Conditions: Metastatic or Locally-advanced Unresectable Breast Cancer
Keywords: BYL719 Letrozole Exemestane 13-027
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the safety of a drug called BYL719 at different dose levels. The investigators want to find out what effects, good and/or bad, BYL719 has on the patient and breast cancer. BYL719 will be given with either letrozole or exemestane to patients with HR+ locally-advanced or metastatic breast cancer. When the recommended phase II dose of BYL719 in combination with letrozole or exemestane has been determined in the dose-finding phase, an additional 10 patients will be enrolled onto each arm in an expansion phase of the study. The purpose of the expansion phase is to further define the safety and feasibility of BYL719 in combination with letrozole or exemestane at the recommended phase II dose, and to estimate efficacy.

Detailed description:

Arms:
arm 1: For both the dose-finding phase and the expansion phase, patients may have stable or progressive disease on letrozole, and BYL719 will be added. A treatment cycle will consist of 28 days. Treatment doses for each AI will be fixed at the established dose. Patients will continue on treatment until progression of disease or unacceptable toxicity. The initial scan interval to assess disease status will be every two cycles (8 weeks) for the first four cycles (16 weeks), and then every 3rd cycle (12 weeks) thereafter. arm 2: For both the dose-finding phase and the expansion phase, patients may have stable or progressive disease on Exemestane, and BYL719 will be added. A treatment cycle will consist of 28 days. Treatment doses for each AI will be fixed at the established dose. Patients will continue on treatment until progression of disease or unacceptable toxicity. The initial scan interval to assess disease status will be every two cycles (8 weeks) for the first four cycles (16 weeks), and then every 3rd cycle (12 weeks) thereafter. arm 3: For both the dose-finding and expansion phases of Arms C and D, patients may have stable or progressive disease on letrozole or exemestane, and BYL719 will be added.Letrozole 2.5mg orally once daily with BYL719 given on days 1-7 and 15-21 of a 28 day cycle. The starting dose of BYL719 in Arms C will be 250mg daily. Patients who are on study under Amendment 13, the scan interval will become every 4th cycle (16 weeks ±4 weeks) from their last scan. arm 4: For both the dose-finding and expansion phases of Arms C and D, patients may have stable or progressive disease on letrozole or exemestane, and BYL719 will be added. Exemestane 25mg orally once daily BYL719 Days 1-5, 8-12, 15-19, 22-26 of 28 day cycle. For Arm D, the established dose is 350mg for BYL719, 10 patients will be assigned to the corresponding arm in the expansion phase of the study. Patients who are on study under Amendment 13, the scan interval will become every 4th cycle (16 weeks ±4 weeks) from their last scan.

Interventions: intervention 1: BYL719 intervention 2: Letrozole intervention 3: Exemestane
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
Page 1 of 82
 
 
IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
 
 
 
 
A Phase I Trial of BYL719 plus Letrozole or Exemestane for Patients 
Positive Locally-Advanced Unresectable or Metastatic Br
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTO 
 
Principal Investigator/Department: 
Sarat Chandarlapaty, MD, PhD 
 
 
 
 
 
with Hormone-Receptor 
east Cancer 
 
 
COL 
 
Medicine/Breast 
Co-Principal 
Pedram Ra
Investigator(s)/Department: 
zavi, MD, PhD
Medicine/Breast
Investigator(s)/Department: 
Ting Bao, MD
Victoria Blinder, MD 
Jacqueline Bromberg, MD, PhD 
Maureen Cannon, NP 
Gabriela D’Andrea, MD 
Chau Dang, MD 
Karen Drucker, NP 
Monica Fornier, MD 
Teresa Gilewski, MD 
Shari Goldfarb, MD 
Ayca Gucalp, MD 
Neil Iyengar, MD 
Komal Jhaveri, MD 
Diana Lake, MD 
Shanu Modi, MD 
Mary Ellen Moynahan, MD 
Larry Norton, MD 
Mark Robson, MD 
Andrew Seidman, MD 
Nancy Sklarin, MD 
Lillian Smyth, MD 
Tiffany Traina, MD 
Valentina Sterlin, NP 
Lauren Wood, RN 
Tina Alano, RN 
Emer Heaney, RN 
Danielle Alleva, NP 
Catherine Keane, NP 
Renee Wisniewski, NP 
 
Sujata Patil, PhD 
Anne Covey, MD 
Betty Ann Caravella, MD 
Edi Brogi, MD 
Michael Berger, PhD 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
 
Biostatistics 
Interventional Radiology 
Radiology 
Pathology 
Pathology 
 


Page 2 of 82
Memorial Sloan Kettering Cancer Center 
IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
 
 
 
 
 
Consenting  Professional(s)/Department: 
Ting Bao, MD
Medicine/Breast
Victoria Blinder, MD
Medicine/Breast
Jacqueline Bromberg, MD, PhD
Medicine/Breast
Sarat Chandarlapaty, MD, PhD
Medicine/Breast
Gabriela D’Andrea, MD
Medicine/Breast
Chau Dang, MD
Medicine/Breast
Monica Fornier, MD
Medicine/Breast
Teresa Gilewski, MD
Medicine/Breast
Shari Goldfarb, MD
Medicine/Breast
Ayca Gucalp, MD
Medicine/Breast
Neil Iyengar, MD
Medicine/Breast
Komal Jhaveri, MD
Medicine/Breast
Diana Lake, MD
Medicine/Breast
Shanu Modi, MD
Medicine/Breast
Mary Ellen Moynahan, MD
Medicine/Breast
Pedram Razavi, MD, PhD
Medicine/Breast
Larry Norton, MD
Medicine/Breast
Mark Robson, MD
Medicine/Breast
Andrew Seidman, MD
Medicine/Breast
Nancy Sklarin, MD
Medicine/Breast
Lillian Smyth, MD
Medicine/Breast
Tiffany Traina, MD
Medicine/Breast
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
Page 3 of 82 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .........................................................................4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ..................................................................................9 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 10 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 21 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 23 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................. 24 
6.1 
Subject Inclusion Criteria ...................................................................................................... 24 
6.2 
Subject Exclusion Criteria .................................................................................................... 26 
7.0 
RECRUITMENT PLAN ......................................................................................................................... 27 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 27 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 28 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 40 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 63 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 64 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 65 
14.0 
BIOSTATISTICS .................................................................................................................. 65 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES69 
15.1 Research Participant Registration ............................................................................................. 69 
15.2 
Randomization ........................................................................................................................ 70 
16.0 
DAT A M ANAGEMENT ISSUES .......................................................................................... 70 
16.1 
Quality Assurance .............................................................................................................. 70 
16.2 
Data and Safety Monitoring .................................................................................................. 70 
17.0 
PROTECTION OF HUMAN SUBJECTS .............................................................................. 71 
17.1 
Privacy ................................................................................................................................ 60 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................. 65 
17.2.1.........................................................................................................................................73 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 74 
19.0 
REFERENCES ........................................................................................................................... 75 
20.0 
APPENDICES ...................................................................................................................... 76 


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IRB Number: 13-027 A(15) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase I study of BYL719 in combination with letrozole or exemestane for the 
treatment of patients with locally-advanced unresectable or metastatic hormone-receptor 
positive (HR+) breast cancer.  BYL719 is an oral PI3K inhibitor which selectively inhibits the 
class IA p110α isoform of PI3K. 
 
