Efficacy and Safety of Everolimus in Combination Therapy, in Patients With HER2-overexpressing Metastatic Breast Cancer

• Phase I: Best Overall Response (BOR) [ Time Frame: every 8 - 9 weeks until disease progression or a new lesion is identified ] [ Designated as safety issue: No ]
  BOR was determined based on investigator assessment of overall lesion response using RECIST criteria guidelines. BOR = objective responses rate (ORR), disease control rate (DCR) or clinical benefit rate (CBR). ORR = (complete response (CR) or partial response(PR); DCR = (CR or PR or Stable disease (SD); CBR = (CR or PR or SD >= 24 weeks).CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for partial disease (PD). PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
• Phase II: Progression Free Survival (PFS) [ Time Frame: every 8 - 9 weeks until disease progression or a new lesion is identified ] [ Designated as safety issue: Yes ]
  PFS is defined as the time from start of treatment to the date of first documented progression or death due to any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment.
• Phase II: Overall Survival (OS) [ Time Frame: every 3 months until death ] [ Designated as safety issue: No ]
  Overall survival (OS) is defined as the time from start of treatment to the date of death due to any cause. If a patient is not known to have died, survival was censored at the last date of contact. OS was to be reported at extension and after 3-year follow-up. The Kaplan-Meier median was used to analyze the OS.

• To assess the ability to deliver the trastuzumab and paclitaxel therapy
• To assess everolimus, trastuzumab and paclitaxel blood levels in this combination
• To evaluate the overall tumor response

Phase I: will look at different dose levels and regimens of everolimus combined with weekly trastuzumab and paclitaxel therapy in patients with HER-2 overexpressing metastatic breast cancer.

Phase II: will assess the efficacy and safety of the 10mg daily dose of everolimus combined with weekly trastuzumab and paclitaxel therapy in patients with HER-2 overexpressing metastatic breast cancer.

• Drug: Everolimus
  Everolimus (RAD001) was supplied as tablets in 3 different dosage strengths, 2.5, 5, and 10 mg. The drug was packaged in blisters containing 10 tablets per blister. Blisters and packaging labels were compliant with local regulations and were printed in local language.
  Other Name: RAD001
• Drug: Trastuzumab
  Commercially-available trastuzumab was used in this study. A 4 mg/kg loading dose was administered, intra-venous (IV), over 90 minutes on Day 1 (if patient was not already receiving trastuzumab); this was followed by weekly trastuzumab 2 mg/kg IV administered over 30 minutes. For patients who continued to receive trastuzumab and everolimus after completion/discontinuation of chemotherapy in the core treatment phase, trastuzumab may have been administered once every 3 weeks at a dose of 6 mg/kg. PT = Paclitaxel & Trastuzumab
• Drug: Paclitaxel
  Commercially-available paclitaxel was used in this study. Paclitaxel infusion was administered on Days 1, 8, and 15 of each 28-day cycle, after administration of trastuzumab. Paclitaxel (80 mg/m2) was administered as a 60-minute continuous IV infusion after standard premedication. Patients received paclitaxel for 6 cycles. At the investigator's discretion, treatment with paclitaxel could continue beyond 6 cycles.

• Experimental: Phase I - RAD001 5mg + PT, daily
  Daily dosing schedule of EPT = Paclitaxel & Trastuzumab verolimus 5mg plus Paclitaxel plus Trastuzumab.
  Interventions:

  • Drug: Everolimus
  • Drug: Trastuzumab
  • Drug: Paclitaxel
• Experimental: Phase I - RAD001 10mg + PT, daily
  Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab
  Interventions:

  • Drug: Everolimus
  • Drug: Trastuzumab
  • Drug: Paclitaxel
• Experimental: Phase I - RAD001 30mg + PT, weekly
  Weekly dosing schedule of Everolimus 30mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab.
  Interventions:

  • Drug: Everolimus
  • Drug: Trastuzumab
  • Drug: Paclitaxel
• Experimental: Phase II - RAD001 10mg + PT, daily
  Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab
  Interventions:

  • Drug: Everolimus
  • Drug: Trastuzumab
  • Drug: Paclitaxel

Inclusion Criteria:

• Female or male patients ≥ 18 years old with WHO performance status ≤ 1
• HER-2 over-expressing metastatic breast cancer cells confirmed by histology
• Progressive disease on prior trastuzumab alone/or in combination with other anticancer agents, or relapsed any time after completion of this therapy (phase l)
• Patient resistance to trastuzumab and taxanes (Phase ll)
• Measurable disease according to RECIST (Phase ll)
• Patients neurologically stable with adequate bone marrow, liver and renal function

Exclusion Criteria:

• Patients receiving endocrine therapy for breast cancer ≤ 2 weeks prior to study treatment start
• Patients currently receiving chemotherapy, immunotherapy or radiotherapy or who have received these ≤ 4 weeks prior to study treatment start or patients who have received lapatinib ≤ 2 weeks prior to study treatment start
• Patients who have previously received mTOR inhibitors

Other protocol-defined inclusion/exclusion criteria may apply