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Phase I Study of Aprotinin in Advanced Breast Cancer

Phase 1
18 Years
90 Years
Not Enrolling
Metastatic Breast Cancer

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Trial Information

Phase I Study of Aprotinin in Advanced Breast Cancer

Urokinase-type plasminogen activator (uPA) is a serine protease whose physiologic function
is to catalyze the conversion of plasminogen to the active proteolytic form, plasmin, for
participation in processes which require tissue remodeling such as wound healing,
embryogenesis and inflammatory responses. uPA is among numerous tissue proteases also found
in association with neoplastic disease, playing a pathologic role in tumor growth and
metastasis. The activity of uPA can be neutralized by a specific inhibitor, plasminogen
activator inhibitor type-1 (PAI-1) which forms inactive complexes of 1:1 stoichiometry with
the plasminogen activators. Through inhibition of uPA and tPA, PAI-1 inhibits plasmin; the
inhibitory effect should limit the extent of extracellular matrix protein degradation and
reduce activation of MMP's and angiogenic growth factors such as VEGF. However, tissue
overexpression of PAI-1 correlates with more aggressive clinical behavior of the malignancy.
In fact, the upregulation of PAI-1 may be a cellular attempt to return to homeostasis,
which is disrupted by activation of uPA or other factors. Upregulation of PAI-1 may be an
indicator that uPA or some other pathway is contributing to an aggressive phenotype.
Co-expression of uPA and PAI-1 in primary breast tumor tissue is associated with a greater
risk of locoregional and distant recurrence, a poorer response to adjuvant hormonal or
chemotherapy, and a shorter survival. Elevation of circulating PAI-1 in patients with
metastatic breast cancer is associated with a shorter survival.

We hypothesize that uPA activation is in part responsible for the clinical progression of
malignancy. Inhibition of uPA is therefore a rational strategy for the control of advanced
breast cancer. Aprotinin is a safe and effective protease inhibitor of both uPA and
plasmin. Aprotinin is approved for the treatment of septic shock, and for the prevention of
blood loss in patients undergoing cardiopulmonary bypass surgery. In patients undergoing
cardiopulmonary bypass surgery, Aprotinin blunts the acute increase in fibrinolytic activity
caused by uPA, and decreases the expression of counter-regulatory PAI-1. In several in vivo
tumor models, Aprotinin inhibits tumor growth, invasiveness, and metastasis. Limited
experience in patients with cancer suggests prolongation of survival in patients treated
with a single or multiple doses of Aprotinin. We hypothesize that Aprotinin would delay
disease progression by decreasing the chronic activation of uPA and PAI-1, and that delay of
tumor progression would correlate with inhibition of laboratory measures of fibrinolysis.

This is a Phase I trial. Patients with metastatic breast cancer will receive escalating
doses of Aprotinin in one of four dose cohorts, ranging from 2.0 x 106 KIU to 6.0 x 106 KIU.
Three to six patients will be entered at each dose cohort, and the maximum tolerated dose
will be defined as the highest dose at which fewer than 33% of patients experience a dose
limiting toxicity. A total of nine patients will be entered at the maximum tolerated dose.
The extent of disease will be assessed radiologically at baseline, and again at 6, 12, 18,
and 24 weeks after treatment with Aprotinin. Coagulation parameters, including PT/PTT,
D-Dimer, FDP's, uPA, and PAI-1 will be assayed at baseline, and at several intervals out to
30 days after treatment with Aprotinin.

Inclusion Criteria:

- Patients with a histologically or cytologically proven metastatic breast cancer.

- Patients with at least one bidimensionally measurable lesion (diameter > 1 cm), or an
evaluable bone lesion that will not undergo biopsy.

- Age > 18 years.

- Life expectancy of at least 6 months.

- ECOG performance status 0-3.

- Screening laboratories within the following parameters: ANC > 1500 cells/mm3,
Platelets > 100,000 cells/mm3, AST < 2 x upper limit of normal, Bilirubin < 1.5 x
upper limit of normal, Calculated creatinine clearance > 30 cc/min by the Cockroft
and Gault equation.

- Concurrent treatment with hormonal therapy or trastuzumab is allowed.

- Patients must be post-menopausal (either as a result of surgery, or amenorrhea for at
least 12 consecutive months), or they must be practicing either abstinence, an
adequate method of contraception (intrauterine device or barrier contraception), or
their sexual partner must be sterile. Women who are pregnant, breast-feeding, or who
are fertile and not practicing an adequate means of contraception will be excluded.

- Patients must have a central venous catheter.

- Patients must be able to give informed consent indicating that they are aware of the
investigational nature of this study.

Exclusion Criteria:

- No known CNS metastases.

- No treatment with cytotoxic chemotherapy allowed within 21 days of treatment with

- No treatment with investigational agents allowed within 21 days of treatment with

- No severe cardiovascular disease including unstable heart rhythm, uncompensated
congestive heart failure, unstable angina or myocardial infarction within 6 months.

- No bleeding diathesis or coagulopathy including concomitant use of anticoagulants for
thromboembolic disease

- No active anticoagulant therapy (including antiplatelet agents) for at least ten

- No active, uncontrolled bacterial, viral or fungal infection.

- No patients who are known or expected to be allergic to aprotinin, or who have
received prior aprotinin.

- No patient with chronic systolic blood pressure (SBP) < 90 mm Hg. If the (SBP) is <
90 mm Hg on the day of treatment intravenous fluid may be administered to restore
intravascular volume, if clinically indicated. In such case, if IV fluid corrects
the SBP then the study drug may be given

Type of Study:


Study Design:

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

Outcome Measure:

To determine the maximum tolerated single dose of Aprotinin in patients with advanced breast cancer

Principal Investigator

Gary N Schwartz, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Norris Cotton Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2006

Completion Date:

April 2007

Related Keywords:

  • Metastatic Breast Cancer
  • breast cancer
  • fibrinolysis
  • urokinase-type plasminogen activator
  • plasminogen activator inhibitor
  • aprotinin
  • plasmin/alpha-2-antiplasmin complex
  • Breast Neoplasms



Norris Cotton Cancer Center - Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire  03756