The primary objective is to determine the recommended phase II dose of BYL719 when 
administered in combination with either letrozole or exemestane.  We are interested in this 
combination because we hypothesize that PI3Kα inhibition will be less toxic than pan-PI3K or 
mTOR inhibition, tolerable in combination with an aromatase inhibitor (AI), and effective in 
combination with an AI, even after progression on the same AI.  As of January 2014, this trial 
is being amended such that an additional primary objective is to determine the recommended 
phase II dose of BYL719 administered in a 7 day on, 7 day off schedule, in combination with 
letrozole, and the recommended phase II dose of BYL719 administered on a 5 day on, 2 day 
off schedule, in combination with exemestane. 
 
This clinical trial was initially comprised of two arms, one for BYL719 in combination with 
letrozole (Arm A) and another for BYL719 in combination with exemestane (Arm B).  As of 
January 2014, Arms A and B will no longer accrue patients and the study will be amended to 
include Arms C and D.  Arm C will involve letrozole with BYL719 given on days 1-7 and 15- 
21 of a 28 day cycle.  Arm D will involve exemestane with BYL719 given on days 1-5, 8-12, 
15-19, 22-26 of a 28 day cycle.  Anastrozole will not be evaluated in this study because 
anastrozole is a non-steroidal AI similar to letrozole.  Arms C and D employ distinct 
aromatase inhibitors for clarity throughout clinical care.  However, given the similar toxicity 
profile seen with both aromatase inhibitors with continuously dosed BYL719 (Arms A and B), 
results from either arm are felt to be generalizable to either aromatase inhibitor. 
 
Subjects currently enrolled onto Arms A and B will continue on Arms A and B.  They will be 
re-consented with the revised Arm A and B consents which will reflect our updated toxicity 
profile.  In addition, planned secondary objectives for Arms A and B (e valuation of safety and 
toxicity, estimation of efficacy, pharmacokinetic studies) will continue, though the analyses 
will only be performed based on those subjects enrolled onto Arms A and B (dose- 
escalation) as no subjects will be enrolled onto Arms A and B dose-expansion. 
 
As of January 2017, this trial is being amended to revise the restaging scans and clinic visit 
requirements for patients who have been receiving protocol therapy for greater than 75 
weeks. At the time of this amendment (Amendment 13) this study has closed to patient 
accrual after enrolling a total of 51 patients. 


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IRB Number: 13-027 A(15) 
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The original study schema (for Arms A and B) is shown above, and the schema for Arms C 
and D is shown below.  Rather than proceed further with the dose-finding phase or continue 
to the expansion phase for Arms A and B, we will proceed directly to the dose-finding phase 
for Arms C and D given toxicity concerns discussed below.  For Arm C and Arm D, there will 
be a dose-finding phase and an expansion phase.  When the recommended phase II dose of 
intermittent BYL719 in combination with letrozole or exemestane has been determined in the 
dose-finding phase, an additional 10 patients will be enrolled onto Arm C and Arm D in an 
expansion phase of the study.  The purpose of the expansion phase is to further define the 
safety and feasibility of BYL719 in combination with letrozole or exemestane given on two 
intermittent schedules, at the recommended phase II dose, and to estimate efficacy. 
 
 


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Patients will be eligible for either Arm C or Arm D depending on which AI they were taking 
before study enrollment.  For both the dose-finding phase and the expansion phase, patients 
may have stable or progressive disease on letrozole or exemestane, and BYL719 will be 
added. 
 
A treatment cycle will consist of 28 days.  The regimen will consist of BYL719 in combination 
with letrozole or exemestane administered orally each day.  Patients will be on treatment 
until unacceptable toxicity or progression of disease.  Treatment doses and schedule are 
shown below: 
 
Arm 
AI dose 
BYL719 schedule (dose per
cohort) 
A 
Letrozole 2.5mg orally once daily
Days 1-28 of 28 day cycle
B 
Exemestane 25mg orally once daily
Days 1-28 of 28 day cycle
C 
Letrozole 2.5mg orally once daily
Days 1-7, 15-21 of 28 day cycle
D 
Exemestane 25mg orally once daily
Days 1-5, 8-12, 15-19, 22-26 of 28
day cycle 
 
The dose-finding phase will follow a standard 3 + 3 design, according to the cohorts in the 
tables below.  The starting dose of BYL719 in Arms A and B will be 300mg daily, which is 
75% of the MTD from the single agent phase I study.  The starting dose of BYL719 in Arms 
C and D will be 250mg daily. 


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IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
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Arms A and B 
 
COHORT 
BYL719 dose
+2 
400mg orally once daily (100% of MTD for single agent BYL719)
+1 
350mg orally once daily (87.5% of MTD for single agent BYL719)
0 (starting dose) 
300mg orally once daily (75% of MTD for single agent BYL719)
-1 
250mg orally once daily (62.5% of MTD for single agent BYL719)
-2 
200mg orally once daily (50% of MTD for single agent BYL719)
 
Arms C and D 
 
COHORT 
BYL719 dose
+2 
350mg
+1 
300mg
0 (starting dose) 
250mg
-1 
200mg
 
Tumor tissue biopsies will be obtained to further define the biology of AI-resistance in 
metastatic ER+ breast cancer, and to evaluate predictive and pharmacodynamic biomarkers 
of treatment with BYL719 (see schema on following page). 
 
We will no longer accrue to Arm A or Arm B.  For Arm C and Arm D, we anticipate 4-18 
patients per arm for the dose-finding phase of the trial, and we estimate an accrual rate of 2 
patients per month, with a total time of 1 year to complete.  We anticipate 20 patients for the 
expansion phase of the trial (10 patients in each arm), which will require an additional 1 year 
to complete. 


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aNumbers represent priority order if insufficient tumor tissue is present in the biopsy for all correlatives 
bPre-treatment biopsy is preferred for the exploratory objectives being studied. We anticipate that tumor tissue 
may be insufficient in up to 3 biopsies, in which case these analyses may be performed on an archival primary 
or metastatic tumor specimen. 
Pre-treatment 
biopsy only
b: 
PTEN immuno- 
histochemistry 
(King lab) 
Pre-treatment biopsy 
only
b: DNA isolation 
and targeted 
sequencing analysis 
(Berger lab) 
Pre-treatment and Day 15 
biopsies: Stay at MSK 
Clinical Pathology for 
routine H&E and routine 
ER, PR and HER2 analysis 
Add BYL719 to letrozole 
or exemestane for two 
28-day cycles 
Pre-treatment 
biopsy 
Patient with metastatic ER+ breast cancer, most recently 
treated with letrozole or exemestane, with stable disease or 
progression of disease 
Core divided, 
RSA to pick up 
Pre-treatment and 
Day 15 biopsies: 
Frozen stored at 
-80°C for 
quantitative 
phosphoproteomic 
analysis 
(Chandarlapaty 
lab) 
3a
1a
2a 
Paraffin- 
Embedded 
4a
Study consent, Screeni ng 
Day 15 on-treatment 
biopsy 
Evidence of disease 
evaluation at 8 weeks 
Progression of disease: 
come off study 
 
