Trastuzumab With or Without Everolimus in Treating Women With Breast Cancer That Can Be Removed By Surgery

A Phase II, Randomized, Multi-center Study, Assessing Value of Adding Everolimus (RAD001) to Trastuzumab as Preoperative Therapy of HER-2 Positive Primary Breast Cancer Amenable to Surgery.

RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Everolimus 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. It is not yet known whether giving everolimus together with trastuzumab is more effective than giving trastuzumab alone in treating women with breast cancer.

PURPOSE: This randomized phase II trial is studying trastuzumab and everolimus to see how well they work compared to trastuzumab alone before surgery in treating patients with breast cancer that can be removed by surgery.

OBJECTIVES:

Primary

• To evaluate the added efficacy obtained by the association of trastuzumab (Herceptin®) with everolimus as preoperative therapy of primary HER2-positive breast cancer as shown by increased clinical tumor response rate.

Secondary

• To compare the inhibition of the two pathways, RAS/RAF/MAP kinase and PI3-kinase/AKT/mTor.
• To evaluate whether the pre-treatment molecular characteristics of tumor and serum or their modifications early in the treatment are predictive of clinical response.
• To compare the frequency of pathological complete response achieved in the two groups after 6 weeks of treatment.
• To determine disease-free survival at 3 years.
• To evaluate safety and tolerability of the two treatment regimens.
• To analyze the possible relationships between treatment toxicity and constitutional gene polymorphisms linked to the administered agents.
• To analyze the possible relationships between response and molecular pharmacodynamic assessments, including proteomics (blood samples), Bio-Plex protein array (tumor), and IHC (tumor).
• To analyze the drug levels and pharmacokinetic assessments of everolimus and trastuzumab (Herceptin®).

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive trastuzumab (Herceptin®) IV once weekly for 6 weeks. Patients then undergo surgery.
• Arm II: Patients receive trastuzumab as in arm I and oral everolimus once daily for 6 weeks. Within 24 hours after completing everolimus, patients undergo surgery.

Blood and tumor samples are collected periodically during study for pharmacogenomic, proteomic, and pharmacokinetic studies.

After completion of study treatment, patients are followed periodically for up to 3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of invasive breast cancer

  • Previously untreated disease

• Candidate for breast-conserving surgery, as defined by both of the following:

  • Clinical stage cT1-3, cN0-2 disease
  • Clinical stage M0 disease (bone scan, chest X-ray, and liver ultrasound required at screening to exclude metastatic disease)

• HER2-positive primary tumor, defined as meeting either of the following criteria:

  • IHC 3+
  • IHC 2+ and FISH positive (centralized confirmation)

• No inflammatory breast cancer or bilateral breast cancer

  • Patients who have been treated for cancer of the contralateral breast can be included if there is at least a 5 year time interval from last systemic treatment for breast cancer before randomization into this study

• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• WHO performance status 0-1

• Menopausal status not specified

• WBC ≥ 3.5 x 10^9/L

• ANC ≥ 1.5 x 10^9/L

• Platelet count ≥ 100 x 10^9/L

• Hb ≥ 10 g/dL

• Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)

• Serum transaminases activity ≤ 2.5 times ULN

• Alkaline phosphatase ≤ 2.5 times ULN

• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

• FEV > 55% by MUGA or ECHO

• Spirometry and DLCO > 50% of normal

• O_2 saturation > 88% at rest on room air

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No known hypersensitivity to everolimus, sirolimus, trastuzumab (Herceptin®), or lactulose

• No hypercholesterolemia/hypertriglyceridemia ≥ grade 3

  • No hypercholesterolemia/hypertriglyceridemia ≥ grade 2 with history of coronary artery disease (despite lipid-lowering treatment if given)

• No uncontrolled infection

• No other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, including any of the following:

  • Uncontrolled hypertension
  • Congestive cardiac failure
  • Ventricular arrhythmias
  • Active ischemic heart disease
  • Myocardial infarction within the past year
  • Chronic liver or renal disease
  • Active gastrointestinal tract ulceration
  • Severely impaired lung function

• No known history of HIV seropositivity

• No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

• Willing to participate in the biological investigations

• Not deprived of liberty or placed under guardianship

• Patients must be affiliated to a Social Security System

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• More than 30 days (from the screening visit) since prior other investigational drugs

• More than 5 days (from randomization) since prior and no concurrent strong inhibitors or inducers of the isoenzyme CYP3A, including any of the following

  • Rifabutin
  • Rifampicin
  • Clarithromycin
  • Ketoconazole
  • Itraconazole
  • Voriconazole
  • Ritonavir
  • Telithromycin

• No other concurrent anti-cancer treatments such as chemotherapy, immunotherapy/biological response modifiers, endocrine therapy, or radiotherapy