A Study Of Everolimus, Trastuzumab And Vinorelbine In HER2-Positive Breast Cancer Brain Metastases

STUDY OBJECTIVES Primary Objective -To determine the intracranial objective response rate of
mTOR inhibition (everolimus) in combination with vinorelbine and trastuzumab in the treatment
of HER2-positive, progressive breast cancer brain metastases as defined via modified RECIST
criteria.

Secondary Objectives

- To determine the intracranial objective response rate of mechanistic target of rapamycin
(mTOR) inhibition (everolimus) in combination with vinorelbine and trastuzumab in the
treatment of HER2-positive, progressive breast cancer brain metastases as defined by
MacDonald criteria.

- To evaluate the safety and tolerability of everolimus in combination with trastuzumab
and vinorelbine as assessed via the NCI CTCAE version 4.0

- To evaluate time to intracranial progression after administration of everolimus in
combination with trastuzumab and vinorelbine as defined via modified RECIST criteria

- To evaluate the extracranial objective response rate as determined by RECIST 1.1
criteria after administration of everolimus in combination with trastuzumab and
vinorelbine.

- To evaluate the extracranial time to progression as determined by RECIST 1.1 criteria
after administration of everolimus in combination with trastuzumab and vinorelbine.

- To evaluate progression free survival (PFS) and overall survival (OS) after
administration of everolimus in combination with trastuzumab and vinorelbine.

- To evaluate the impact of everolimus in combination with trastuzumab and vinorelbine on
quality of life as measured by the Functional Assessment of Cancer Therapy Breast
(FACT-B) and Functional Assessment of Cancer Therapy Brain (FACT-Br) questionnaires.

Exploratory Objective

-To evaluate biomarkers in archival tumor tissue samples and correlate with therapeutic
response to everolimus in combination with vinorelbine and trastuzumab.

Following Hepatitis B antiviral prophylaxis if required, or following screening and informed
consent if antiviral therapy is not needed, treatment will be initiated with everolimus PO
daily in combination with weekly intravenous (IV) vinorelbine and trastuzumab (Days 1, 8, and
15)

A cycle is defined as 3 weeks (21 days). Cycles of therapy will be repeated until documented
disease progression, unacceptable toxicity, or patient withdrawal from study for other
reasons, including death.

Inclusion Criteria

- Histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization
(FISH) amplified; by clinical assay on either primary or metastatic tumor)
adenocarcinoma of the breast with at least one progressive and/or new metastatic brain
lesion (>/=5 mm on radiographic imaging) after receipt of intracranial radiation
therapy (whole brain radiation therapy, stereotactic radiosurgery, gamma knife, or
equivalent). Patients in whom brain metastases (BM) are asymptomatic and detected
during routine brain MRI screening per institutional protocols are eligible.

- Prior intracranial radiation therapy (whole brain radiation therapy, stereotactic
radiosurgery, gamma knife or equivalent) is allowed but not required.

- Patients with no prior treatment with intracranial Response (ICR) may be included
unless ICR is emergently indicated (in consultation with a local therapist, ie
neurosurgeon or radiation oncologist)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

- Life expectancy >12 weeks.

- At least 21 years of age.

- No prior mTOR inhibitors

- Prior navelbine allowed provided navelbine therapy discontinued >/= 12 months from Day
1 of treatment under this protocol.

- Last anti-cancer treatment (including any investigational drug) >/= 2 weeks from
initiation of protocol based therapy, provided all adverse events (AEs) (other than
alopecia) have resolved to ≤grade 1 at baseline.

- No active serious infection or other comorbid illness which would impair ability to
participate in the trial.

- Left ventricular ejection fraction assessment (echocardiogram or multigated
acquisition scan (MUGA) scan) performed within 4 weeks prior to study initiation,
showing a Left ventricular ejection fraction (LVEF) value ≥ lower limit of normal
(LLN).

- If patient is on dexamethasone, must be on stable or decreasing dose of dexamethasone
for ≥7 days. If patient is on different glucocorticoid e.g., prednisone, must be
converted to dexamethasone prior to enrollment. Refer to dose modification of
everolimus for patients taking dexamethasone.

- Interval ≥4 weeks between open brain biopsy and initiation of protocol-based therapy.

- international normalized ratio (INR) ≤2.0. Anticoagulation is allowed if target INR
≤2.0 on a stable dose of warfarin or if patient on a stable dose of
Low-molecular-weight (LMW) heparin for >1 weeks at time of enrollment.