Stable disease, partial 
response, or complete 
response: 
continue treatment 


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IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
Page 9 of 82 
 
 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 Primary Objective 
 
Arm A and Arm B: To determine the recommended phase II dose of BYL719 
when administered in combination with either letrozole or exemestane to 
patients with HR+ locally-advanced or metastatic breast cancer 
 
Arm C and Arm D: To determine the recommended phase II dose of BYL719 
when administered in combination with letrozole in a 1 week on, 1 week off 
schedule, or with exemestane in a 5 of 7 days weekly schedule, to patients 
with HR+ locally-advanced or metastatic breast cancer 
 
2.2 Secondary Objectives 
 
Arms A, B, C and D: To describe the safety and tolerability of BYL719 when 
administered in combination with either letrozole or exemestane to patients 
with HR+ locally-advanced or metastatic breast cancer 
 
 
Arm A and Arm B: To estimate the efficacy of BYL719 plus letrozole or 
exemestane in patients with HR+ locally-advanced or metastatic breast cancer, 
by calculation of the following in an expansion cohort: 
o Progression-free survival 
o Overall response rate (complete response + partial response) 
o Clinical benefit rate at 16 weeks (complete response + partial response 
+ stable disease) 
o Time to treatment failure 
 
 
Arm C and Arm D: To estimate the efficacy of BYL719 in two distinct 
schedules, plus letrozole or exemestane, in patients with HR+ locally-advanced 
or metastatic breast cancer, by calculation of the following in an expansion 
cohort: 
o Progression-free survival 
o Overall response rate (complete response + partial response) 
o Clinical benefit rate at 16 weeks (complete response + partial response 
+ stable disease) 
o Time to treatment failure 
 
 
Arm A and Arm B: To describe the pharmacokinetics of daily BYL719 when 
given in combination with letrozole or exemestane 
 
 
Arm C and Arm D: To describe the pharmacokinetics of BYL719 on two distinct 
administration schedules when given in combination with letrozole or 
exemestane 
 
2.3 Exploratory Objectives 
 
Arms A, B, C and D: To evaluate mechanisms of AI resistance and predictors 
of BYL719 sensitivity through next generation sequencing and fine copy 
number analysis of a pre-treatment biopsy 


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 
Arms A, B, C and D: To evaluate predictive and pharmacodynamic markers of 
PI3K pathway inhibition with BYL719 through proteomic analysis of pre- 
treatment and on-treatment biopsies 
 
 
Arms A, B, C and D: To evaluate cell free DNA (cfDNA) as a predictive 
biomarker of PI3K pathway inhibition with BYL719 through the sequential 
quantification of PIK3CA mutant alleles by digital PCR (dPCR) on serial plasma 
collections. 
 
 
Arms A, B, C and D: To evaluate mechanisms of acquired resistance with 
correlative studies of on-treatment and optional post-progression tumor 
biopsies 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Hormone-Receptor Positive (HR+) Metastatic Breast Cancer 
 
Despite advances in treatment, breast cancer remains the second highest cause of cancer 
deaths in women.  Over two thirds of breast tumors are found to be positive for the estrogen 
receptor (ER) and/or progesterone receptor (PR).  Growth of these HR+ tumors is often 
estrogen-dependent, and therefore, endocrine therapy plays an important role in the 
treatment of HR+ metastatic breast cancer. 
3.2 Endocrine Therapy for HR+ Metastatic Breast Cancer 
 
Endocrine therapy is generally better tolerated than standard cytotoxic chemotherapy and 
often the first line treatment for HR+ metastatic breast cancer1.  Several endocrine agents 
are FDA-approved for treatment of HR+ metastatic breast cancer.  Tamoxifen is a selective 
ER modulator which antagonizes ER in breast tissue.  Aromatase inhibitors (AIs) block the 
conversion of androgens to estrogens and include the non-steroidal AIs, letrozole and 
anastrozole, and the steroidal AI, exemestane1.  Fulvestrant is an ER antagonist which binds 
to and downregulates ER. 
 
For patients with HR+ metastatic breast cancer, the development of resistance to endocrine 
therapy is a major cause of disease progression and mortality.  Delaying resistance to 
endocrine therapy may significantly impact management of this large group of patients. 
3.3 Role of PI3K in Resistance to Anti-Estrogen Therapy 
 
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that are important in controlling 
signaling pathways involved in cell proliferation, motility, cell death and cell invasion. There is 
substantial evidence that, in many tumors, the PI3K signaling pathway is constitutively 
activated. This is thought to be a critical step in mediating the transforming potential and 
growth stimulating activity of various oncogenes (i.e., HER2, EGFR, IGF1R).  When 
activated, PI3K catalyzes the phosphorylation of the cell membrane-embedded 
phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). 
In turn, PIP3 acts as a docking site for signaling proteins, most notably PDK1, where 
activation can take place, effecting downstream cellular pathways critical for cell growth and 


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IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
Page 11 of 82
 
 
 
 
survival, including the AKT and mTOR pathway. Whereas normal cells rely on these 
pathways for regulatory functions, such as insulin signaling, cancer cells exploit these 
pathways for tumorigenesis. 
 
Class I PI3K contains four isoforms, p110α, p110β, p110δ and p110γ, which carry out non- 
redundant signaling functions.  Mutations in PIK3CA, the gene encoding p110α, are found in 
multiple human tumor types, suggesting that p110α is a key isoform for promoting tumor 
growth.  The PIK3CA gene is frequently mutated in human breast cancers, and more 
commonly in HR+ disease.  In our clinical database of tumor tissue genotyped for PIK3CA 
mutations, from 590 patients who underwent resection of primary breast tumors at Memorial 
Sloan-Kettering Cancer Center (MSKCC), 480 had HR+ breast tumors; of these, 182 (37.9%) 
were found to harbor PIK3CA mutations.2 
Laboratory studies have demonstrated that hormonal and PI3K signaling cooperate in breast 
cancer pathogenesis.  Crowder et al demonstrated that the combination of estrogen 
deprivation and knockdown of the PI3Kα catalytic subunit promoted cell death in multiple 
HR+ breast cancer cell lines.
3    Miller et al showed that PI3K pathway hyperactivation was 
associated with endocrine resistance and that PI3K pathway inhibition suppressed hormone- 
independent cell growth in long-term estrogen-deprived HR+ breast cancer cell lines.
4
 
The cross-talk of the PI3K pathway with ER transcriptional activity is summarized in Figure 3- 
1 below, adapted from Miller et al.4    PI3K pathway activation contributes to ligand- 
independent phosphorylation of ER and activation of associated transcription cofactors.  In 
turn, ER promotes gene transcription of ligands and growth factor receptors upstream of the 
PI3K pathway.5 
 
 
 
Figure 3-1, from Miller T et al5 


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3.4 Activity of mTOR Inhibition in Breast Cancer 
 
The mTOR protein is activated downstream of PI3K/AKT, and forms the TORC1 complex 
(see Figure 3-1), which is involved in cell growth and survival signaling. 
 
