Sunitinib Malate and Exemestane in Treating Postmenopausal Women With Breast Cancer

Pilot / Phase II Randomised, Double Blind, Placebo Controlled Multicenter Study With Biomarker Evaluation of Neoadjuvant Exemestane in Combination With Sunitinib in Post-menopausal Women With Hormone- Sensitive, Her-2 Negative Primary Breast Cancer.

RATIONALE: Sunitinib malate and exemestane may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving sunitinib malate and exemestane before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of sunitinib malate to see how well it works when given together with exemestane in treating postmenopausal women with breast cancer.

Study Overview

• Status: Unknown
• Conditions: Breast Cancer
• Intervention / Treatment: Other: placebo; Drug: sunitinib malate; Drug: exemestane

Detailed Description

OBJECTIVES:

Primary

• Determine the safe dose level of sunitinib malate that can be combined with exemestane (pilot phase I).
• Evaluate the clinical response of neoadjuvant therapy comprising exemestane and sunitinib malate in postmenopausal women with hormone receptor-positive and HER-2 negative primary breast cancer (phase II).

Secondary

• Evaluate the safety and feasibility of this regimen in these patients.
• Evaluate the percentage of patients undergoing breast-conserving surgery after completion of study therapy.
• Determine the safety profile of this regimen in these patients.
• Determine the rate of complete pathological response in the breast and axillary lymph nodes at the time of surgery.
• Determine the extent of treatment-related inhibition of phosphorylation of VEGFR-2, PDGF, and c-KIT receptor tyrosine kinases.
• Find a genetic profile, based on the analysis of CYP19A1 polymorphisms, able to predict response to exemestane in neoadjuvant setting.
• Conduct exploratory investigation of biomarkers expression before and during therapy in order to identify molecular characteristics of responding tumors.

OUTLINE: This is a multicenter, dose-escalation study of sunitinib malate followed by a phase II study.

• Phase I pilot: Patients receive oral sunitinib malate and oral exemestane once daily on days 1-28. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

• Phase II: Patients are randomized to 1 of 2 treatment groups:

  • Group 1: Patients receive oral exemestane and oral placebo once daily on days 1-28. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
  • Group 2: Patients receive oral exemestane once daily and oral sunitinib malate once daily on days 1-28. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

At 7-15 days after completion of study therapy, patients undergo definitive surgery.

Blood and tissue samples are collected at baseline and periodically during study to examine inhibition of phosphorylation of VEGFR-2, PDGF, and c-KIT receptor tyrosine kinases; CYP19A1 polymorphisms; and biomarkers analysis by cDNA microarrays, ELISA, and RT-PCR.

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • l'Hospitalet de Llobregat, Spain, 08907
    • Recruiting
    • Institut Catala D'oncologia
    • Contact: Sonia Pernas, MD; Phone Number: 34-93-260-7744

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive breast carcinoma meeting the following criteria:

  • Estrogen receptor-positive ≥ 50% or Allred score > 6
  • HER-2 negative defined as IHC < 2+ and negative FISH/CISH
  • Primary tumor measuring ≥ 3 cm if there is no node involvement

  • Any T if N1 or N2 disease

    • No inflammatory breast cancer (T4d)
  • No metastatic disease
• Measurable disease by mammography and/or ultrasound and MRI (if available)

PATIENT CHARACTERISTICS:

• Postmenopausal

  • Prior bilateral oophorectomy
  • ≥ 60 years of age
  • < 60 years of age AND have experienced amenorrhea for ≥ 12 months in the absence of chemotherapy, tamoxifen, or toremifene OR have undergone ovarian suppression and follicle-stimulating hormone and estradiol levels in the postmenopausal range
• ECOG performance status 0-1
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10 g/dL
• Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min
• Bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN
• Albumin > 2.5. g/dL
• No known HIV infection
• Adequate left ventricular ejection fraction (LVEF) at baseline defined as LVEF not below normal range by echocardiogram or MUGA

