Inclusion Criteria

PATIENT ELIGIBILITY Inclusion Criteria

Subject must meet all of the inclusion criteria listed below to participate:

- Age ≥18 years (no upper age limit)

- Confirmed pathologic diagnosis of breast cancer which is metastatic and for which
capecitabine is a reasonable treatment option

- ARMS C & D: Histologically confirmed HER2+ breast cancer: IHC 3+ or
fluorescence in situ hybridization [FISH] amplified; by clinical assay on either
primary or metastatic tumor

- Brain metastases permitted in Arms A and B if:

- CNS-directed treatment has been given;

- ≥4 weeks interval between whole brain radiation therapy and initiation of
protocol-based therapy;

- ≥2 weeks interval between stereotactic radiosurgery or gamma knife (or equivalent)
and initiation of protocol-based therapy;

- No CNS-directed therapy for the past 3 months, including glucocorticoids; AND

- CNS disease has been clinically and radiographically stable for at least 8 weeks

- Brain metastases permitted in Arms C and D if:

- CNS-directed treatment has been given;

- CNS disease has been clinically and radiographically stable for at least 4 weeks

- In Arm C, if patient on glucocorticoids, must be on stable (4 weeks) dose of no
more than 2 mg/day of dexamethasone or equivalent.

- In Arm D, no steroids are allowed.

- Measurable or non-measurable (but evaluable) disease as defined via RECIST 1.1

- No more than 4 prior chemotherapy regimens for metastatic disease for those in the
dose-escalation cohorts. Prior trastuzumab and lapatinib are allowed for the HER2+
population. Once we reach the expanded RP2D cohorts (see Section 4.5), patients
enrolled must have received ≤3 prior regimens

- Patients enrolled in ARM C may remain on trastuzumab without a washout period

- Patients enrolled in ARM D may remain on lapatinib without a washout period

- Normal organ and marrow function as defined below:

- Absolute neutrophil count ≥1,500/μL

- Platelets ≥100,000/μL

- Hemoglobin ≥8.5g/dL

- ARMs A, C, D: Total bilirubin within normal range (or ≤1.5 X upper limit of
normal (ULN) if liver metastases are present); or total bilirubin ≤3.0 x ULN
with direct bilirubin within normal range in patients with Gilbert Syndrome.

ARM B: Total bilirubin ≤1.5 X ULN (in patients with known Gilbert Syndrome a total
bilirubin ≤3.0 x ULN with direct bilirubin ≤1.5 X ULN)

- ARMs A, C, D: AST(SGOT)/ALT(SGPT) within normal range (or ≤ 3.0X ULN if liver
metastases are present) ARM B: AST(SGOT)/ALT(SGPT) ≤3.0X ULN or ≤ 5.0X ULN if liver
metastases are present)

- Serum creatinine ≤1.5 X ULN OR 24-hour creatinine clearance ≥60 mL/min

- Amylase and lipase levels ≤ ULN

- Left Ventricular Ejection Fraction ≥ 50% by ECHO or MUGA

- Total calcium (corrected for serum albumin) within normal limits (bisphosphonate
use for malignant hypercalcemia control is not allowed)

- Magnesium levels >lower limit of normal

- ARM A: Fasting plasma glucose ≤120 mg/dL (6.7 mmol/L) ARM B: Fasting plasma
glucose ≤140 mg/dL (7.8) mmol/L); HbA1c ≤ 8% ARMS C and D: Fasting plasma
glucose ≤150 mg/dL

- INR ≤2

- Life expectancy ≥12 weeks

- ECOG performance status 0-2 (Karnofsky >60%)

- Time since the last dose of prior therapy to treat underlying malignancy:

- Cytotoxic chemotherapy or endocrine therapy: ≥ the duration of the most recent cycle
of the previous regimen (with a minimum of 3 weeks for all, except 6 weeks for
nitrosourea, mitomycin-C)

- Biologic therapy (e.g., antibodies): ≥4 weeks

- ≥5 X half-life of a small molecule therapeutic

- ≥4 weeks interval between whole brain radiation therapy and initiation of
protocol-based therapy for ARM C or D patient with stable brain metastases;

- ≥2 weeks interval between stereotactic radiosurgery (SRS) or gamma knife (or
equivalent) and initiation of protocol-based therapy for ARM C or D patient with
stable brain metastases

- Patients enrolled in ARM C may remain on trastuzumab without a washout period

- Patients enrolled in ARM D may remain on lapatinib without a washout period - Adults
of reproductive potential must be able and agree to use appropriate contraception.
Double barrier contraceptives must be used throughout the trial by both sexes. Women
assigned to ARMS A, B, C and D must continue contraceptive measures for 16 weeks
after stopping treatment.

Women of childbearing potential, defined as sexually mature women who have not undergone a
hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive
months (i.e., who have had menses any time in the preceding 12 consecutive months), must
have a negative serum pregnancy test ≤72 hours prior to initiating treatment

- Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (e.g. age appropriate, history of vasomotor symptoms) or six months of
spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [and estradiol < 20 pg/mL]
or have had surgical bilateral oophorectomy (with or without hysterectomy) at least
six weeks ago. In the case of oophorectomy alone, only when the reproductive status
of the woman has been confirmed by follow up hormone level assessment is she
considered not of child bearing potential.

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, must use highly effective contraception during the study. Women
assigned to ARMS A, B, C and D must use highly effective contraception for 16 weeks
after stopping treatment; The highly effective contraception is defined as either:

- True abstinence: When this is in line with the preferred and usual lifestyle of
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception.

- Sterilization: have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment.

- Male partner sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate). For female subjects on the study, the
vasectomized male partner should be the sole partner for that patient.