Two recent clinical trials have evaluated the role of everolimus, an mTOR inhibitor, in 
combination with endocrine therapy for the treatment of HR+ metastatic breast cancer after 
progression on treatment with an AI.  In the phase II TAMRAD study, 111 patients with 
metastatic HR+ breast cancer who progressed on prior AI therapy were randomized to 
everolimus in combination with tamoxifen versus tamoxifen alone.
6    The 6 month clinical 
benefit rate was 61% for the combination and 42% for tamoxifen alone, suggesting increased 
activity in the combination arm.6 
The recent phase III BOLERO-2 study demonstrated that the addition of everolimus to 
exemestane in patients with metastatic breast cancer who developed resistance to a non- 
steroidal AI (letrozole or anastrozole) resulted in improved progressive-free survival.7 
Median progression-free survival for patients receiving everolimus in combination with 
exemestane was 6.9 months, compared to 2.8 months in the group receiving placebo plus 
exemestane (HR 0.43, 95% CI 0.35-0.45, p<0.001).7    This was an unselected population in 
regards to PIK3CA mutation status, and biomarker data is not available. 
 
Notably, mTOR inhibition with rapalogs has had virtually no efficacy in breast cancer as a 
single agent, further suggesting synergy between the PI3K-mTOR pathway and ER 
activation.  A phase II study of temsirolimus as a single agent for the treatment of 31 
unselected patients with metastatic breast cancer did not result in any objective responses.
8
 
Adverse effects related to mTOR inhibition were seen in both the TAMRAD and BOLERO-2 
studies.  These included stomatitis, rash, fatigue, diarrhea, decreased appetite, 
hyperglycemia and pneumonitis.
6,7    Although perhaps considered acceptable in the context 
of metastatic disease, there is notable toxicity associated with mTOR inhibition, which may 
conceivably be improved with more direct inhibition of the mutant oncoprotein.  The 
preclinical work described in Section 3.3 (and also in Section 3.6 below) suggests that 
targeting PI3K may be optimal in the setting of HR+ breast cancer which has developed 
resistance to endocrine therapy. 
3.5 PI3Kα Inhibition with BYL719 
 
Class I PI3K contains four isoforms, p110α, p110β, p110δ and p110γ, which carry out non- 
redundant signaling functions.  Mutations in PIK3CA, the gene encoding p110α, are found in 
multiple human tumor types, suggesting that p110α is the main PI3K isoform which drives 
tumor growth. Therefore, the development of a p110α specific PI3K inhibitor is expected to 
reduce the potential for inducing treatment-related toxicity, resulting in an improved 
therapeutic window. 
 
NVP-BYL719 (BYL719) is an oral class I α-specific PI3K inhibitor belonging to the 2- 
aminothiazole class of compounds. It strongly inhibits the PI3Kα isoform (wild-type and 
mutant) and much less strongly the β, δ and γ isoforms. BYL719 has demonstrated anti- 
tumor activity in preclinical in vitro and in vivo tumor models. In vivo, BYL719 has 
demonstrated dose dependent tumor growth inhibition in various subcutaneous tumor 


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transplant models. BYL719 is currently being investigated in a Phase I dose escalation trial 
and the maximum tolerated dose (MTD) was declared at 400 mg once daily. 
 
For further details on preclinical and clinical experience, please refer to Section 3.5.1 and 
Section 3.5.2 and the current BYL719 Investigator’s Brochure (IB). 
 
 
3.5.1 Preclinical Experience with BYL719 
 
In biochemical assays, BYL719 inhibits p110α (IC50  = 5 nM) much more potently than the 
p110δ and γ isoforms and PI4Kβ and has weak or no activity against p110β, Vps34 and 
mTOR.  BYL719 is equipotent against the most common somatic mutations of p110α 
(H1047R, E545K) compared to wild type p110α, and is selective against a wide range of 
protein kinases with at least a 50-fold selectivity window compared to p110α. 
 
In vitro, BYL719 was found to inhibit proliferation of cancer cell lines, regardless of their 
PIK3CA mutation status.  BYL719 inhibited PIK3CA-mutated breast cancer cell lines, and  
this activity correlated with inhibition of downstream targets of the PI3K-AKT-mTOR pathway. 
In PIK3CA-mutant mice xenograft models, BYL719 demonstrated statistically significant 
dose-dependent anti-tumor activity. 
BYL719 demonstrates low plasma clearance (CL), a moderate volume of distribution at 
steady state (Vss) and a good absolute oral bioavailability in all preclinical species tested 
(Wistar rats, Beagle dogs, mice). The compound is moderately bound to plasma proteins and 
showed a rapid distribution to almost all rat tissues, except the brain. 
BYL719 is a substrate of breast cancer resistant protein (BCRP) and has low affinity for 
Permeability glycoprotein (P-gp). BYL719 does not inhibit BCRP or multidrug resistance- 
associated protein 2 (MRP2), but showed very weak inhibition of P-gp (IC50 97 µM). As the 
maximal inhibition of P-gp was only about 32% with respect to positive control, the overall 
interaction potential is expected to be low. 
 
BYL719 was found to be a time dependent inhibitor of cytochrome P450 3A4 (CYP3A4). 
Reversible inhibition of CYP2C8, CYP2C9 and CYP2C19 was also observed. BYL719 may 
inhibit metabolic clearance of co-medications metabolized by CYP3A4 and, to a lesser 
extent, CYP2C8, CYP2C9 and CYP2C19, if sufficiently high concentrations are achieved in 
vivo. Results from 4-week GLP toxicology studies in dog showed a roughly dose-proportional 
increase in exposure, while in rat the exposure increased up to a dose of 30 mg/kg beyond 
which no further increase was noted following single dose administration. The toxicology 
studies provided no clear evidence of increase in exposure following multiple dosing. No 
gender differences in exposure were observed in rat or dog. 
 
The overall biotransformation of BYL719 in hepatocytes was low. The main biotransformation 
pathway that was observed was hydrolysis. CYP450 dependent oxidative metabolism is 
expected to be minor. No covalent drug protein adduct formation was noted in human 
microsomes or hepatocytes. Please refer to the BYL719 IB for further details. 


