A Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Weekly Paclitaxel/Bevacizumab +/- Everolimus as First-Line Chemotherapy for Patients With HER2-Negative Metastatic Breast Cancer (MBC)
1. Female or male patients >=18 years of age.
2. Histologically confirmed invasive breast cancer, locally unresectable or metastatic.
3. No prior chemotherapy for MBC. Patients may have received adjuvant or neoadjuvant
chemotherapy (including taxanes and/or bevacizumab) as long as treated was completed
>12 months prior to relapse. Prior hormonal therapy in the adjuvant or metastatic
setting will be permitted.
4. Prior hormonal therapy in the adjuvant or metastatic setting is permitted. Estrogen
receptor positive patients should be considered candidates for chemotherapy.
5. HER2-negative breast cancer, defined as follows:
· FISH-negative (FISH ratio <2.2), or
· IHC 0-1+, or
· IHC 2-3+ AND FISH-negative (FISH ratio <2.2).
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
7. Adequate hematologic function, defined by:
· Absolute neutrophil count (ANC) >1500/mm3
- Platelet count >=100,000/mm3
- Hemoglobin >9 g/dL
8. Adequate liver function, defined by:
- AST and ALT <=2.5 x the upper limit of normal (ULN) or <=5 x ULN in presence of
- Total bilirubin <=1.5 x ULN
9. Adequate renal function, defined by:
· Serum creatinine <=1.5 x ULN or calculated creatinine clearance of >=40 ml/min
10. International normalized ratio (INR) <=1.5 or prothrombin time (PT)/partial
thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient
is not on anti-coagulation therapy). Patients receiving anti-coagulation treatment
with an agent such as warfarin or heparin are eligible if the INR is stable and
within the therapeutic range prior to study treatment initiation.
11. Adequate lipid profile: total cholesterol <=300 mg/dL OR <=7.75 mmol/L and fasting
triglyceride 2.5 x ULN. Note: In case one or both of these thresholds are
exceeded,the patient can only be included after initiation of appropriate lipid
12. Patients with proteinuria at screening as demonstrated by either:
· Urine protein creatinine (UPC) ration >1.0 at screening or
- Urine dipstick for proteinuria >=2+ (patients discovered to have >=2+
proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine
collection and must demonstrate <1 g of protein in 24 hours to be eligible).
13. Measurable disease by RECIST criteria.
14. Life expectancy >=12 weeks.
15. Ability to swallow oral medications.
16. Adequate cardiac function, defined by baseline left ventricular ejection fraction
(LVEF) value >= normal per institutional guidelines by MUGA scan or echocardiogram
17. Adequate recovery from recent surgery. · Major surgical procedure >28 days from study
· Minor surgical procedure >7 days from study entry (Portacath placement excepted -
patients can start treatment <7 days after portacath placement.)
18. Patients with previous history of invasive cancers (including breast cancer) are
eligible if definitive treatment was completed more than 5 years prior to initiating
current study treatment, and there is no evidence of recurrent disease.
19. Patient must be accessible for treatment and follow-up.
20. All patients must be able to understand the investigational nature of the study and
give written informed consent prior to study entry.
1. Patients with active brain metastases or meningeal metastases. Patients who have had
brain metastases resected, or have received brain radiation therapy >4 weeks prior to
study entry are eligible, if they meet all of the following criteria: 1) residual
symptoms < grade 2, 2) no dexamethasone requirement, and 3) follow-up MRI shows
regression of lesions after treatment and no new lesions appearing.
2. Previous treatment with an m-TOR inhibitor (sirolimus, temsirolimus, everolimus) or
anti-angiogenesis agent unless:
- in the adjuvant setting, and
- >=12 months prior to recurrence.
3. Previous radiotherapy for metastatic disease completed <2 weeks prior to study
4. Patients who are current receiving systemic cancer therapy or have received previous
systemic therapy within 4 weeks of the start of study drug (e.g. chemotherapy,
antibody therapy, targeted agents).
5. Women who are pregnant or lactating. All patients with reproductive potential must
agree to use effective contraception from time of study entry until at least 3 months
after the last administration of study drug.
6. Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or diastolic
pressure >100 mmHg, despite optimal medical management.
7. Concurrent use of CYP3A4 inhibitors and inducers from 72 hours prior to initiation of
study treatment until the end of treatment with everolimus.
8. Cardiac disease, including: congestive heart failure (CHF) > Class II per New York
Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest)
or new-onset angina (i.e., began within the last 3 months), or myocardial infarction
within the past 6 months; symptomatic CHF, unstable angina pectoris, or cardiac
ventricular arrhythmias requiring anti-arrhythmic therapy.
9. History of stroke or transient ischemic attack within 6 months prior to first
10. Patients with any non-healing wound, ulcer, or long-bone fracture.
11. Patients with clinical history of hemoptysis or hematemesis.
12. Patients with any history of a bleeding diathesis or coagulopathy.
13. Patients with a PEG or G tube cannot be enrolled into this trial.
14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to beginning bevacizumab.
15. Patients with an impairment of gastrointestinal function or gastrointestinal disease
that may significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
16. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation such as:
- severe impaired lung functions as defined as spirometry and DLCO that is 50% of
the normal predicted value and/or 02 saturation that is 88% or less at rest on
- uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.
17. History of any other disease, physical examination finding, or clinical laboratory
finding giving reasonable suspicion of a disease or condition that contraindicates
use of an investigational drug, or that might affect interpretation of the results of
this study, or render the subject at high risk for treatment complications.
18. History of hypersensitivity to Cremophor EL (polyoxyethylated castor oil) or a drug
formulated in Cremophor EL, such as paclitaxel.
19. Patients may not receive any other investigational or anti-cancer treatments while
participating in this study.
20. Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
21. Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period.
22. Concurrent severe, uncontrolled infection or intercurrent illness including, but not
limited to, ongoing or active infection, or psychiatric illness/social situations
that would limit compliance with study requirements.
23. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins
(sirolimus, temsirolimus) or its excipients.
24. Patients with a known HIV seropositivity. -