Lapatinib and RAD-001 for HER2 Positive Metastatic Breast Cancer

Twenty to twenty five percent of Human Breast Cancers are HER2 positive. HER2 positivity
confers a poor prognosis in the absence of HER2 targeted therapies (trastuzumab and
lapatinib). With these targeted agents often combined with chemotherapy, the treatment of
HER2 positive breast cancer has improved greatly, both in metastatic and adjuvant settings.
However most patients with metastatic HER2 positive breast cancer will eventually develop
resistance to these agents and succumb to their disease. Therefore, there is a need to test
new agents and new combinations that can increase the efficacy of HER2 targeted therapy
and/or prevent resistance to HER2 targeted therapies.

A unique feature of HER2 positive breast cancers is a rather high incidence of brain
metastasis in this population. Brain metastases develop in one third to one half of patients
with advanced HER2+ breast cancer and CNS is a frequent site of trastuzumab failure.
Effective therapy for patients with central nervous system (CNS) progression after cranial
radiation is extremely limited and represents a major clinical challenge. Compared to
trastuzumab, which has no CNS activity, lapatinib, an epidermal growth factor receptor/HER2
inhibitor, has modest CNS activity. In a study of more than 200 patients by Lin et al, 21%
of patients experienced a 20% volumetric reduction in their CNS lesions on lapatinib. An
association was observed between volumetric reduction and improvement in progression-free
survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the
lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40%
experienced a 20% volumetric reduction in their CNS lesions. Mammalian target of Rapamycin
(mTOR) is a serine/threonine kinase that regulates key functions associated with cell
growth, survival and angiogenesis. mTOR is activated by HER signaling, PI3K oncogenic
mutation and loss of PTEN function. In vitro data suggests that activation of mTOR by PTEN
loss and PI3K mutation induces trastuzumab resistance. Preclinical studies have shown that
mTOR inhibition enhances the efficacy of trastuzumab and reverses trastuzumab resistance
caused by PTEN loss. This preclinical finding was confirmed in 2 recent Phase 1 studies
where addition of mTOR inhibitor (RAD-001) to trastuzumab and chemotherapy reversed the
resistance to Trastuzumab in patients with heavily pretreated metastatic HER2 positive
breast cancer. Thus, mTOR inhibition would be an attractive modality to add to HER2 targeted
therapy for improving outcomes in women with HER2 positive breast cancer. Everolimus
(RAD001), a rapamycin analogue, is an orally administered inhibitor of mTOR. Everolimus has
shown promising activity in solid tumors. PK data in mouse models indicated that penetration
of rapamycin and Everolimus into the CNS is substantial. Everolimus brain levels are
approximately one-third that of systemic levels at 48 hours after a dose.

A small molecule inhibitor of HER2, lapatinib is clinically active in women with advanced
HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the
effectiveness of this class of agents is limited by either primary resistance or acquired
resistance. Using an unbiased genetic approach, Eichhorn et al performed a genome wide
loss-of-function short hairpin RNA screen to identify novel modulators of resistance to
lapatinib. Tumor suppressor PTEN was identified as a modulator of lapatinib sensitivity in
vitro and in vivo. In addition, they show that two dominant activating mutations in PI3K
pathway which are prevalent in breast cancer, also confer resistance to lapatinib. They also
showed that PI3K-induced lapatinib resistance could be abrogated through the use of
NVP-BEZ235, a dual inhibitor of PI3K/mTOR. This suggests that deregulation of the PI3K
pathway leads to lapatinib resistance, which can be effectively reversed by inhibition of
PI3K/mTOR pathway.

In summary, the combination of Everolimus and lapatinib needs to be studied in women with
metastatic breast cancer who have progressed on at least one prior anti-HER2 therapy. If
RAD-001 is able to overcome resistance to anti-HER2 therapies, a very desirable response
rate and prolongation in TTP can be expected. Moreover, both lapatinib and Everolimus appear
to be able to cross the blood brain barrier, and this combination may prove to be effective
in controling CNS metastases in this population. The investigators hypothesize that
combining mTOR inhibitor Everolimus with lapatinib will be an effective strategy for
patients who have progressed on a prior anti-HER2 therapy, both systemically and within the
CNS.

INCLUSION CRITERIA

- Females > 18 years of age

- Histologically proven adenocarcinoma of breast in primary or metastatic setting.
Stage: Locally advanced (inoperable) or metastatic

- HER2 positive breast cancer (IHC 3+ or FISH ratio of > 2.0)

- ECOG Performance status 0-2

- Up to four prior chemotherapy regimens and anti-HER2 agents in metastatic setting
allowed. Must have progressed on at least one HER2 targeted therapy (lapatinib or
Herceptin) for metastatic breast cancer.

- Women of childbearing potential must have negative urine or serum pregnancy test
within 7 days prior to administration of Everolimus. If barrier contraceptives are
used, they must be continued throughout trial by both sexes. Hormonal contraceptives
not acceptable as a sole method of contraception.

