This phase I trial studies the side effects and the best dose of trebananib when given together with or without low-dose cytarabine in treating patients with acute myeloid leukemia (AML). Trebananib may stop the growth of AML by blocking blood flow to the cancer. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving trebananib together with cytarabine may be an effective treatment for patients with AML.
PRIMARY OBJECTIVES: I. To evaluate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profile of AMG 386 (trebananib) when administered alone and in combination with low-dose cytarabine in adult patients with: untreated AML considered ineligible for standard induction chemotherapy; refractory and/or relapsed AML following at least one cycle of prior therapy who are not currently eligible for stem cell transplantation. SECONDARY OBJECTIVES: I. To evaluate clinical responses in AML patients following AMG 386 therapy alone or in combination with low-dose cytarabine therapy. II. To characterize the biological changes occurring in AML patients treated with AMG 386 alone or in combination with low-dose cytarabine, specifically: alteration in angiopoietin (Ang)1, Ang2, Tie2, vascular endothelial growth factor (VEGF), and VEGF receptor (VEGFR) expression; changes in bone marrow vascularization and hypoxia; changes in gene and/or micro ribonucleic acid (microRNA) expression; PK/PD modeling to characterize the time course of AMG 386 concentrations in relation to target inhibition and hematological response. III. To determine whether the above biological changes correlate with and/or predict for clinical response in AML patients treated on this study. OUTLINE: This is a dose-escalation study of trebananib. Patients are assigned to 1 of 2 treatment arms. ARM A: Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15, and 22. ARM B: Patients receive trebananib as in Arm A. Patients also receive cytarabine subcutaneously (SC) twice daily (BID) on days 1-14 of course 1 and days 1-7 of each subsequent course. In both arms, treatment repeats every 28 days\* for up to 12 courses in the absence of disease progression or unacceptable toxicity. NOTE: \*Course 1 is 35 days. After completion of study treatment, patients are followed up for 30 days, every month for 1 year, every 3 months for 1 year, and then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Roswell Park Cancer Institute
Buffalo, New York, United States
University of Rochester
Rochester, New York, United States
Safety of trebananib when administered alone and in combination with low-dose cytarabine measured by number of participants with toxicities according to CTCAE
Adverse events will be tabulated overall and by arm.
Time frame: Up to 30 days after the last dose of study drug
PK/PD profile of trebananib when administered alone
A population PK/PD model will be developed to characterize the time course of AMG 386 concentrations in relation to target inhibition and hematological response. Model-predicted PK parameters will be generated, such as individual areas-under-the-curve (AUCs) and Cmax for AMG 386, to correlate with targeted biomarkers, such as Ang1, and Ang2, and VEGF as well as leukocyte count.
Time frame: Days 1, 3-5, 7, 8, 22, 24-26, and 29 of course 1
PK/PD profile of trebananib when administered in combination with low-dose cytarabine
A population PK/PD model will be developed to characterize the time course of AMG 386 concentrations in relation to target inhibition and hematological response. Model-predicted PK parameters will be generated, such as individual AUCs and Cmax for AMG 386, to correlate with targeted biomarkers, such as Ang1, and Ang2, and VEGF as well as leukocyte count.
Time frame: Days 1 and 7 of course 1
Clinical response in AML patients following trebananib therapy alone or given in combination with low-dose cytarabine therapy
Time frame: Up to 5 years
Alterations in Ang1, Ang2, Tie2, VEGF, and VEGFR expression
Identified by flow cytometric analysis of peripheral blood and marrow aspirate cells.
Time frame: Up to 30 days post-treatment
Changes in bone marrow vascularization and hypoxia
Bone marrow vascularization will be assessed by cluster of differentiation (CD)31+ and/or CD34 microvessel staining as well as VEGF-A expression and hypoxia using hypoxia-inducible factor (HIF)-1alpha and/or CAIX immunohistochemistry.
Time frame: Baseline up to 30 days post-treatment
Changes in gene and/or microRNA expression
Microarray profiling for all human microRNAs will be performed on stored leukemia marrow cells and confirmed by real time-polymerase chain reaction (Q-PCR) analysis for specific microRNAs of interest.
Time frame: Baseline up to 30 days post-treatment
Characterization of time course of trebananib concentrations in relation to target inhibition and clinical response using PK/PD modeling
Time frame: Up to 5 years
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