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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.


Phase 1/Phase 2
N/A
N/A
Open (Enrolling)
Female
Breast Cancer

Thank you

Trial Information

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.


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.

Inclusion Criteria


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)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Masking: Double-Blind, Primary Purpose: Treatment

Outcome Measure:

Recommended dose of sunitinib malate that can be combined with exemestane

Safety Issue:

Yes

Principal Investigator

Sonia Pernas, MD

Investigator Affiliation:

Institut Catala D'Oncologia

Authority:

Unspecified

Study ID:

CDR0000640330

NCT ID:

NCT00931450

Start Date:

March 2009

Completion Date:

Related Keywords:

  • Breast Cancer
  • estrogen receptor-positive breast cancer
  • HER2-negative breast cancer
  • stage IA breast cancer
  • stage IB breast cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • Breast Neoplasms

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