Phase I Study of Aprotinin in Advanced Breast Cancer
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00354900|
Recruitment Status : Terminated (The FDA changed the labeling for this agent, and we felt we could not offer it to patients on a non-surgical study.)
First Posted : July 20, 2006
Last Update Posted : August 4, 2009
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Breast Cancer||Drug: Aprotinin||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of Aprotinin in Advanced Breast Cancer|
|Study Start Date :||July 2006|
|Actual Study Completion Date :||April 2007|
- To determine the maximum tolerated single dose of Aprotinin in patients with advanced breast cancer
- To determine the toxicities of a single infusion of Aprotinin in patients with advanced breast cancer
- To determine the progression free survival and overall survival following a single dose of Aprotinin in patients with advanced breast cancer
- To determine the effects of a single dose of Aprotinin on markers of the coagulation pathway
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00354900
|United States, New Hampshire|
|Norris Cotton Cancer Center - Dartmouth-Hitchcock Medical Center|
|Lebanon, New Hampshire, United States, 03756|
|Principal Investigator:||Gary N Schwartz, MD||Norris Cotton Cancer Center|