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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Recurrent Adult Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

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


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 Ang1, Ang2,
Tie2, vascular endothelial growth factor (VEGF), and VEGF receptor (VEGFR) expression;
changes in bone marrow vascularization and hypoxia; changes in gene and/or 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, 5, 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 and then
periodically thereafter.


Inclusion Criteria:



- Diagnosis of AML as defined by the World Health Organization (excluding acute
promyelocytic leukemia and chronic myeloid leukemia- blast/accelerated phase) in an
adult patient

- Patients with newly diagnosed untreated AML for whom the treatment of choice is
low-intensity therapy by investigator assessment or who has declined intensive
induction therapy recommended by the investigator OR

- Patients with refractory or relapsed AML following at least one prior treatment
course who are not currently considered eligible for stem cell transplantation
at the time of screening due to non-optimal AML disease control, lack of
suitable transplantation donor, failure to meet other transplantation criteria,
or refusal to undergo transplantation

- Eastern Cooperative Oncology Group (ECOG) status 0-2 (ECOG 3 is excluded)

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal (ULN)

- Creatinine clearance > 40ml/min per 24 hour urine collection or calculated according
to the Cockcroft-Gault formula

- Urinary protein quantitative value of less than 30mg/dL in urine analysis or less
than 1+ on dipstick, unless quantitative protein is < 1000mg in a 24 hour urine
sample

- Partial thromboplastin time (PTT) or activated (aPTT) =< 1.5 x ULN per institution
laboratory range and international normalized ratio (INR) =< 1.5

- Patient or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

- Individuals of childbearing potential must agree to use acceptable contraceptive
methods (e.g., double barrier) during treatment

Exclusion Criteria:

- History of central nervous system involvement with leukemia

- History of venous or arterial thromboembolism within 12 months prior to enrollment

- History of clinically significant bleeding within 6 months of enrollment

- Unresolved toxicities from prior systemic therapies that are Common Terminology
Criteria for Adverse Events (CTCAE) version 4 >= Grade 2 in severity except alopecia
excluding hematological toxicities attributable to underlying disease

- Currently or previously treated with AMG 386, or other molecules that inhibit the
angiopoietins or Tie2 receptor

- Current or within 30 days prior to enrollment treatment with immune modulators such
as systemic cyclosporine or tacrolimus

- Has not yet completed a 14 day washout period for any previous anti-cancer systemic
therapies (30 days for prior bevacizumab) with the exception of hydroxyurea or
leukopheresis for uncontrolled leukocytosis

- Enrolled in or has not yet completed at least 14 days since ending other
investigational device or drug trials, or currently receiving other investigational
treatments

- Clinically significant cardiovascular disease within 12 months prior to enrollment,
including myocardial infarction, unstable angina, grade 2 or greater peripheral
vascular disease, cerebrovascular accident, transient ischemic attack, congestive
heart failure, or arrhythmias not controlled by outpatient medication or placement of
percutaneous transluminal coronary angioplasty/stent

- Major surgery within 28 days prior to enrollment or still recovering from prior
surgery

- Minor surgical procedures, placement of tunneled central venous access device within
3 days prior to enrollment

- Uncontrolled hypertension as defined as diastolic > 90mmHg OR systolic > 140mmHg; the
use of anti-hypertensive medication to control hypertension is permitted

- Non-healing wound, ulcer (including gastrointestinal) or fracture

- Active uncontrolled infection, including human immunodeficiency virus (HIV) and
active hepatitis infection

- Subject not consenting to the use of highly effective contraceptive, e.g., double
barrier method (i.e., condom plus diaphragm) precautions during the course of the
study and for 6 months after administration of the last study medication

- Subject has known sensitivity to any of the products to be administered during dosing

- History of allergic reactions to bacterially produced proteins

- Subject has previously been enrolled onto this study

- Subject will not be available for follow-up assessment

- Pregnant or nursing female patients

- Active second malignancy other than AML which is not in remission and/or for which
the patient is currently receiving treatment

- Subject has any kind of disorder that compromises the ability of the subject to give
written informed consent and/or to comply with study procedures

- Any condition which in the investigator's opinion makes the patient an unsuitable
candidate for study participation

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerability of trebananib when administered alone and in combination with low-dose cytarabine measured by number of participants with adverse events according to CTCAE

Outcome Description:

Adverse events will be tabulated overall and by arm.

Outcome Time Frame:

Up to 30 days after the last dose of study drug

Safety Issue:

Yes

Principal Investigator

Eunice Wang

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

I 186010

NCT ID:

NCT01555268

Start Date:

October 2011

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
University of RochesterRochester, New York  14642