Clinical Trial: Trebananib With or Without Low-Dose Cytarabine in Treating Patients With Acute Myeloid Leukemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase lb Study of the Safety, Feasibility, and Pharmacokinetics of AMG 386 Alone and in Combination With Low Dose Cytarabine in Acute Myeloid Leukemia (AML) Patients

Brief Summary: 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.

Detailed Summary:

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 rec
Sponsor: Roswell Park Cancer Institute

Current Primary Outcome:

  • Safety of trebananib when administered alone and in combination with low-dose cytarabine measured by number of participants with toxicities according to CTCAE [ Time Frame: Up to 30 days after the last dose of study drug ]
    Adverse events will be tabulated overall and by arm.
  • PK/PD profile of trebananib when administered alone [ Time Frame: Days 1, 3-5, 7, 8, 22, 24-26, and 29 of course 1 ]
    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.
  • PK/PD profile of trebananib when administered in combination with low-dose cytarabine [ Time Frame: Days 1 and 7 of course 1 ]
    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.


Original Primary Outcome:

  • Safety and tolerability of AMG 386 when administered alone and in combination with low-dose cytarabine measured by number of participants with adverse events according to CTCAE [ Time Frame: Up to 30 days after the last dose of study drug ]
    Adverse events will be tabulated overall and by arm.
  • PK/PD profile of AMG 386 when administered alone [ Time Frame: Days 1, 3-5, 7, 8, 22, 24-26, and 29 of course 1 ]
    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.
  • PK/PD profile of AMG 386 when administered in combination with low-dose cytarabine [ Time Frame: Days 1 and 7 of course 1 ]
    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.


Current Secondary Outcome:

  • 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 [ Time Frame: Up to 30 days post-treatment ]
    Identified by flow cytometric analysis of peripheral blood and marrow aspirate cells.
  • Changes in bone marrow vascularization and hypoxia [ Time Frame: Baseline up to 30 days post-treatment ]
    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.
  • Changes in gene and/or microRNA expression [ Time Frame: Baseline up to 30 days post-treatment ]
    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.
  • 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 ]


Original Secondary Outcome:

  • Clinical response in AML patients following AMG 386 therapy alone or given in combination with low-dose cytarabine therapy [ Time Frame: Within 3 weeks of completion of treatment ]
  • Alterations in Ang1, Ang2, Tie2, VEGF, and VEGFR expression [ Time Frame: Baseline to approximately 2 years ]
  • Changes in bone marrow vascularization and hypoxia [ Time Frame: Baseline to approximately 2 years ]
  • Changes in gene and/or microRNA expression [ Time Frame: Baseline to approximately 2 years ]
  • Characterization of time course of AM 386 concentrations in relation to target inhibition and clinical response using PK/PD modeling [ Time Frame: Up to approximately 2 years ]
  • Correlation of biological changes with clinical response in AML patients treated on this study [ Time Frame: Up to approximately 2 years ]


Information By: Roswell Park Cancer Institute

Dates:
Date Received: February 16, 2012
Date Started: October 31, 2011
Date Completion:
Last Updated: February 14, 2017
Last Verified: February 2017