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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00244881
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arm: 1
• Duration (Months): 27
• Patients Per Site Per Month: 1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer	Drug: cediranib maleate; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Evaluation of the fraction of patients with increased levels of circulating endothelial cells after 3 weeks of treatment with AZD2171.

2. Estimation of the objective response rate (ORR = CR + PR) among patients with refractory breast cancer receiving AZD2171.

SECONDARY OBJECTIVES:

1. Estimation of the response/stable disease rate (RSDR = CR + PR + SD). II. Characterization of the toxicity associated with AZD2171 in this cohort of patients.

2. Analyses to correlate serial quantification of circulating endothelial cells and circulating tumor cells with traditional clinical endpoints including RR and TTP.

3. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of AZD2171 in Breast Cancer Stage IV (10006202)
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Aug 1, 2007
• Actual Study Completion Date: Dec 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (cediranib maleate) 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; Given orally; Other Names: AZD2171 Recentin ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Fraction of Patients With Increased Levels of Circulating Endothelial Cells [After 3 weeks of treatment]

   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%).

2. Objective Response Rate (ORR = CR + PR) Classified According to RECIST Criteria [Up to 7 years]

   RECIST 1.0 Criteria

Secondary Outcome Measures

1. Response/Stable Disease Rate Defined as the Percentage of Patients Demonstrating CR + PR + SD [12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Harold Burstein, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00244881
• Other Study ID Numbers: NCI-2012-02937; 05-160; U01CA062490; CDR0000445438; NCT00215488
• First Posted: Oct 27, 2005
• Last Update Posted: Dec 7, 2015
• Last Verified: Nov 1, 2013

• Additional relevant MeSH terms: Breast Neoplasms; Breast Neoplasms, Male; Cediranib

Study Results

Participant Flow

Recruitment Details	Participants were recruited at Dana-Farber/Harvard Cancer Center

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	26
COMPLETED	23
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	26
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	22 84.6%
>=65 years	4 15.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.3 (11)
Sex: Female, Male (Count of Participants)
Female	26 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	26 100%

Outcome Measures

1. Primary Outcome

Title	Fraction of Patients With Increased Levels of Circulating Endothelial Cells
Description	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%).
Time Frame	After 3 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	26
Number [percentage of participants]	30 115.4%

2. Primary Outcome

Title	Objective Response Rate (ORR = CR + PR) Classified According to RECIST Criteria
Description	RECIST 1.0 Criteria
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	26
Number (95% Confidence Interval) [percentage of participants]	8 30.8%

3. Secondary Outcome

Title	Response/Stable Disease Rate Defined as the Percentage of Patients Demonstrating CR + PR + SD
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	26
Number [percentage of participants]	45 173.1%

Adverse Events

Time Frame	2 years
Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily for 42 days. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Cediranib Maleate)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Cediranib Maleate)
	Affected / at Risk (%)	# Events
Total	7/26 (26.9%)
Cardiac disorders
Left Ventricular Systolic Dysfunction	1/26 (3.8%)	1
Hypertension	1/26 (3.8%)	1
Gastrointestinal disorders
Vomiting	1/26 (3.8%)	1
Esophagitis	1/26 (3.8%)	1
Gallbladder Abnormality	1/26 (3.8%)	1
Diarrhea	1/26 (3.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Cediranib Maleate)
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Cardiac disorders
Hypertension	21/26 (80.8%)	21
LFT Abnormalities	7/26 (26.9%)	7
LV systolic dysfunction	2/26 (7.7%)	2
Endocrine disorders
Hypothyroidism	5/26 (19.2%)	5
Gastrointestinal disorders
Diarrhea	10/26 (38.5%)	10
Esophagitis/Mucositis	7/26 (26.9%)	7
Nausea	5/26 (19.2%)	5
Vomiting	3/26 (11.5%)	3
Anorexia	3/26 (11.5%)	3
Abdominal Pain	3/26 (11.5%)	3
General disorders
Fatigue	10/26 (38.5%)	10
Renal and urinary disorders
Proteinuria	8/26 (30.8%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.