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤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 lowering medication.

- Patients must have adequate organ function as evidenced by:

- Absolute neutrophil count ≥1.5/µL

- Platelet count ≥100,000/µL

- Hg ≥9 g/dL

- Bilirubin ≤1.5 x upper limit of normal (ULN)

- aspartate aminotransferase (AST) or Alanine transaminase (ALT) ≤2.5 x ULN (≤5 x ULN if
liver metastases are present)

- Serum creatinine ≤1.5 x ULN

- Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic
studies is required.

- Signed, institutional review board (IRB)-approved written informed consent.

Exclusion Criteria

- Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus,
temsirolimus, everolimus); patients who have received prior treatment with navelbine
within prior 12 months.

- patients with a known hypersensitivity to everolimus or other rapamycins (e.g.
sirolimus, temsirolimus) or to its excipients.

- Patients requiring treatment with any other systemic glucocorticoid. Note: This
restriction regarding choice of glucocorticoid does not apply should patient need <2
week course of glucocorticoid for treatment of non-infectious pneumonitis during study
(see section 4.5.2).

- Patients with a known hypersensitivity to vinorelbine or to its excipients.

- Prior allergic reaction to trastuzumab for the treatment of metastatic breast cancer.

- Concurrent or planned radiation, hormonal, chemotherapeutic, experimental or targeted
biologic therapy.

- Peripheral neuropathy ≥grade 3.

- Evidence of frank hemorrhage or impending herniation on baseline brain imaging. Note:
asymptomatic micro-hemorrhage is allowed.

- Evidence of diffuse leptomeningeal disease on brain MRI or by previously documented
Cerebrospinal fluid (CSF) cytology. Note: discrete dural metastases are permitted.

- Active cardiac disease including any of the following:

- Angina pectoris that requires the use of anti-anginal medication;

- Ventricular arrhythmias except for benign premature ventricular contractions;

- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication;

- Conduction abnormality requiring a pacemaker;

- Valvular disease with documented compromise in cardiac function;

- Symptomatic pericarditis

- History of cardiac dysfunction including any one of the following:

- Myocardial infarction documented by elevated cardiac enzymes or persistent
regional wall abnormalities on assessment of left ventricular (LV) function;

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV);

- Documented cardiomyopathy

- Patients who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia), or patients that may require
major surgery during the course of the study.

- Patients should not receive immunization with attenuated live vaccines within 1 week
of study entry or during study period. Close contact with those who have received
attenuated live vaccines should be avoided during treatment with everolimus. Examples
of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio,
Bacillus Calmette-Guérin (BCG), yellow fever, varicella, and Typhoid Vaccine Live Oral
(TY21a) typhoid vaccines.

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- severely impaired lung function, defined as spirometry and diffusion lung
capacity for carbon monoxide (DLCO) that is 50% of the normal predicted value
and/or 02 saturation that is ≤88% at rest on room air

- uncontrolled diabetes, defined as fasting serum glucose >1.5 x ULN (Note: Optimal
glycemic control should be achieved before starting trial therapy)

- active (acute or chronic) or uncontrolled severe infections

- liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class
C).

Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done
at screening for all patients. Hepatitis B Virus (HBV) DNA and hepatitis C Virus (HCV) RNA
polymerase chain reaction (PCR) testing are required at screening for all patients with a
positive medical history based on risk factors and/or confirmation of prior HBV/HCV
infection.

- A known history of HIV seropositivity.

- 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
resection).

- Patients with an active, bleeding diathesis or on oral anti-vitamin K medication
(except low-dose warfarin and aspirin or equivalent, as long as the INR ≤2.0).

- Unable or unwilling to discontinue use of prohibited fruit (or its juices) and
prohibited medications listed in Appendices II and III for at least 14 days or 5
half-lives of a drug (whichever is longer) prior to the first dose of study drug and
for the duration of the study.

- Female patients who are pregnant or breastfeeding, or adults of reproductive potential
who are not using effective birth control methods. Adequate contraception must be used
throughout the trial and for 8 weeks after the last dose of study drug, by both sexes.
Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy
test within 7 days prior to everolimus initiation.

- Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment

- Contraindication to gadolinium-enhanced MRI imaging.

- Inability to comply with study and/or follow-up procedures.

- History of noncompliance to medical regimens.