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A Randomized, 4-Arm, Placebo-Controlled Phase 2 Trial of AMG 386 in Combination With Bevacizumab and Paclitaxel or AMG 386 Plus Paclitaxel as First-Line Therapy in Subjects With Her2-Negative, Metastatic or Locally Recurrent Breast Cancer


Phase 2
18 Years
N/A
Open (Enrolling)
Female
Locally Recurrent and Metastatic Breast Cancer

Thank you

Trial Information

A Randomized, 4-Arm, Placebo-Controlled Phase 2 Trial of AMG 386 in Combination With Bevacizumab and Paclitaxel or AMG 386 Plus Paclitaxel as First-Line Therapy in Subjects With Her2-Negative, Metastatic or Locally Recurrent Breast Cancer


Primary Objective: To estimate the treatment effect as measured by progression free survival
(PFS) of subjects receiving AMG 386 (at 2 doses) in combination with paclitaxel +
bevacizumab relative to paclitaxel + bevacizumab + placebo.

Secondary Objective(s):

- To compare the treatment effect as measured by PFS of subjects receiving open-label AMG
386 in combination with paclitaxel relative to paclitaxel + bevacizumab + placebo

- To compare the treatment effect as measured by PFS of subjects receiving AMG 386 in
combination with paclitaxel and bevacizumab relative to paclitaxel + AMG 386

- To evaluate the safety and tolerability of the combination and non-bevacizumab regimens

- To estimate other measures (RR, DOR, TTR, TTP) of treatment effect

- To evaluate the pharmacokinetics (PK) of AMG 386 and bevacizumab when used in
combination

- To estimate the incidence of anti-AMG386 antibody formation

Exploratory Objective(s):

- To explore the pharmacodynamic (PD) response as assessed by changes in blood levels of
angiogenic cytokines, tumor apoptosis, and other markers

- To explore the association of histological features and selected immunologic,
biochemical, pharmacogenetic, or angiogenic markers in tumor biopsies, plasma, or serum
samples with safety and/or efficacy outcomes

Study Design:

This is a phase 2, randomized, placebo controlled, multi-center study to estimate the
treatment effect and evaluate the safety and tolerability of AMG 386 in combination with
paclitaxel and paclitaxel/bevacizumab in the treatment of subjects with Her2-negative
metastatic or locally recurrent breast cancer.

Two hundred twenty subjects will be randomized 1:1:1:1 to each of the following arms:

Arm A: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W + AMG 386 10
mg/kg IV QW Arm B: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg IV Q2W +
AMG 386 3 mg/kg IV QW Arm C: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + bevacizumab 10 mg/kg
IV Q2W + AMG 386 placebo IV QW Arm D: Paclitaxel 90 mg/m² IV QW (3 on/1 off) + Open Label
AMG 386 10 mg/kg IV QW To maintain the double-blind in arms A, B, and C, each subject will
be infused weekly with a volume of investigational product equivalent to 10 mg/kg AMG 386
IV. Arm D will receive open label AMG 386 and will not receive a placebo for bevacizumab.

Subjects will be discontinued from study treatment at any time for radiographic disease
progression, clinical progression, unacceptable toxicity, subject withdrawal of consent, or
death.

Subjects alive at the time of discontinuation of all study medications will be followed for
up to 48 months from the date of the last subject enrolled into the trial to evaluate
overall survival.

Radiological imaging to assess disease status will be performed every 8 weeks ± 7 days (2
cycles) for 2 years and then every 4 months ± 1 month thereafter during the study until
subjects develop radiographic disease progression per the modified RECIST criteria. In
addition, any subject who discontinues study drug treatment prior to disease progression
will continue to have radiological imaging performed every 8 weeks ± 7 days during the long
term follow up period if the subject has not been in the study for 2 years until the subject
develops radiographic disease progression or begins a new treatment. If the subject has been
on study for 2 years, radiological imaging every 4 months ± 1 month will be performed during
long term follow-up period until the subject develops radiographic disease progression or
begins a new treatment.

The overall study design is described by a study schema immediately following this synopsis.
Amgen Global Safety (AGS) will charter a data review team (DRT) that is independent of the
team conducting the study and will review unblinded safety data after 20, 40, and 80
subjects have been randomized and have had the opportunity to receive at least 1 cycle (4
weeks) of study treatment.


Inclusion Criteria:



- Subjects must have histologically or cytologically confirmed adenocarcinoma of the
breast with locally recurrent or metastatic disease. Locally recurrent disease must
not be amenable to resection with curative intent.

