A Phase II Study of AZD2171 in Breast Cancer Stage IV (10006202)

Study Overview
=================
Brief Summary
-----------------
AZD2171 (cediranib maleate) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. This phase II trial is studying how well AZD2171 works in treating patients with refractory stage IV breast cancer

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Evaluation of the fraction of patients with increased levels of circulating endothelial cells after 3 weeks of treatment with AZD2171. II. Estimation of the objective response rate (ORR = CR + PR) among patients with refractory breast cancer receiving AZD2171. SECONDARY OBJECTIVES: I. Estimation of the response/stable disease rate (RSDR = CR + PR + SD). II. Characterization of the toxicity associated with AZD2171 in this cohort of patients. III. Analyses to correlate serial quantification of circulating endothelial cells and circulating tumor cells with traditional clinical endpoints including RR and TTP. IV. Develop pharmacodynamic measures of AZ2171 activity based on monocyte count and VEGFR-1 phosphorylation within monocytes. OUTLINE: This is a nonrandomized, open-label, multicenter study. Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 3 months. PROJECTED ACCRUAL: A total of 26 patients will be accrued for this study.

Official Title
-----------------
A Phase II Study of AZD2171 in Breast Cancer Stage IV (10006202)

Conditions
-----------------
Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
-----------------
* Drug: cediranib maleate
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically or cytologically confirmed Breast Cancer, stage IV, including: Breast neoplasms malignant and unspecified (incl nipple),Breast and nipple neoplasms malignant,Breast cancer stage IV,10006202 Breast neoplasms malignant and unspecified (incl nipple),Breast and nipple neoplasms malignant,Breast cancer recurrent,10006198 Breast neoplasms malignant and unspecified (incl nipple),Breast and nipple neoplasms malignant,Inflammatory carcinoma of breast stage IV,10021979 Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan Patients must have refractory breast cancer, defined as overt clinical tumor progression on most recent treatment with either hormonal therapy, chemotherapy, and/or trastuzumab therapy; patients with up to 3 prior chemotherapy regimens and with any number of biological (hormonal, trastuzumab) regimens for metastatic breast cancer will be eligible Life expectancy of greater than 3 months as assessed by the patient's primary oncologist Absolute neutrophil count > 1,500/mcL Platelets > 100,000/mcL Hemoglobin >= 8 g/dL Prothrombin time < institutional upper limit of normal (ULN) Total bilirubin =< 1.5 x ULN AST(SGOT)/ALT(SGPT) =< 2.5 × ULN Creatinine within normal institutional limits Urinalysis with < 1+ proteinuria Troponin T or I within normal institutional limits LVEF >= 45%, as assessed by echocardiogram or nuclear medicine gated study, within 30 days prior to initiating protocol-based treatment At present, the potential of AZD2171 for clinically significant drug interactions involving the CYP isozymes is unknown; however, studies of the agent in rats indicated possible suppression of CYP1A that may be of biological significance; eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or PK of AZD2171 will be determined following review of their case by the Principal Investigator. AZD2171 has been shown to terminate fetal development in the rat, as expected for a process dependent on VEGF signaling; for this reason, women of child-bearing potential must have a negative pregnancy test prior to study entry; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately No therapeutic anti-coagulation; the use of low dose warfarin (1-2 mg/day), intermittent doses of TPA (2 mg x 1), or heparin flushes to prophylax against central venous catheter-associated clots is acceptable Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy, radiotherapy, or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients may not be receiving any other investigational agents nor have participated in an investigational trial within the past 30 days Patients may not have been previously treated with an anti-angiogenesis agent \Patients may not be receiving any medication that may markedly affect renal function (e.g., vancomycin, amphotericin, pentamidine); these medications will also not be permitted after the start of the study Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; a head CT or MRI must be performed at baseline History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD2171 Any contraindications/barrier to oral medication EKG abnormalities of known clinical significance, such as prolonged QT (mean QTc > 470 msec, with Bazett's correction, in screening electrocardiogram or history of familial long QT syndrome); an EKG is required for study entry Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because AZD2171 is a VEGF inhibitor with known abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD2171, breastfeeding should be discontinued if the mother is treated with AZD2171 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD2171; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated Patients at increased risk for compromised LVEF requiring concurrent use of drugs or biologics with proarrythmic potential; these drugs are prohibited during studies with AZD2171 (refer to Appendix J for a listing of these agents) Patients with a New York Heart Association classification of III or IV are excluded (NOTE: patients classified as class II are eligible if controlled on medication and stable with increased monitoring)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cediranib maleate)<br>Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. | Drug: cediranib maleate<br>* Given orally<br>* Other names: Recentin;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fraction of Patients With Increased Levels of Circulating Endothelial Cells | An exact 95% confidence interval (CI) will be calculated for the CEC response rate. With 26 patients, this CI will be no wider than 40% (e.g., if 13 of 26 patients respond, the CI is 30% to 70%). | After 3 weeks of treatment | 
| Objective Response Rate (ORR = CR + PR) Classified According to RECIST Criteria | RECIST 1.0 Criteria | Up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response/Stable Disease Rate Defined as the Percentage of Patients Demonstrating CR + PR + SD |  | 12 weeks |