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Routine safety pharmacology and toxicology studies were conducted in rats and dogs. In 
addition, for exploratory studies, such as insulin/glucose tolerance tests, mice were also 
used.  BYL719 was relatively well tolerated in the repeated-dose toxicity studies (daily dosing 
of up to 4 weeks of duration) at dosages at which tumor growth control was achieved. 
BYL719 affected rapidly dividing tissues, which resulted only in pharmacological relevant 
observation in the animals exposed to a BYL719 dose close to or at MTD. The most 
frequently affected organs were the bone marrow, lymphoid tissue (spleen, thymus), and the 
epithelia of the alimentary tract, while other tissues like the vagina and uterus in rats, or 
prostate in dogs were also affected at higher doses. Bone/cartilage and tooth-forming 
structures were only affected in rats. In dogs, epithelial effects were seen in the cornea; 
however, the dose-dependency of this cornea observation was not evident. No other 
ophthalmologic abnormalities, associated with BYL719 treatment, were observed in rats or in 
dogs. Abnormal clinical chemistry and histopathology (pancreatic islets) findings indicated an 
altered glucose metabolism, correlating with a clear effect towards insulin insensitivity. In  
both rats and dogs, histopathology and clinical pathology findings were generally observed at 
higher doses which were also associated with reduced body weight development (in the 
growing animals) and reduced food intake. All toxic events were reversible or showed a 
tendency to reversibility after a 4-week treatment-free recovery period. 
Cardiac safety studies, conducted in vitro and in vivo, did not indicate an electrophysiological 
risk. Furthermore, BYL719 in the rat safety pharmacology studies showed no effect on 
neuronal or pulmonary function, and no evidence of a phototoxic potential was found in a  
3T3 neutral red uptake test in vitro. 
In conclusion, the majority of the observed toxicological effects of BYL719 were related to the 
pharmacological activity of BYL719 as a p110α specific inhibitor of PI3K pathway, such as an 
influence on insulin (and potentially glucose) homeostasis and the risk of increased blood 
pressure. The pharmacologically relevant toxicity was mainly observed at dosages close to  
or at MTD with the bone marrow and lymphoid tissue, pancreas, and some reproductive 
organs of both genders being the main target organs of the toxic effects.  Please refer to the 
BYL719 IB for further details. 
BYL719 is not genotoxic in vitro, based on the results of an Ames test and a chromosome 
aberration test. 
3.5.2 Clinical Experience with BYL719 
 
BYL719 is currently tested in 3 clinical studies. CBYL719X2101 is a first-in-human phase IA, 
multicenter, open-label dose escalation study of oral BYL719, in adult patients with advanced 
solid malignancies, whose tumors have an alteration of the PIK3CA gene. CBYL719X1101 is 
a phase I study of BYL719, in adult Japanese patients with advanced solid malignancies. 
CMEK162X2109 is a phase Ib, open-label, multi-center, dose escalation and expansion 
study of an orally administered combination of BYL719 plus MEK162 in adult patients with 
selected advanced solid tumors. 
In CBYL719X2101 dose escalation phase, 7 dose levels have been tested from 30 mg QD to 
450 mg daily. The maximum tolerated dose (MTD) was declared at 400 mg daily. A safety 


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expansion cohort at 400 mg daily is currently being tested, and an additional cohort of BID 
dosing is also under testing. 
 
As of 20 Apr 2012, a total of 50 patients with advanced cancer have received at least one 
dose of BYL719 and have been evaluated for safety. 
Overall, 43 (86%) patients experienced AEs which were suspected to be related to BYL719. 
The most frequently reported treatment-related AEs, regardless of CTCAE Grade and dose 
were hyperglycemia 23/50 (46%), decreased appetite 17/50 (34%), nausea 17/50 (34%), 
diarrhea 16/50 (32%), fatigue (12/50; 24%) and vomiting (12/50; 24%). Among these, 16 
(32%) patients experienced at least one CTCAE Grade 3/4 AE suspected to be treatment- 
related. The most common treatment-related CTCAE Grade 3/4 AEs were hyperglycemia 
and nausea. 
Six DLTs were reported by the cut-off date, all from the CBYL719X2101 study. There were 4 
cases in 450 mg daily cohort (2 x CTCAE Grade 3 hyperglycemia, CTCAE Grade 3 nausea, 
and intractable nausea), one case in 400 mg daily expansion cohort (Grade 3 nausea and 
Grade 3 vomiting), and one case in 200 mg BID cohort (CTCAE Grade 3 hyperglycemia). 
In summary, the current data indicate a favorable clinical safety profile of BYL719. 
 
Signs of single-agent clinical efficacy were also reported.  There were 3 partial tumor 
responses per RECIST, including a partial response in a patient with ER+ breast cancer 
treated at 270mg daily.10  
Preliminary clinical pharmacokinetic data of BYL719 after single and multiple daily dosing is 
available from the first-in-human trial CBYL719X2101. BYL719 was administered orally as a 
tablet (doses ranging between 30 and 450 mg) and full pharmacokinetic profiles were 
collected on Day 1 and Day 8 of Cycle 1 and on Day 1 of Cycle 2. 
Following administration of the first dose, BYL719 was well absorbed, with median time to 
reach peak plasma concentration (Tmax) ranging from 1.5 to 7.1 hours across cohorts. 
Median Tmax appeared to be independent of dose and was unchanged after multiple oral 
doses. Maximum Tmax spanned a wide range across cohorts (2.15-22.4 hours), indicating 
slow absorption in some subjects. Geometrical mean plasma peak drug concentration 
(Cmax) and drug exposure (AUCinf) after single oral dose of BYL719 increased in an 
approximate dose-proportional manner. At the MTD (400 mg daily), the Cmax and AUCinf 
were ~2617 ng/ml and ~36858 ng.hr/ml (geometrical mean), and showed moderate inter- 
individual variability (41% and 49% in CV% for Cmax and AUCinf). 
Plasma concentrations of BYL719 generally declined in a mono-exponential manner, 
suggesting rapid distribution towards the peripheral tissues. Mean terminal half-life was 
approximately 10 hours, and generally appeared to be independent of dose and time. 
 
At lower daily doses (30 mg-180 mg), oral drug clearance appeared to be independent of 
both dose and time, and an approximate dose-proportional increase in drug exposure (Cmax 
and AUC) was observed after one week and one month of daily dosing.  Apparent total body 
clearance (CL/F) calculated from exposure data after 1 month of dosing ranged between 
9.40 and 10.8 L/hr across the lower dose cohorts (30 – 180 mg), indicating that BYL719 is a 


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low clearance drug. Similar oral clearance values were obtained from total drug exposure 
(AUCinf) after single dose administration. 
 
At higher daily doses (> 180 mg), oral drug clearance within the first week of dosing (C1D8) 
ranged between 9.48 and 11.3 L/hr, which is in close agreement with the CL/F observed 
after single dose administration. However, after one month of dosing at 270 mg and 400 mg, 
a tendency towards an increase in drug exposure (AUC0-24h) and Cmax with time was 
observed. At 400 mg daily, the geomean drug accumulation ratio (Racc) was ~3 fold (range 
1.91 and 4.42). 
 
 
 
 
 
 
3.6 Role of mTOR in Negative Feedback 
 
Chandarlapaty and colleagues have investigated the consequences of PI3K pathway 
inhibition and found that targeting mTOR almost invariably leads to activation of receptor 
tyrosine kinases and PI3K through a loss-of-feedback mechanism9  (see Figure 3-2).  So, 
mTOR inhibition may lead to activation of the upstream PI3K pathway.  Therefore, we 
hypothesize that patients who experience progression on an mTOR inhibitor, such as 
everolimus, may still obtain benefit from subsequent treatment with a PI3Kα inhibitor. 
 
 
 
Figure 3-2,  adapted from Chandarlapaty et al9 
3.7 Rationale for evaluating non-daily dosing schedules 
 
As discussed above, there is a strong rationale for the therapeutic combination of BYL719 
with endocrine therapy in hormone receptor-positive breast cancer.  However, clinical 
experience at our institution and elsewhere suggests that escalation to potentially efficacious 
doses of BYL719 may be hindered by the development of dose-limiting toxicity (DLT), and in 


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particular, skin toxicity. Maculopapular rash is being seen with increasing frequency when 
BYL719, and to a lesser extent, other PI3K inhibitors, are administered in conjunction with 
endocrine therapy (Figure 3-3). 
 
