A Multi-Center Phase 2 Study of VEGF Trap as a Single Agent in Acute Myeloid Leukemia

Sponsor

Vanderbilt-Ingram Cancer Center (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00601991

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Duration (Months)

Study Details

Study Description

Brief Summary

RATIONALE: Aflibercept may stop the growth of cancer cells by blocking blood flow to the cancer.

PURPOSE: This phase II trial is studying how well aflibercept works in treating patients with advanced refractory, relapsed, or untreated acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: VEGF Trap Procedure: Bone marrow biopsy Procedure: bone marrow aspiration Procedure: Venipuncture	Phase 2

Detailed Description

OBJECTIVES:

Primary

To determine the response rate to aflibercept as a single agent in adult patients with advanced refractory, relapsed, or untreated acute myeloid leukemia (AML).
To determine the 3-month progression-free survival following treatment with at least 4 courses of aflibercept in these patients.

Secondary

To determine if there is any correlation between pre-treatment expression of VEGFR1 or VEGFR2 by marrow myeloblasts and disease response to aflibercept.
To determine if bone marrow microvessel density (MVD) pre-treatment correlates with disease response to aflibercept, and if any decrease in MVD following treatment correlates with changes in bone marrow blast percentage (disease response).
To assess changes in circulating endothelial cells (CEC) and circulating endothelial progenitor cells (EPC) as pharmacodynamic markers of aflibercept activity and possible correlates of disease response to aflibercept.
To measure blood levels of free VEGF versus VEGF bound by aflibercept post-treatment to determine if the chosen dose of aflibercept is sufficient to bind all detectable soluble VEGF in these patients.
To characterize the population pharmacokinetics of aflibercept with its associated interpatient variability and to explore for demographic and clinical covariates.
To derive individual estimates of the duration over which VEGF-saturating aflibercept concentrations were systematically present and to examine their distribution across the population.
To explore the potential relationship between the systemic-free and bound aflibercept levels and safety and efficacy data.

OUTLINE: This is a multicenter study.

Patients receive aflibercept IV over 1 hour on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow and blood sample collection periodically for pharmacokinetic/pharmacodynamic studies. Samples are analyzed for peak plasma-free aflibercept levels after the first infusion, trough plasma-free and bound aflibercept levels prior to each subsequent infusion and 60 days after the last infusion, and anti-aflibercept antibody via ELISA methods; circulating endothelial cells (CEC's) via ELISA and flow cytometry to determine if there is correlation between changes in circulating endothelial cells and changes in bone marrow blast percentage (i.e., disease response); myeloblast expression of VEGFR-1 and VRGFR-2 via immunohistochemistry (IHC); endothelial progenitor cells colony forming units (EPC-CFU's) to determine via in situ staining if changes in circulating endothelial progenitors following treatment with aflibercept correlates with disease response, and if there is a subpopulation of patients identified by pre-treatment circulating EPC-CFU's that may benefit from aflibercept; and bone marrow microvessel density (MVD) determination via immunohistochemistry.

After completion of study treatment, patients are followed for 60 days.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multi-Center Phase 2 Study of Vascular Endothelial Growth Factor (VEGF) Trap as a Single Agent in Acute Myeloid Leukemia

Study Start Date :

Mar 1, 2007

Anticipated Primary Completion Date :

Mar 1, 2009

Actual Study Completion Date :

Oct 1, 2009

Outcome Measures

Primary Outcome Measures

Response rate of aflibercept [day 14 of cycle 4 (14-day cycle)]
As determined by the International Working Group: Complete response: bone marrow blast(BMB) percentage (%) <=5% of nucleated cells and no detectable extramedullary disease; Partial response: BMB >5% but decreased by at least 50% pre-treatment (pre-tx) value OR extramedullary disease still present; Stable disease: BMB >5% and decreased or increased by <50% of pre-tx value and no new extramedullary disease; Progressive disease: BMB >=20% and an increase of at least 50% of pre-tx value and/or appearance of at least 50% in circulating blasts

Secondary Outcome Measures

Bone marrow microvessel density determination at baseline, after courses 2 and 4 of treatment [at baseline, at day 29 and at day 57]
Density of microscopically small blood vessels in bone marrow biopsies
Pharmacokinetics of free versus bound VEGF Trap [Before and after 1st infusion on day 1, before infusion on day 1 of each 14-day cycle, and 60 days after last dose]
Blood levels of free VEGF Trap compared to bound VEGF trap to determine if the chosen level of VEGF Trap is sufficient to bind all detectable soluble VEGF in this group of patients
Progression-free survival in patients who achieve either a complete or partial response OR stable disease [at 12 weeks]
Patients who undergo a minimum of 4 cycles of treatment and who have either a complete or partial response to treatment or who have stable disease and who are free of progressive disease at 12 weeks

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Acute myeloid leukemia (AML), as defined by WHO criteria and documented by morphologic examination of bone marrow aspirate and biopsy, including the following stages:
AML that is refractory to at least one course of induction chemotherapy
AML that has relapsed following one or more histologically documented complete remissions
Patients relapsing following chemotherapy alone, following autologous hematopoietic stem cell transplant, or following allogeneic hematopoietic stem cell transplant
Patients with untreated AML if they are felt not to be eligible for standard induction chemotherapy because of age or comorbidity
No CNS disease

PATIENT CHARACTERISTICS:

Inclusion criteria:

ECOG performance status 0-2
Life expectancy ≥ 60 days
AST/ALT ≤ 2.5 times upper limit of normal (ULN)
Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
Urine protein:creatinine ratio < 1 OR 24-hour urine protein < 500 mg
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception prior to, during, and for at least 6 months after completion of study therapy

Exclusion criteria:

Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
Serious or nonhealing wound, ulcer, or bone fracture
History of allergic reactions attributed to compounds of similar chemical or biological composition to other agents used in the study
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of treatment
Clinically significant cardiovascular disease within the past 6 months, including any of the following:
History of cerebrovascular accident
Myocardial infarction, coronary artery bypass graft, or unstable angina
New York Heart Association class III-IV congestive heart failure or serious cardiac arrhythmia requiring medication
Clinically significant peripheral vascular disease
Pulmonary embolism, deep venous thrombosis, or other thromboembolic event
Uncontrolled hypertension, defined as BP > 150/100 mm Hg, or systolic BP > 180 mm Hg if diastolic blood pressure is < 90 mm Hg, on at least 2 repeated determinations on separate days within the past 3 months
Evidence of bleeding diathesis or coagulopathy
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
Significant traumatic injury within 28 days prior to day 1 of therapy

PRIOR CONCURRENT THERAPY:

Recovered from all therapy
At least 4 weeks since prior chemotherapy and radiotherapy
At least 4 weeks since prior FDA approved agents for treatment of myelodysplastic syndromes and/or AML, including lenalidomide and arsenic trioxide
No prior anti-VEGF, anti-VEGFR, or antiangiogenic agents (e.g., bevacizumab)
More than 28 days since prior major surgical procedure or open biopsy
More than 2 days since prior bone marrow aspirate/biopsy or central venous catheter placement
No anticipation of need for major surgical procedure during the study course
Full-dose anticoagulation (e.g., warfarin) with PT/INR > 1.5 allowed provided that both of the following criteria are met:
In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant
No active bleeding or pathological condition that carries a high risk of bleeding (e.g., known varices)
Prior and concurrent hydroxyurea allowed for blast control
Hydroxyurea must be discontinued no more than 24 hrs after the first dose of aflibercept
No HIV-positive patients on combination antiretroviral therapy
No other concurrent investigational agents