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Aflibercept in Treating Patients With Myelodysplastic Syndromes

Primary Purpose

Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
ziv-aflibercept
laboratory biomarker analysis
pharmacological study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed myelodysplastic syndromes (MDS), including any of the following:

    • Secondary MDS
    • MDS/myeloproliferative disorders (MPD) (e.g., chronic myelomonocytic leukemia or atypical chronic myeloid leukemia)
    • IPSS scores of 0.5 or greater (≥ INT-1) OR transfusion dependent despite use of growth factors
    • No more than 20% blasts in the marrow
    • Patients who have not responded after 3 courses of hypomethylating agents (azacitidine or decitabine) OR; who are unable to tolerate hypomethylating agents OR who refused to receive hypomethylating agents are eligible for this study
  • ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  • AST/ALT ≤ 2.5 x ULN
  • Creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 60 mL/min
  • Urine protein:creatinine ratio < 1 OR urine protein < 500 mg by 24-hour urine collection
  • PT INR ≤ 1.5

  • Patients with PT INR > 1.5 on full-dose anticoagulants (e.g., warfarin) are eligible provided both of the following criteria are met:

    • Patient has an in-range INR (usually between 2 and 3) and is on a stable dose of oral anticoagulant or low molecular weight heparin
    • Patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • Not pregnant or nursing
  • Fertile patients must use effective contraception during and for at least 6 months after completion of study treatment
  • Prior DNA-demethylating agent therapy or lenalidomide therapy allowed
  • Prior treatment with other molecular agents, such as thalidomide, valproic acid, or imatinib mesylate allowed

Exclusion Criteria:

  • Evidence of active malignancies other than squamous cell or basal cell carcinoma of the skin
  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study
  • Serious or non-healing wound, ulcer, or bone fracture
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
  • Significant traumatic injury within the past 28 days

  • Clinically significant cardiovascular disease, including any of the following:

    • History of cerebrovascular accident (CVA) within the past 6 months
    • Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg or systolic BP > 180 mm Hg if diastolic blood pressure < 90 mm Hg (on at least 2 repeated determinations on separate days) within the past 3 months
    • Myocardial infarction or unstable angina within the past 6 months
    • New York Heart Association class III or IV congestive heart failure, serious cardiac arrhythmia requiring medication, or unstable angina pectoris within the past 6 months
  • Clinically significant peripheral vascular disease within the past 6 months
  • Pulmonary embolism, deep vein thrombosis (DVT), or other thromboembolic event within the past 6 months
  • Evidence of bleeding diathesis or coagulopathy
  • Concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situation that would limit compliance with study requirements
  • Prior cytotoxic chemotherapy for MDS
  • Molecular therapy or immunosuppressive agents (including steroids) within the past 3 weeks
  • Other prior antiangiogenesis agents
  • Coronary artery bypass graft (CABG) within the past 6 months
  • Valproic acid should be discontinued at least 24 hours before aflibercept administration, unless needed for seizure control
  • Major surgical procedure or open biopsy within the past 28 days
  • Core biopsy (other than bone marrow biopsy) within the past 7 days
  • Anticipation of need for major surgical procedures during the course of the study
  • Patients may not be receiving any other investigational agents

Sites / Locations

  • City of Hope Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

Patients will receive aflibercept IV at 4 mg/kg over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Hematological Response Rate
Complete Response (CR): repeat bone marrow (BM) shows <5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (>110 g/L), neutrophils (≥1.0x10^9/L), platelets (≥100x10^9/L), blasts (0%) and no dysplasia. Partial Response (PR): same as CR for peripheral blood except BM shows blasts decrease by ≥ 50% but still > 5% or a less advanced FAB classification from pretreatment. Hematological response=CR+PR.

Secondary Outcome Measures

Full Information

First Posted
July 30, 2007
Last Updated
January 7, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00509249
Brief Title
Aflibercept in Treating Patients With Myelodysplastic Syndromes
Official Title
A Phase II Study of VEGF Trap (NSC 724770) in Patients With MDS
Study Type
Interventional