Thus far, in the dose-escalation phase of the current phase I trial, BYL719 was administered 
daily in conjunction with either letrozole (Arm A) or exemestane (Arm B).  In both arms, dose- 
limiting toxicity required dose-reductions from BYL719 300mg orally daily to BYL719 250mg, 
as compared with the single-agent maximally tolerated dose of 400mg orally daily.  Three of 
four dose-limiting toxicities were grade 3 maculopapular rash. Our data (discussed below  
and displayed in Tables 3-1 and 3-2) and clinical experience suggest that this rash generally 
occurs between days 10-14 of treatment.  Typically, patients report a burning, prickly skin 
sensation followed by the relatively rapid eruption of erythematous macules and papules that 
encompass the majority of patients’ body surface area.  Upon withholding therapy and 
initiating timely referral to dermatology, in addition to oral corticosteroids, topical 
corticosteroids, and oral antihistamine therapy, the rash generally resolves quickly without 
long-term sequelae.  However, it is bothersome to patients and conceivably may affect 
adherence to this oral medication.  Furthermore, the rash is generally grade 3 in extent and 
therefore necessitates treatment interruptions for patients who are on clinical trial with this 
therapeutic combination. 
 
In Arm A, the overall incidence of rash (any grade) that was possibly, probably, or definitely 
related to BYL719 is 57% (4 of 7 patients), with 3 of 4 patients having grade 3 rash. 
Furthermore, one of these patients with grade 3 rash was on treatment with BYL719 at 
dosing cohort -1 (250mg).  In Arm B, the overall incidence of rash that was possibly, 
probably, or definitely related to BYL719 is also 57% (4 of 7 patients), and all affected 
patients had grade 3 rash.  Of all 8 patients across arms who developed maculopapular rash 
that was possibly, probably or definitely related to BYL719, 75% developed rash between 
days 10-14 of treatment.  One of 7 patients on the letrozole arm and 1 of 7 patients on the 
exemestane arm discontinued therapy on study due to rash.  Complete data is displayed in 
Table 3-1 and Table 3-2 below. 
 
Despite this rash, preliminary signals of efficacy are encouraging and support the use of 
alternate dosing schedules to mitigate the need for dose de-escalation of this potentially 
efficacious therapy.  In Arm A, 2 of 2 patients who have undergone evaluation of disease 
assessments continue on study.  One patient who previously had progress ion of disease on 
letrozole achieved stable disease with addition of BYL719, most recently on cycle 5 day 1 
scan, and a second patient had a 43% reduction of disease from baseline per RECIST 
criteria.  On Arm B, 2 of 5 patients who have undergone imaging assessments continue had 
minor responses at first EOD imaging, yielding a preliminary clinical benefit rate at 8 weeks 
of 40%. 
Table 3-1: Skin toxicity and patient responses from continuously dosed BYL, Arm A - 
Letrozole + BYL719 
 
Patient 
BYL719 dose 
PIK3CA 
mutation 
status 
On-study
status 
Worst skin
toxicity* 
Timing 
of skin 
toxicity 
onset 
Patient’s
response to 
BYL719 + 
AI** 


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003 
300mg 
Unknown
Off study due 
to DLT (rash) 
Grade 3 
rash 
C1d11 
n/a 
004 
300mg 
Positive 
On study
none
n/a 
Stable
disease, most 
recently on 
C5d1 imaging 
005 
300mg 
Unknown
Off study due 
to 
nonadherence 
Grade 3 
rash 
C1d14 
n/a 
009 
300mg 
Positive 
On study
 
Required dose 
reduction due 
to DLT (grade 
3 abd pain, 
hyperglycemia) 
none
n/a 
Partial
response at 
C3d1 with 
43% decrease 
fro baseline 
013 
250mg 
Positive 
On study
Grade 1 
rash 
C1d22 
n/a 
016 
250mg 
Negative
On study
Grade 3 
rash 
C1d12 
n/a 
017 
250mg 
Positive 
On study
None
n/a 
n/a 
 
Table 3-2: Skin toxicity and patient responses from continuously dosed BYL, Arm B – 
Exemestane + BYL719 
 
Patient 
BYL719 dose 
PIK3CA 
mutation 
status 
On-study
status 
Worst skin
toxicity* 
Timing 
of skin 
toxicity 
onset 
Patient’s
response to 
BYL719 + 
AI** 
001 
300mg 
Negative
Off study due 
to DLT (rash) 
Grade 3 
rash 
C1d13 
n/a 
002 
300mg 
Positive 
Off study due 
to POD 
(C4d1) 
none
n/a
Minor 
response at 
C3d1 with 
24% decrease 
from baseline, 
then POD 
006 
300mg 
Negative
Off study due 
to POD 
(C3d1) 
Grade 3 
rash 
C1d13 
POD at C3d1


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007 
300mg 
Positive 
On study
Grade 3 
rash 
C1d27 
SD at C3d1
008 
300mg 
Positive 
Off study due
to POD 
(C3d1) 
none
n/a
POD at C3d1
012 
300mg 
Positive 
Off study due 
to rapid POD 
(C1d7) 
None
n/a
n/a 
014 
300mg 
Negative
Off study due 
to POD 
(C3d1) 
Required 
dose 
reduction 
Grade 3 
rash 
C1d10 
POD at C3d1
 
*Only skin toxicity that is possibly, probably, or definitely related to BYL719 is noted 
**N/a refers to patients who are off study prior to first EOD assessment, or who have not yet 
undergone EOD assessment 
 
Colleagues at the Washington University School of Medicine recently presented data from 
their Phase I trial involving fulvestrant with BKM120, a pan-PI3K inhibitor, dosed daily or 
dosed 5 of 7 days weekly, with findings that further support the exploration of alternate, non- 
daily dosing schedules.  Grade 3 rash was seen in 2 of 7 patients treated with daily BKM120, 
while only 1 of 11 patients treated during 5 of 7 days developed grade 3 rash.  The 
incidences of other adverse events, including transaminase elevation, hyperglycemia, and 
diarrhea were also lower with intermittent dosing.  No DLTs were seen in either group. 
Stable disease or better at 6 months was seen in 57% (4 of 7) patients receiving daily 
BKM120 and 45% (5 of 11) patients receiving BKM120 on 5 of 7 days.  It should be noted 
that one patient who achieved a partial response with daily dosing withdrew from study 
participation in the setting of grade 3 rash.  Furthermore, the longest sustained responses 
were seen on the intermittent dosing arm, with 2 patients achieving disease stability and 
continuing on treatment for 15 and 17 months at the time of data presentation in December 
2013.  These data demonstrate that toxicity is not infrequently seen with daily dosing of PI3K 
inhibitors, that alternate dosing schedules may reduce rate of toxicity, and that alternate 
dosing schedules may still allow for significant and prolonged therapeutic responses. 
Increasing recognition of this dose-limiting toxicity seen with daily PI3K inhibitor dosing has 
lead to efforts by Dr. Sarat Chandarlapaty of the Memorial Sloan Kettering Human Oncology 
and Pathogenesis Program to pursue preclinical modeling of alternate dosing schedules. 
Preliminary findings further suggest that alternate dosing schedules warrant further clinical 
exploration. 
 