- Use of a combination of any two of the following (a+b):

1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel /film/cream/vaginal
suppository

- Oral contraception, injected or implanted hormonal methods are not allowed as BKM120
and BEZ235 potentially decrease the effectiveness of hormonal contraceptives.

- Recovered from all reversible toxicities related to their previous treatment
(other than alopecia) to ≤grade 1 or baseline

- Ability to understand and the willingness to sign a written informed consent
document

- Exclusion Criteria:

Subjects meeting any of the exclusion criteria listed below at baseline will be excluded
from study participation:

- Receiving concurrent endocrine, cytotoxic, or biologic agent(s) or within time limits
specified above prior to study day 1

- Receiving any other investigational agents currently, or within time limits specified
above prior to study day 1

- Received wide field radiotherapy ≤4 weeks, or SRS or gamma knife for brain metastasis
≤ 2 weeks or limited field radiation for palliation ≤2 weeks prior to starting either
BEZ235 or BKM120 or have not recovered from side effects of such therapy

- Have undergone major surgery ≤2 weeks prior to starting BKM120 or BEZ235 or have not
recovered from side effects of such therapy

- Prior treatment with treatment doses of capecitabine (prior radio-sensitizing doses
of capecitabine are allowed as long as the patient did not progress on capecitabine)

- Prior treatment with a PI3K inhibitor

- Known dihydropyrimidine dehydrogenase (DPD) deficiency

- Treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF,
GM-CSF) ≤2 weeks prior to starting study drug. Erythropoietin or darbepoetin
therapy, if initiated at least 2 weeks prior to enrollment, may be continued

- Currently receiving treatment with medication known to prolong the QT interval or
inducing Torsades de Pointes and the treatment cannot either be discontinued or
switched to a different medication prior to starting study drug

- Patients currently receiving chronic systemic treatment with steroids or another
immunosuppressive agent; 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, or if ARM C patient with brain metastases
treated with glucocorticoid is enrolled Topical applications (e.g., rash), inhaled
sprays, eye drops or local injections of steroids are allowed.

- Known coagulopathies, and those who require therapeutic anticoagulation with
coumarin-derivative anticoagulants

- Presence of acute or chronic liver, renal disease, or pancreatitis

- Patients with poorly controlled diabetes mellitus or steroid-induced diabetes
mellitus

- History of gestational diabetes mellitus

- Known diagnosis of human immunodeficiency virus (HIV) infection

- For Arms A, C or D, patients with the following mood disorders as judged by the
investigator or a psychiatrist, or as result of patient's mood assessment
questionnaire:

- Medically documented history of major depressive episode, bipolar disorder (I or
II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt
or ideation, or homicidal ideation (immediate risk of doing harm to others)

- ≥ CTCAE grade 3 anxiety

- At screening, meets the cut-off score of ≥10 in the Patient Health Questionnaire
(PHQ-9) or a cut-off of ≥ 15 in the Generalized Anxiety Disorder (GAD-7) mood
scale, respectively, or selects a positive response of 1, 2 or 3 to question
number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of
the total score of the PHQ-9) will be excluded from the study unless overruled
by the psychiatric assessment

Note: The psychiatric judgment overrules the mood assessment questionnaire
result/investigator's judgment.

- Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville
oranges, pummelos, and exotic citrus fruits from 7 days prior to the dose of study
medication and during the entire study due to potential CYP3A4 interaction with the
study medication. Orange juice is allowed

- Intake of any herbal preparations or medications (e.g., including, but not limited
to, Saint-Johns Wort and ginkgo biloba) and dietary supplements within 7 days prior
to first dose of study drug

- Unable or unwilling to discontinue use of any drug known to be a strong or moderate
inhibitor or inducer of CYP3A4 (prohibited inducers and inhibitors must be
discontinued within 2 weeks prior to first dose of study drug) (see Appendix B);
please note that co-treatment with weak inhibitors of CYP3A4 is allowed. Patients on
Arm B are prohibited to receive LHRH agonists while on study.

- Patients who received live vaccines or who have close contact with people who have
received live vaccines within 7 days of day 1 of study treatment (see Appendix B)

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of BKM120 or BEZ235 (e.g., ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection);
Patients with unresolved diarrhea will be excluded.

- Inadequately controlled hypertension (i.e. SBP >180 mmHg or DBP >100mmHg)

- Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study:

- Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated
acquisition (MUGA) scan or echocardiogram (ECHO)

- ST depression or elevation of ≥1.5 mm in 2 or more leads

- Congenital long QT syndrome

- History or presence of ventricular arrhythmias or atrial fibrillation

- Clinically significant resting bradycardia (<50 beats per minutes)

- QTc >480 msec on screening ECG

- Complete left bundle branch block

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Unstable angina pectoris ≤6 months prior to starting study drug

- Acute myocardial infarction ≤6 months prior to starting study drug

- Other clinically significant heart disease such as congestive heart failure
requiring treatment (New York Heart Association [NYHA] Class III or IV) or
uncontrolled hypertension (please refer to WHO-ISH guidelines)

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
active or uncontrolled infection) that could cause unacceptable safety risks or
compromise compliance with the protocol

• Significant symptomatic deterioration of lung function. If clinically indicated,
pulmonary function tests including measures of predicted lung volumes, DLco, 02
saturation at rest on room air should be considered to exclude pneumonitis or
pulmonary infiltrates

- Prior malignancy Exceptions: Subjects who have had another malignancy and have been
disease-free for 3 years or subjects with a history of completely resected
non-melanomatous skin carcinoma or successfully treated in situ carcinoma are
eligible

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition of BKM120, BEZ235, capecitabine (including fluorouracil), trastuzumab or
lapatinib

- Pregnant or lactating women

- Patient is unable or unwilling to abide by the study protocol or cooperate fully with
the investigator