Neo-adjuvant Therapy With Anastrozole Plus Pazopanib in Stage II and III ER+ Breast Cancer

• Sponsor: University of Arizona (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01394211
• Collaborator: National Cancer Institute (NCI) (NIH), GlaxoSmithKline (Industry)
• Enrollment: 2
• Location: 1
• Arm: 1
• Actual Duration (Months): 9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies how well giving pazopanib hydrochloride and anastrozole before surgery works in treating patients with stage II-III estrogen receptor-positive breast cancer. Pazopanib hydrochloride and anastrozole may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pazopanib hydrochloride and anastrozole together before surgery may make the tumor smaller and reduce the amount of normal cells that have to be removed

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor-positive Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Male Breast Cancer; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer	Drug: anastrozole; Drug: pazopanib hydrochloride; Procedure: therapeutic conventional surgery	Phase 2

Detailed Description

OBJECTIVES:

1. To determine the pathologic complete response (pCR) rate at surgery.

SECONDARY OBJECTIVES:

1. To evaluate alternative measurements of anti-tumor activity: proportion of patients achieving sustained decrease in antigen KI-67 (ki-67) at 12 weeks of therapy with anastrozole plus pazopanib (pazopanib hydrochloride); proportion of patients achieving down-staging to a pathologic stage 0 or 1 at surgery.

2. To assess qualitative and quantitative toxicity of this combination, with special emphasis on the frequency of events grade 3 or greater, or the occurrence of unexpected toxicities.

OUTLINE:

Patients receive pazopanib hydrochloride* orally (PO) once daily (QD) and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo definitive surgery.

NOTE: *Pazopanib hydrochloride is stopped 7-14 days before surgery.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Neo-adjuvant Therapy With Anastrozole Plus Pazopanib in Stage II and III ER+ Breast Cancer
• Actual Study Start Date: Jul 13, 2011
• Actual Primary Completion Date: Apr 12, 2012
• Actual Study Completion Date: Apr 12, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neoadjuvant enzyme inhibitor therapy Patients receive pazopanib hydrochloride* PO QD and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo therapeutic conventional surgery. NOTE: *Pazopanib hydrochloride is stopped 7-14 days before definitive surgery.	Drug: anastrozole; Given PO; Other Names: ANAS Arimidex ICI-D1033 ; Drug: pazopanib hydrochloride; Given PO; Other Names: GW786034 Votrient ; Procedure: therapeutic conventional surgery; Undergo definitive surgery

Outcome Measures

Primary Outcome Measures

1. Rate of pCR at Primary Site (T0) and Nodal Sites (T0N0) [Six months from the initiation of neoadjuvant therapy]

   Defined as no evidence of microscopic invasive tumor present. Determined by pathology. Estimated with an exact 95% confidence interval.

Secondary Outcome Measures

1. Proportion of Patients Achieving Sustained Decrease in Ki-67 [12 weeks from the initiation of neoadjuvant therapy]

2. Proportion of Patients Achieving Down-staging to a Pathologic Stage 0 or 1 [Six months from the initiation of neoadjuvant therapy]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up; procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are within the protocol determined screening or baseline timeframes, and equivalent to the specifications in the protocol; also note, a written waiver/approval from the Investigator/Sponsor is still required

• Histologically confirmed diagnosis of estrogen receptor-positive (ER+), HER2 negative breast cancer, with clinical stage II or III disease

• Stage IIA T0-1 N1 M0, T2 N0 M0, OR

• Stage IIB T2 N1 M0, T3 N0 M0 OR

• Stage IIIA T0-2 N2 M0, T3 N1-2 M0, OR

• Stage IIIB T4 N0-2 M0

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• No evidence of distant metastatic disease

• Baseline Oncotype DX score of 29 or lower; patients with known Oncotype DX recurrence score (RS) of 30 or greater are not eligible

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

• Hemoglobina >= 10 g/dL (5.6 mmol/L); subjects may not have had a transfusion within 7 days of screening assessment

• Platelets >= 100 x 10^9/L

• Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 x upper limit of normal (ULN); subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation

• Activated partial thromboplastin time (aPTT) =< 1.2 x ULN

• Total bilirubin =< 1.5 x ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN; concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN is not permitted

• Serum creatinine =< 1.5 mg/dL (133 umol/L) or, if > 1.5 mg/dL: calculated creatinine clearance (CLCR) >= 50 mL/min

• Urine protein to creatinine ratio (UPC) < 1; if UPC >= 1, then a 24-hour urine protein must be assessed; subjects must have a 24-hour urine protein value < 1 g to be eligible

• A female is eligible to enter and participate in this study if she is:

• Is post-menopausal

• Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for >= 1 year and be greater than 45 years in age, OR, in questionable cases, have follicle stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40 pg/mL (< 140 pmol/L)

• Subjects using HRT must have experienced total cessation of menses for >= 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT; patients will be required to be off of HRT for at least 2 weeks prior to initiating therapy

Exclusion Criteria:

• Prior malignancy; note: subjects who have had another malignancy and have been disease-free for >= 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible

• Known distant metastases at any site; history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis

• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:

• Active peptic ulcer disease

• Known intraluminal metastatic lesion/s with risk of bleeding

• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or

• Other gastrointestinal conditions with increased risk of perforation

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of registration to the study; clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:

• Malabsorption syndrome

• Major resection of the stomach or small bowel

• Presence of uncontrolled infection

• Corrected QT interval (QTc) > 480 msecs using Bazett's formula

• History of any one or more of the following cardiovascular conditions within 6 months of registration on the study:

• Cardiac angioplasty or stenting

• Myocardial infarction

• Unstable angina

• Coronary artery bypass graft surgery

• Symptomatic peripheral vascular disease

• Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)

• Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >= 140 mmHg or diastolic blood pressure (DBP) of >= 90 mm Hg]; note: initiation of adjustment of antihypertensive medication(s) is permitted prior to study entry

• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months of registration on the study; note: subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks of registration to the study are eligible

• Prior major surgery or trauma within 28 days of registration on the study prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major)

• Evidence of active bleeding or bleeding diathesis

• Hemoptysis within 8 weeks of registration to the study

• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures

• Treatment with any of the following anti-cancer therapies for the current diagnosis of stage 2-3 estrogen positive breast carcinoma:

• Radiation therapy, surgery or tumor embolization within 14 days prior to first dose of pazopanib OR

• Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib

• Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity, except alopecia

• Concomitant anti-cancer therapies are not permitted

• Patients may not be receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Pazopanib or Anastrozole used in the study

• Concomitant use of medications or substances that are inhibitors or inducers of strong CYP3A4 inhibitors are ineligible

• Concomitant: the concomitant use of strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided; if coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of pazopanib to 400 mg; further dose reductions may be needed if adverse effects occur during therapy; this dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors; however, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors; grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib

• Concomitant strong CYP3A4 inducer: the concomitant use of strong CYP3A4 inducers (e.g. rifampin) may decrease pazopanib concentrations and should be avoided

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center	Tucson	Arizona	United States	85724-5024

Sponsors and Collaborators

• University of Arizona
• National Cancer Institute (NCI)
• GlaxoSmithKline

Investigators

• Principal Investigator: Robert Livingston, University of Arizona

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Arizona
• ClinicalTrials.gov Identifier: NCT01394211
• Other Study ID Numbers: 11-0269-04; NCI-2011-01114; 3P30CA023074
• First Posted: Jul 14, 2011
• Last Update Posted: Jul 26, 2018
• Last Verified: Jul 1, 2018

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

Study Results

Participant Flow

Recruitment Details	Through physician

Arm/Group Title	Neoadjuvant Enzyme Inhibitor Therapy
Arm/Group Description	Patients receive pazopanib hydrochloride* PO QD and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo therapeutic conventional surgery. NOTE: *Pazopanib hydrochloride is stopped 7-14 days before definitive surgery. anastrozole: Given PO pazopanib hydrochloride: Given PO therapeutic conventional surgery: Undergo definitive surgery
Period Title: Overall Study
STARTED	2
COMPLETED	0
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Neoadjuvant Enzyme Inhibitor Therapy
Arm/Group Description	Patients receive pazopanib hydrochloride* PO QD and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo therapeutic conventional surgery. NOTE: *Pazopanib hydrochloride is stopped 7-14 days before definitive surgery. anastrozole: Given PO pazopanib hydrochloride: Given PO therapeutic conventional surgery: Undergo definitive surgery
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	2 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

Title	Rate of pCR at Primary Site (T0) and Nodal Sites (T0N0)
Description	Defined as no evidence of microscopic invasive tumor present. Determined by pathology. Estimated with an exact 95% confidence interval.
Time Frame	Six months from the initiation of neoadjuvant therapy

Outcome Measure Data

Analysis Population Description

Participants withdrew from participation

Arm/Group Title	Neoadjuvant Enzyme Inhibitor Therapy
Arm/Group Description	Patients receive pazopanib hydrochloride* PO QD and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo therapeutic conventional surgery. NOTE: *Pazopanib hydrochloride is stopped 7-14 days before definitive surgery. anastrozole: Given PO pazopanib hydrochloride: Given PO therapeutic conventional surgery: Undergo definitive surgery
Measure Participants	0

2. Secondary Outcome

Title	Proportion of Patients Achieving Sustained Decrease in Ki-67
Time Frame	12 weeks from the initiation of neoadjuvant therapy

Outcome Measure Data

Analysis Population Description

Participants withdrew from participation

Arm/Group Title	Neoadjuvant Enzyme Inhibitor Therapy
Arm/Group Description	Patients receive pazopanib hydrochloride* PO QD and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo therapeutic conventional surgery. NOTE: *Pazopanib hydrochloride is stopped 7-14 days before definitive surgery. anastrozole: Given PO pazopanib hydrochloride: Given PO therapeutic conventional surgery: Undergo definitive surgery
Measure Participants	0

3. Secondary Outcome

Title	Proportion of Patients Achieving Down-staging to a Pathologic Stage 0 or 1
Time Frame	Six months from the initiation of neoadjuvant therapy

Outcome Measure Data

Analysis Population Description

Participants withdrew from participation

Arm/Group Title	Neoadjuvant Enzyme Inhibitor Therapy
Arm/Group Description	Patients receive pazopanib hydrochloride* PO QD and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo therapeutic conventional surgery. NOTE: *Pazopanib hydrochloride is stopped 7-14 days before definitive surgery. anastrozole: Given PO pazopanib hydrochloride: Given PO therapeutic conventional surgery: Undergo definitive surgery
Measure Participants	0

Adverse Events

Time Frame	Nine months
Arm/Group Title	Neoadjuvant Enzyme Inhibitor Therapy
Arm/Group Description	Patients receive pazopanib hydrochloride* PO QD and anastrozole PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo therapeutic conventional surgery. NOTE: *Pazopanib hydrochloride is stopped 7-14 days before definitive surgery. anastrozole: Given PO pazopanib hydrochloride: Given PO therapeutic conventional surgery: Undergo definitive surgery
All Cause Mortality
	Neoadjuvant Enzyme Inhibitor Therapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Neoadjuvant Enzyme Inhibitor Therapy
	Affected / at Risk (%)	# Events
Total	0/2 (0%)
Other (Not Including Serious) Adverse Events
	Neoadjuvant Enzyme Inhibitor Therapy
	Affected / at Risk (%)	# Events
Total	0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.