Given the above, we propose an amendment to include two additional study arms, Arm C 
and Arm D, to examine intermittent dosing of BYL719.  As further discussed in Section 4.0, 


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Overview of Study Design/Intervention, and Section 9.2, BYL719 administration, patients on 
Arm C will receive BYL719 daily during days 1-7 and days 15-21 of a 28 day cycle, 
representing a 1 week on, 1 week off schedule.  Patients on Arm D will receive BYL719 daily 
during days 1-5, 8- 12, 15-19, and 22-26 of a 28 day cycle, representing a 5 days on, 2 days 
off schedule.  The starting dose of BYL719 in both arms will be 250mg orally daily.  Dose and 
daily administration of aromatase inhibitors will remain unchanged. 
 
The rationale for the current amendment is founded on our experiences to date, as well as 
the experiences of others as discussed above.  The incidence of rash with BYL719 when 
used with an aromatase inhibitor is prohibitive, both in the setting of clinical trial dose 
escalation, as well as conceivably in clinical practice.  The general timing of rash onset on 
days 10-14, and its prompt reversal with interventions including withholding therapy, argue 
for intermittent dosing. 
Given the similar toxicity rates of the two arms seen during daily continuous BYL719 dosing, 
findings from both arms are felt to be applicable to either aromatase inhibitor. 
3.8 Hypothesis 
 
We therefore propose a clinical trial of BYL719 in combination with an AI.  We hypothesize 
that the combination of BYL719 with an AI will represent a highly potent, non-chemotherapy 
combination that safely, effectively and durably treats HR+ breast cancers.  We additionally 
hypothesize that intermittent dosing of BYL719 will allow for dose escalation and treatment 
with less toxicity than daily BYL719. 
 
Hyperglycemia is the most common side effect of BYL719, and may even represent a 
pharmacodynamic marker of clinical efficacy.  Significant overlapping toxicity between 
BYL719 and either letrozole or exemestane is not anticipated.  However, these drugs have 
not been tested together in humans.  Therefore, we propose a phase I trial of this  
combination to evaluate the safety and tolerability of this regimen.  The starting dose of 
BYL719 on Arms A and B of this study (300mg daily) will be 75% of the single-agent MTD 
(400mg daily).  As of January 2014, we are closing accrual to Arms A and B and amending 
the study to allow for examination of intermittent dosing through the addition of Arms C and D 
to the trial.  The starting dose of BYL719 on Arms C and D of this study will be 250mg, with 
intermittent dosing schedules as outlined above.  Once a safe dose of BYL719 in the 
combination has been established for Arms C and D, we propose an expansion phase for 
these arms to further evaluate safety, and to estimate the efficacy of this combination. 
 
We propose testing BYL719 in an unselected population in regards to PIK3CA genotype. 
Preclinical data suggest that subsets of tumors with alterations in the PI3K pathway may be 
particularly sensitive (e.g., PIK3CA mutation) or resistant (e.g., PTEN loss) to this 
combination.  This has yet to be evaluated clinically.  It is not clear that the presence or 
absence of a PIK3CA mutation restricts the efficacy of BYL719 in patients with HR+ breast 
cancer which has progressed on endocrine therapy.  The BOLERO-2 study showed efficacy 
of mTOR inhibition in an unselected population in regards to PIK3CA genotype, and no 
biomarker data is available.7    We therefore propose testing BYL719 in an unselected 
population in regards to PIK3CA genotype, and a detailed molecular analysis of tumor 
biopsies of patients on this trial, looking at next generation sequencing and fine copy number 


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analysis to identify determinants of sensitivity.  In order to understand the action of BYL719 
on HR+ breast cancer treated with an AI, we will also evaluate a Day 15 on-treatment biopsy 
for pharmacodynamic markers of pathway inhibition which correlate with improved PFS. 
 
If this study is successful, these results may lead to further study of this non-chemotherapy 
combination, supported by science from MSKCC labs and Novartis, ultimately moving 
towards our goal of delaying or preventing resistance to endocrine therapy in the treatment of 
HR+ breast cancer. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
This is a single institution phase I dose-finding study with an expansion cohort.  The primary 
objective is to determine the recommended phase II dose of BYL719 when administered in 
combination with either letrozole or exemestane to patients with HR+ locally-advanced or 
metastatic breast cancer.  As of January 2014, this trial is being amended such that an 
additional primary objective is to determine the recommended phase II dose of BYL719 
administered in a 7 day on, 7 day off schedule, in combination with daily letrozole, and the 
recommended phase II dose of BYL719 administered on a 5 day on, 2 day off schedule, in 
combination with daily exemestane.  An expansion cohort for Arms C and D will be treated at 
the final dose level to further define the safety and feasibility of each combination, and to 
estimate efficacy. 
 
This clinical trial was initially comprised of two arms, one for daily BYL719 in combination 
with letrozole (Arm A) and another for BYL719 in combination with exemestane (Arm B).  As 
of January 2014, Arms A and B will no longer accrue patients and the study will be amended 
to include Arms C and D.  Arm C will involve letrozole with BYL719 given on days 1-7 and 
15-21 of a 28 day cycle.  Arm D will involve exemestane with BYL719 given on days 1-5, 8- 
12, 15-19, 22-26 of a 28 day cycle.  The figure below shows the overall study scheme for 
Arms C and D.  Patients will be eligible for only one of the two arms depending on which AI 
(letrozole or exemestane) they were taking before study enrollment.  Patients will not be 
randomized to one of the two arms. 


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For both the dose-finding and expansion phases of Arms C and D, patients may have stable 
or progressive disease on letrozole or exemestane, and BYL719 will be added.  We 
anticipate 12-30 patients for the dose-finding phase of the trial (6-15 patients in Arm C, and 
6-15 patients in Arm D), and 20 patients for the expansion phase of the trial (10 patients in 
Arm C, and 10 patients in Arm D). 
 
As of June 2015, the recommended phase II dose of BYL719 has been determined to be 
350mg for Arm D and we are currently enrolling 10 patients to the corresponding arm in the 
expansion phase of the study. Dose Expansion to Arm C is currently on hold. 
A treatment cycle will consist of 28 days.  Treatment doses for each AI will be fixed at the 
established dose (see Section 9.1) and treatment doses for BYL719 will be determined 
based on patient cohort.  Treatment schedule of BYL719 is as above.  The dose-finding 
phase will follow a standard 3+3 design (see Section 9.4). 


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Subjects currently enrolled onto Arms A and B will continue on Arms A and B.  They will be 
re-consented with the revised Arm A and B consents which will reflect our updated toxicity 
profile.  In addition, planned secondary objectives for Arms A and B (evaluation of safety and 
toxicity, estimation of efficacy, pharmacokinetic studies) will continue, though the analyses 
will only be performed based on those subjects enrolled onto Arms A and B (dose- 
escalation) as no subjects will be enrolled onto Arms A and B dose-expansion. 
 