• No evidence of prior uncontrolled hypertension

  • Patients with controlled hypertension (systolic < 150 mm Hg and/or diastolic < 90 mm Hg) by antihypertensive therapies allowed
• No prior uncontrolled or symptomatic angina, myocardial infarction, congestive heart failure, clinically significant arrhythmias, or prolongation of the QTc interval
• No hemorrhagic or thrombotic events, including transient ischemic attack, pulmonary embolism, or deep-vein thrombosis, within the past 12 months
• No gross hemorrhage within the past 6 months (e.g., gastrointestinal bleeding, hemoptysis, or hematuria)
• No history or evidence of an inherited bleeding diathesis or coagulopathy at risk of bleeding

• None of the following:

  • Unable to swallow oral medications
  • Active inflammatory bowel disease
  • Partial or complete bowel obstruction
  • Chronic diarrhea
• No history of another malignancy within the past 5 years except for cured non-melanoma skin cancer or successfully treated carcinoma in situ of the cervix
• No psychiatric disease or social situations that would limit compliance with study requirements or patient unwilling or unable to comply with protocol for the duration of study
• No unstable or severe intercurrent medical condition that, in the opinion of the investigator, might interfere with the achievement of study objectives
• No known immediate or delayed hypersensitive reaction or idiosyncrasy to drugs chemically related to exemestane or sunitinib malate or their excipients

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior or other concurrent chemotherapy, radiotherapy, immunotherapy, biologic therapy, or hormonal therapy for primary invasive breast cancer
• No concurrent anticoagulant therapy except for low-dose anticoagulants (i.e., low molecular weight heparin or aspirin) for the prevention of deep-vein thrombosis
• No chronic therapy with corticosteroids, except for steroids administered by inhalation
• More than 4 weeks since prior major surgery and ≥ 7 days since prior minor surgery
• No prior or other concurrent investigational anticancer agent
• No concurrent participation in another clinical trial
• No concurrent drugs with potential proarrhythmic activity
• No concurrent known CYP3A4 inhibitors (i.e., grapefruit, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, diltiazem, nefazodone, voriconazole, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, delavirdine)
• No concurrent known CYP3A4 or CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, efavirenz, tipranavir, phenobarbital, phenytoin, primidone, rifabutin, rifampicin, St. John's wort)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Group 1; Patients receive oral exemestane and oral placebo once daily on days 1-28. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.	Other: placebo; Given orally; Drug: exemestane; Given orally
EXPERIMENTAL: Group 2; Patients receive oral exemestane once daily and oral sunitinib malate once daily on days 1-28. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.	Drug: sunitinib malate; Given orally; Drug: exemestane; Given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Recommended dose of sunitinib malate that can be combined with exemestane
Objective clinical response (complete or partial response) according to WHO criteria

Secondary Outcome Measures

Outcome Measure
Safety profile
Safety and feasibility of the combination of sunitinib malate and exemestane
Rate of breast-conserving surgery
Percentage of pathological complete response in the breast and axillary lymph nodes
Grade of inhibition of phosphorylation of VEGFR-2, PDGF, and c-KIT receptor tyrosine kinases
Genetic profile, based on the analysis of CYP19A1 polymorphisms, able to predict response to neoadjuvant exemestane
Molecular biomarkers predictive of response

Collaborators and Investigators

• Sponsor: Institut Català d'Oncologia
• Investigators: Sonia Pernas, MD, Institut Catala D'oncologia

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (ANTICIPATED): October 1, 2011

Study Registration Dates

• First Submitted: July 1, 2009
• First Submitted That Met QC Criteria: July 1, 2009
• First Posted (ESTIMATE): July 2, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): August 12, 2013
• Last Update Submitted That Met QC Criteria: August 9, 2013
• Last Verified: July 1, 2009

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IA breast cancer; stage IB breast cancer; estrogen receptor-positive breast cancer; HER2-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Sunitinib; Exemestane
• Other Study ID Numbers: ICO-SUT-EXE-08; CDR0000640330 (REGISTRY: PDQ (Physician Data Query)); PFIZER-ICO-SUT-EXE-08