- Adequate kidney function: serum creatinine of < 1.5 mg/dl and/or creatinine clearance
of > 60 mL/min

- Adequate hepatic function: transaminases < 2.5 x upper limit of normal (up to 5 x ULN
in patients with liver metastases) and total bilirubin < 1.5 mg/dL. Adequate
coagulation: INR ≤ 2.0 and PTT < 1.5 X the upper limit of institution normal range.
Oral anticoagulants, eg, warfarin are CYP2C9 substrates and, as such, no interaction
with Everolimus is expected. Anticoagulation with Coumadin is allowed if target INR
is ≤ 2.0 and stable for > 2weeks. Anticoagulation with LMW is allowed.

- Must be informed of investigational nature of study, and must sign an informed
consent

- Pretreatment lab values (must be performed within 14 days of patient registration
unless otherwise specified. Other baseline studies must be performed within 30 days
of registration.

- Patients will have baseline CT chest, abdomen and pelvis within 30 days of
registration.

- Adequate cardiac function (LVEF ≥ 50% as measured by echocardiogram or MUGA scan).

- 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, patient may be
included after initiation of appropriate lipid lowering medication with approval from
the principal investigator.

- Must have measurable or non-measurable disease by RECIST criteria (version 1.1), with
radiologic scans performed within 30 days of registration. Baseline scans can
include:

- CT Scan or MRI and Bone Scan OR

- PET/CT provided it is performed with both IV and oral contrast and the CT is
acquired with 5mm or less slice thickness. If IV contrast administration is
contraindicated, patients should have CT scan without contrast and bone scan or
MRI and bone scan.

- MRI of brain will be used for baseline assessment and tumor response assessment
for CNS lesions.

- Baseline imaging method(s) should be used to determine tumor response throughout
course of study.

- Measurable disease: lesions with clearly defined margins that can be accurately
measured in at least one diameter (longest diameter to be recorded) with a
minimum size of:

- 10mm by CT scan (CT scan slice thickness no greater than 5mm)

- 10mm caliper measurement by clinical exam (lesions which cannot be
accurately measured with calipers should be recorded as non-measurable)

- 20mm by chest xray

- Malignant lymph nodes: to be considered pathologically enlarged and
measurable. Lymph node must be > 15mm in short axis when assessed by CT
scan. At baseline and in follow-up, only short axis will be measured and
followed.

- Non-measurable disease: all other lesions including small lesions (longest
diameter < 10mm or pathological lymph nodes with > to <15 mm (short axis), and
masses with margins not clearly defined. Lesions that are considered
non-measurable include:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Abdominal masses that are not confirmed and followed by imaging techniques

- Cystic lesion

- Lymphangitic involvement of skin or lung

- The following pre-study tests should be obtained within 14 days prior to registration
in accordance with good medical practice. Results of these tests do not determine
eligibility and minor deviations are acceptable if they do not impact patient safety
in the judgment of the treating physician:

- ANC > 1,000/mm3

- platelet count > 100,000/mm3

- hemoglobin > 9 g/dL

Exclusion Criteria:

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring parenteral antibiotics or psychiatric illness/social situations
that would limit compliance with study requirements.

- GI tract disease resulting in an inability to take oral medication, malabsorption
syndrome, a requirement for IV alimentation, prior surgical procedures affecting
absorption, uncontrolled inflammatory GI disease (eg, Crohn's, ulcerative colitis).

- Current active hepatic or biliary disease (exception of patients with Gilbert's
syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease
per investigator assessment)

- Pregnant and lactating women. Women of reproductive potential not using or unwilling
to use effective birth control methods throughout the trial.

- Severe and/or uncontrolled medical conditions or other conditions that could affect
participation in the study such as:

- Symptomatic congestive heart failure of NYHA Class III or IV

- unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- 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. HBV DNA and HCV RNA PCR
testing required at screening for all patients with a positive medical history
based on risk factors and/or confirmation of prior HBV/HCV infection.

- Patients with symptomatic brain metastases who have not completed radiation therapy
and/or are receiving systemic steroid therapy. Patients with leptomeningeal disease
will be excluded.

- Patients receiving chronic, systemic treatment with corticosteroids (of more than
4mg/day or equivalent of dexamethasone. Doses of dexamethasone of up to 8mg/day may
be administered for less than 2 weeks) or another immunosuppressive agent. Topical or
inhaled corticosteroids are allowed.

- Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period.

- Severely impaired lung function 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 room air.

- Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.

- Active (acute or chronic) or uncontrolled severe infections.

- Known history of HIV seropositivity.

- Active, bleeding diathesis.

- Patients who have received prior treatment with an mTOR inhibitor (eg, sirolimus,
temsirolimus, everolimus).

- Known hypersensitivity to Everolimus or other rapamycins (eg, sirolimus,
temsirolimus) or to its excipients.

- Active Hepatitis B or C infection.

- Life expectancy of < 2 months.

- Prior anti-cancer therapy (eg, biologic or other targeted therapy, chemotherapy,
hormonal therapy) within 2 weeks prior to Day 1 if the patient has recovered from all
AEs to grade 1 except for alopecia.

- Prior investigational anti-cancer therapy within 4 weeks prior to Day 1.

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

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