Aflibercept in Treating Patients With Myelodysplastic Syndromes

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.

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