache	1/13 (7.7%)	1
Facial Pain	1/13 (7.7%)	1
Hepatobiliary disorders
Liver Function Test Abnormality	1/13 (7.7%)	4
Infections and infestations
Upper respiratory infection	1/13 (7.7%)	1
Sinusitis	1/13 (7.7%)	1
Urinary Tract Infection	1/13 (7.7%)	1
Metabolism and nutrition disorders
Metabolic Laboratory Abnormality	1/13 (7.7%)	3
Musculoskeletal and connective tissue disorders
Malaise and Fatigue	2/13 (15.4%)	2
Infective Myositis	1/13 (7.7%)	1
Myalgia	1/13 (7.7%)	1
Pain in extremity	1/13 (7.7%)	1
Nervous system disorders
Memory Impairment	2/13 (15.4%)	2
Dizziness	1/13 (7.7%)	1
Renal and urinary disorders
Protein positive urine	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Infection	1/13 (7.7%)	1
Bruising	1/13 (7.7%)	1
Vascular disorders
Fluid Overload	1/13 (7.7%)	1

Limitations/Caveats

The study was terminated due to lack of response activity in the setting of an unacceptable toxicity profile at the completion of the first stage.

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.