- Measurable or non-measurable disease per modified RECIST guidelines

- ECOG of 0 or 1 (within 14 days prior to randomization)

- Adequate organ and hematological function as evidenced by the following laboratory
studies within 14 days prior to randomization:

• Cardiac function, as follows:

- Normal sinus rhythm (no significant ECG changes)

- Left ventricular ejection fraction ≥ LLN, as determined by echocardiogram or MUGA
scan, according to institutional standards within 28 days prior to randomization

Exclusion Criteria:

- Inflammatory Breast Cancer

- Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 peripheral
neuropathy > grade 1 at randomization

- History of arterial or venous thrombosis, including transient ischemic attack (TIA),
within 1 year prior to randomization

- Adjuvant or neoadjuvant taxane treatment within 12 months of randomization. Any other
adjuvant chemotherapy regimen must be discontinued at least 21 days prior to
randomization

- Prior chemotherapy, vaccine, or biological therapy for locally recurrent or
metastatic breast cancer (prior endocrine therapy is permitted)

- Prior radiation therapy, radiofrequency ablation, percutaneous cryotherapy or hepatic
chemoembolization on all sites of disease unless disease progression was subsequently
documented 14 days prior to randomization.

- Overexpression of HER-2 (gene amplification by FISH or 3+ over expression by
immunohistochemistry).

- Current or prior history of central nervous system metastasis

- History of bleeding diathesis or clinically significant bleeding within 6 months
prior to randomization

- Major surgical procedure within 28 days prior to randomization

- Open breast biopsy within 14 days prior to randomization

- Minor surgical procedure, placement of access device, or fine needle aspiration
within 7 days of first dose

- Prior malignancy (other than thyroid cancer, in situ cervical cancer, or basal cell
cancer of the skin, treated with curative intent and without evidence of disease for
≥ 3 years prior to randomization)

- Clinically significant cardiac disease within 12 months prior to randomization,
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

- Non-healing wound, ulcer or fracture

- Known hypersensitivity to paclitaxel or drugs using the vehicle cremophor

- Known hypersensitivity to bacterial proteins, or any of the drugs required in this
study

- Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis
B surface antigen

- Known active or chronic hepatitis

- Uncontrolled hypertension as defined as systolic blood pressure ≥ 150 mm Hg and
diastolic blood pressure ≥ 90 mm Hg. Anti-hypertensive medications are allowed if
the subject is stable on their current dose at the time of randomization

- Currently or previously treated with any VEGF or VEGFr inhibitor, including but not
limited to, bevacizumab, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AEE-788,
BAY 43-9006 (sorafenib) and AMG 706.

- Treatment with coumarin-type anticoagulants, (other than low dose prophylaxis for
central venous catheters ≤ 1mg/day) within 7 days prior to randomization

- Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1
or TIE-2 including, but not limited to, AMG 386, XL880, XL820

- Treatment with immune modulators such as cyclosporine and tacrolimus within 30 days
prior to randomization

- Concomitant therapy with any hormonal agent such as raloxifene, tamoxifen, or other
selective estrogen receptor modulators (SERMS), given for breast cancer prevention or
for osteoporosis. Subjects must have discontinued these agents 28 days prior to
randomization

- Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS)

Outcome Time Frame:

3 YEARS

Safety Issue:

No

Principal Investigator

MD

Investigator Role:

Study Director

Investigator Affiliation:

Amgen

Authority:

Austria: AGES - PharmaMed Austria Institut Wissenschaft & Information

Study ID:

20060341

NCT ID:

NCT00511459

Start Date:

July 2007

Completion Date:

October 2013

Related Keywords:

  • Locally Recurrent and Metastatic Breast Cancer
  • Randomized
  • 4-Arm
  • Placebo controlled
  • Phase 2 Trial
  • AMG 386
  • Paclitaxel
  • Bevacizumab
  • First-line Therapy
  • Her-2 Negative
  • Metastatic or Locally Recurrent Breast Cancer
  • Breast Neoplasms

Name

Location

Research SiteMesa, Arizona  
Research SiteBentonville, Arkansas  
Research SiteAnaheim, California  
Research SiteDanbury, Connecticut  
Research SiteBoca Raton, Florida  
Research SiteAlexandria, Minnesota  
Research SiteLas Vegas, Nevada  
Research SiteHooksett, New Hampshire  
Research SiteBelleville, New Jersey  
Research SiteAsheville, North Carolina  
Research SiteAllentown, Pennsylvania  
Research SiteCharleston, South Carolina  
Research SiteAbilene, Texas  
Research SiteIvins, Utah