2. Study Status

Record Verification Date
November 2012
Overall Recruitment Status
Terminated
Why Stopped
Early termination for discouraging results
Study Start Date
September 2007 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
December 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial is studying how well aflibercept works in treating patients with myelodysplastic syndromes. Aflibercept may be able to carry cancer-killing substances directly to myelodysplastic syndrome cells. It may also stop the growth of cancer cells by blocking blood flow to the cancer
Detailed Description
OBJECTIVES: I. To determine the antitumor activity of aflibercept as assessed by the hematological response rate. II. To determine overall and progression-free survival in patients with myelodysplastic syndromes. III. To assess hematologic improvement and time to leukemic transformation. IV. To assess the toxicity profile of aflibercept in this patient population. V. To perform correlative studies to better understand the ability of aflibercept to reach and modulate its respective targets. OUTLINE: This is a multicenter study. Patients will receive aflibercept IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood and bone marrow samples will be obtained periodically for pharmacokinetic and biomarker correlative studies. Pharmacokinetic analysis by ELISA; anti-aflibercept antibody measurements; analysis of VEGF and VEGFR expression; and analysis of gene expression by quantitative PCR will be conducted. The effect of aflibercept on apoptosis and proliferation of CD34+ cells will also be analyzed by flow cytometry based assays. After completion of study treatment, patients are followed periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Previously Treated Myelodysplastic Syndromes, Secondary Myelodysplastic Syndromes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
Patients will receive aflibercept IV at 4 mg/kg over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
ziv-aflibercept
Other Intervention Name(s)
aflibercept, vascular endothelial growth factor trap, VEGF Trap, Zaltrap
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Hematological Response Rate
Description
Complete Response (CR): repeat bone marrow (BM) shows <5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (>110 g/L), neutrophils (≥1.0x10^9/L), platelets (≥100x10^9/L), blasts (0%) and no dysplasia. Partial Response (PR): same as CR for peripheral blood except BM shows blasts decrease by ≥ 50% but still > 5% or a less advanced FAB classification from pretreatment. Hematological response=CR+PR.
Time Frame
Up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically or cytologically confirmed myelodysplastic syndromes (MDS), including any of the following: Secondary MDS MDS/myeloproliferative disorders (MPD) (e.g., chronic myelomonocytic leukemia or atypical chronic myeloid leukemia) IPSS scores of 0.5 or greater (≥ INT-1) OR transfusion dependent despite use of growth factors No more than 20% blasts in the marrow Patients who have not responded after 3 courses of hypomethylating agents (azacitidine or decitabine) OR; who are unable to tolerate hypomethylating agents OR who refused to receive hypomethylating agents are eligible for this study ECOG performance status ≤ 2 (Karnofsky ≥ 60%) Total bilirubin ≤ 1.5 x upper limit of normal (ULN) AST/ALT ≤ 2.5 x ULN Creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 60 mL/min Urine protein:creatinine ratio < 1 OR urine protein < 500 mg by 24-hour urine collection PT INR ≤ 1.5 Patients with PT INR > 1.5 on full-dose anticoagulants (e.g., warfarin) are eligible provided both of the following criteria are met: Patient has an in-range INR (usually between 2 and 3) and is on a stable dose of oral anticoagulant or low molecular weight heparin Patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) Not pregnant or nursing Fertile patients must use effective contraception during and for at least 6 months after completion of study treatment Prior DNA-demethylating agent therapy or lenalidomide therapy allowed Prior treatment with other molecular agents, such as thalidomide, valproic acid, or imatinib mesylate allowed Exclusion Criteria: Evidence of active malignancies other than squamous cell or basal cell carcinoma of the skin Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study Serious or non-healing wound, ulcer, or bone fracture History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days Significant traumatic injury within the past 28 days Clinically significant cardiovascular disease, including any of the following: History of cerebrovascular accident (CVA) within the past 6 months Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg or systolic BP > 180 mm Hg if diastolic blood pressure < 90 mm Hg (on at least 2 repeated determinations on separate days) within the past 3 months Myocardial infarction or unstable angina within the past 6 months New York Heart Association class III or IV congestive heart failure, serious cardiac arrhythmia requiring medication, or unstable angina pectoris within the past 6 months Clinically significant peripheral vascular disease within the past 6 months Pulmonary embolism, deep vein thrombosis (DVT), or other thromboembolic event within the past 6 months Evidence of bleeding diathesis or coagulopathy Concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situation that would limit compliance with study requirements Prior cytotoxic chemotherapy for MDS Molecular therapy or immunosuppressive agents (including steroids) within the past 3 weeks Other prior antiangiogenesis agents Coronary artery bypass graft (CABG) within the past 6 months Valproic acid should be discontinued at least 24 hours before aflibercept administration, unless needed for seizure control Major surgical procedure or open biopsy within the past 28 days Core biopsy (other than bone marrow biopsy) within the past 7 days Anticipation of need for major surgical procedures during the course of the study Patients may not be receiving any other investigational agents
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Kirschbaum
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States

12. IPD Sharing Statement

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Aflibercept in Treating Patients With Myelodysplastic Syndromes

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