Aflibercept in Treating Patients With Myelodysplastic Syndromes

Phase 2

Terminated

Conditions: de Novo Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Secondary Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Interventions: Biological: ziv-aflibercept
Other: laboratory biomarker analysis
Other: pharmacological study

Registration Number: NCT00509249

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 18

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	pharmacological study	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.
Arm I	laboratory biomarker analysis	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.
Arm I	ziv-aflibercept	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.

Primary Outcome Measures

Name	Time	Method
Hematological Response Rate	Up to 3 years	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