A randomized Phase III, double-blind, placebo-controlled multicenter trial of daily everolimus in combination with trastuzumab and vinorelbine, in pretreated women with HER2/neu over-expressing locally advanced or metastatic breast cancer

Summary

This is a multi-center, double-blind, randomized, placebo-controlled, international phase III study evaluating treatment with everolimus (10 mg daily) versus placebo in combination with exemestane (25 mg daily) in postmenopausal women with locally advanced or metastatic ER positive breast cancer refractory to non steroidal aromatase inhibitors.

Patients will be randomized in 2:1 ratio to receive either everolimus or matching placebo in a blinded manner in addition to open label exemestane (25 mg daily tablets). Considering the safety of exemestane is already well established, the 2:1 randomization ratio will allow collection of more data from the experimental arm to better evaluate the safety of the everolimus/exemestane combination. Randomization will be stratified by documented
sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes vs. no). Visceral refers to lung, liver, brain, pleural and peritoneal involvement.
Sensitivity to prior hormonal therapy is defined as either
1. documented clinical benefit (complete response, partial response, stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or
2. at least 24 months of adjuvant hormonal therapy prior to recurrence.

Dose adjustment (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings will be allowed. Regular safety reviews by an Independent Data Monitoring Committee (IDMC) will be performed. Tumor assessments will be performed every 6 weeks until disease progression. To account for potential discrepancies between local and central review, if additional tumor assessments are performed prior to starting further
anticancer therapy, the corresponding tumor assessments should also be sent for central review. Additional evaluation should be performed to confirm response at least 4 weeks after it was first observed. Study treatment will continue until progression, intolerable toxicity or consent withdrawal. Further treatment after progression will be at the investigator[Right Quote]s discretion. Subjects on placebo arm will not be allowed to cross over to study supplied everolimus at the time progression, as everolimus remains an investigational drug for this patient population.

Participant Eligibility

1. Written informed consent must be obtained prior to any study-related procedures;
2. Women ≥ 18 years old;
3. Histologically or cytologically confirmed invasive breast carcinoma with locally recurrent
or radiological evidence of metastatic disease. Locally recurrent disease must not be
amenable to resection with curative intent;
4. HER2+ status defined as IHC 3+ staining or in situ hybridization positive.
Note: The pathology report confirming HER2+ status must be available at the study center
prior to randomization;
5. Patients with resistance to trastuzumab, defined as:
• Recurrence while on trastuzumab or within 12 months since the last infusion for
patients who received trastuzumab as adjuvant treatment.
• Progression while on or within 4 weeks since the last infusion of trastuzumab for
patients who received trastuzumab for metastatic disease.
• Note: "..since last infusion of trastuzumab" refers to the last infusion of
trastuzumab at any point in the patient's prior treatment history. Trastuzumab
treatment need not be the latest (or most recent) treatment received by the patient
prior to entering the study. If the patient meets the definition of trastuzumab
resistance at any time during her treatment history, the patient is considered
resistant to trastuzumab.
6. Prior taxane therapy.
7. Patients with an ECOG performance status of 0 - 2;
8. Patients with measurable disease as per RECIST criteria;
• Note: Patients with CNS-only lesions are not eligible.
9. Documentation of negative pregnancy test for patients of child bearing potential prior to
enrollment within 7 days prior to randomization. Sexually active pre-menopausal women
must use adequate contraceptive measures, excluding estrogen containing contraceptives,
while on study;
10. Patients must meet the following laboratory criteria within 21 days prior to randomization:
• Hematology
• Absolute neutrophil count (ANC) ≥ 1500 /mm3 or 1.5 × 109/L;
This document (090095af82bdc4af in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
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Approved for report publication by Alexandris Ekaterine in East Hanover at Wed, 09 Feb 2011 06:59:08 PM EST
Approved for report publication by Mukhopadhyay Pabak in East Hanover at Thu, 10 Feb 2011 12:21:06 PM EST
Approved for report publication by El-Hashimy Mona in East Hanover at Thu, 10 Feb 2011 11:49:43 AM EST
Novartis Confidential Page 52
Amended Protocol Version 02 Oncology Clean Protocol No. CRAD001W2301
• Platelets ≥ 100,000 /mm3 or 100 × 109/L;
• Hemoglobin ≥ 90 g/L or 5.6 mmol/L;
• INR ≤ 2;
• Biochemistry
• AST/SGOT and ALT/SGPT ≤ 2.5 × upper limit of normal (ULN) )or ≤ 5.0 ×
ULN if the transaminase elevation is due to liver metastases);
• Total serum bilirubin ≤ 1.5 × ULN (In patients with known Gilbert syndrome,
total bilirubin ≤ 3 × ULN, with direct bilirubin ≤1.5 × ULN);
• Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤
2.5 × ULN (with lipid-lowering drugs permitted);
• Serum creatinine ≤ 1.5 × ULN;
11. Left ventricular ejection fraction assessment (echocardiogram or MUGA scan) performed
within 4 weeks prior to randomization, showing a LVEF value ≥ LLN;
12. Radiological or clinical evidence of recurrence or progression on or after the last systemic
therapy prior to randomization.
• Note: Patients must have recovered to grade 1 or better from any adverse events
(except alopecia) related to any previous therapy prior to randomization