Patients will continue on treatment until progression of disease or unacceptable toxicity.  The 
initial scan interval to assess disease status will be every two cycles (8 weeks) for the first 
four cycles (16 weeks), and then every 3
rd  cycle (12 weeks) thereafter (see Section 10.10). 
For patients who are on study under Amendment 13, the scan interval will become every 4th 
cycle (16 weeks ±4 weeks) from their last scan. Toxicity will be tabulated using the NCI 
Common Toxicity Criteria (CTCAE), version 4.0, and data will be entered into the MSKCC 
Clinical Research Data Base (CRDB). 
 
 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 BYL719 Mode of Action 
 
BYL719 is an oral PI3K inhibitor which selectively inhibits the class IA p110α isoform of PI3K. 
BYL719 will be considered the investigational treatment or the “study drug” for this study. 
See Section 3.5 for an overview of the pre-clinical and clinical experience with BYL719. 
 
5.2 BYL719 Availability and Storage 
 
BYL719 will be supplied by Novartis as tablets for oral use of 50mg and 200mg dosage 
strength.  The tablets will be differentiated through different tablet sizes and/or colors. 
BYL719 will be dosed on a flat scale and not individually adjusted by weight or body surface 
area. 
 
Study drug must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access.  Upon receipt, BYL719 should be stored according to the 
instructions specified on the drug labels.  Study medication will be dispensed by an 
authorized person at MSKCC. 
 
Clinical drug supply must be accounted for and patients will be asked to return all unused 
study drug and packaging on a regular basis, at the end of the study or at the time of study 
drug discontinuation. 
 
At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to Novartis. 


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The drug supply will be destroyed at a Novartis facility, or Novartis will provide guidelines for 
destruction, if investigational site is approved to destroy drug per prior agreement with 
Novartis. 
5.3 BYL719 Administration 
 
Please refer to Section 9.2 for BYL719 administration guidelines. 
 
5.4 BYL719 Toxicity 
 
Please refer to Section 11.0 for BYL719 Toxicity. 
 
5.5 BYL719 Pharmacology 
 
For details on preclinical and clinical experience, please refer to Section 3.5.1 and Section 
3.5.2 and the current BYL719 Investigator’s Brochure (IB). 
 
5.6  BYL719 Drug Interactions 
 
Please refer to Section 9.6 entitled “Concomitant medications” for information regarding 
BYL719 drug interactions. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
 
6.2.1 Women age ≥ 18 years 
 
6.2.2 Willing and able to comply with scheduled visits, treatment plan and laboratory tests 
 
6.2.3 Willing and able to consent for biopsy of locally-advanced or metastatic breast cancer 
prior to treatment 
6.2.4 Metastatic or locally-advanced unresectable breast cancer (includes metastatic or 
locally-advanced unresectable breast cancer which is diagnosed while on adjuvant 
letrozole or exemestane) 
 
6.2.5 Histologically documented HR+ breast cancer in either the primary or metastatic 
setting, as defined by ER+ or PR+; results from the local lab are acceptable.  Eligibility 
will not be affected by HER2 status. 
6.2.6 The most recent treatment prior to enrollment must be one of the following (duration of 
treatment ≥2 weeks), and must have been adequately tolerated according the treating 
physician’s judgment: 
 
Letrozole 
 
Exemestane 
 
Exemestane + everolimus (everolimus must be discontinued for ≥ 3 weeks prior to 
starting study treatment) 


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 
Letrozole or exemestane in combination with an experimental agent(s) on a 
clinical trial, provided that the experimental agent(s) is not a PI3K inhibitor or AKT 
inhibitor (see Section 6.2.3) (experimental agent(s) must be discontinued for ≥ 3 
weeks prior to starting study treatment) 
 
6.2.7 Any number of prior endocrine therapies (including tamoxifen, fulvestrant and/or 
aromatase inhibitors in either the adjuvant or metastatic setting) and any number of 
prior chemotherapy regimens.  Anti-cancer systemic therapy, such as chemotherapy 
or biologics or endocrine therapy, other than the AI, must be discontinued for ≥ 3 
weeks prior to starting study treatment. 
 
 
6.2.8 For the dose-finding phase, patients may have stable disease OR progression of 
disease on the most recent treatment.  For the expansion phase, patients must also 
have stable disease OR progression of disease on the most recent treatment. 
Progression of disease is defined as new or worsening disease on objective imaging. 
Progression of disease includes recurrence diagnosed while on adjuvant letrozole or 
exemestane. 
6.2.9 Postmenopausal women, as defined by one of the following (estradiol assay cutoff 
takes into account that the patient is on aromatase inhibitor therapy): 
 
Age ≥ 55 years and one year or more of amenorrhea 
 
Age < 55 years and one year or more of amenorrhea, with an estradiol assay 
within the post-menopausal range 
 
Age < 55 years with prior hysterectomy but intact ovaries, with an estradiol assay 
within the post-menopausal range 
 
Surgical menopause with bilateral oophorectomy 
 
Ovarian suppression with a LH-RH agonist, with an estradiol assay within the 
post-menopausal range at baseline and periodically on-study 
 
6.2.10 Measurable or non-measurable disease per RECIST criteria v1.1 
 
6.2.11 ECOG performance status 0-1 
 
6.2.12 Adequate organ function, as defined by all of the following: 
 
Hematologic parameters: 
o Absolute neutrophil count (ANC) ≥ 1500/µl (without growth factor support) 
o Platelets ≥ 100,000/µl (no transfusion allowed within 2 weeks) 
o Hemoglobin ≥ 9.0 g/dl (may be reached by transfusion) 
 
Liver function: 
o Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) unless attributable to 
Gilbert’s syndrome 
o AST ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present 
o ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present 
 
Kidney function: 
o Creatinine ≤ 1.5 ULN 


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 
Endocrine function: 
o Fasting plasma glucose <140 mg/dl (may be on antiglycemic agents other 
than insulin).  Fasting glucose measurement must be obtained at least 8 
hours after the most recent caloric intake. 
 
6.2.13 Ability to swallow oral medication 
 
6.2.14 Willing to discontinue all herbal preparations / medications at least 7 days prior to the 
first dose of study drug and throughout the study.  These include, but not limited to, 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, and ginseng. 
 
6.3 
Subject Exclusion Criteria 
 
Patients eligible for this study must not meet any of the following criteria: 
 
6.3.1 Pregnant patients or women who are breast-feeding (patients must be 
postmenopausal, see Section 6.1.9) 
 
6.3.2 Patients with central nervous system (CNS) involvement may participate if: 
 
Clinically stable with respect to the CNS tumor at the time of screening and >4 
weeks from prior therapy completion (including radiation and/or surgery) to the 
start of study treatment 
 
Not receiving steroid therapy 
 
Not receiving enzyme inducing anti-epileptic medications that were started for 
brain metastases (these include carbamazepine, phenytoin, phenobarbital, 
primidone, oxcarbazepine, topiramate, and vigabatrin) 
6.3.3 Prior PI3K inhibitor or AKT inhibitor (patients previously treated with everolimus are 
eligible, see rationale in Section 3.6) 
6.3.4 History of toxicity to the most recent AI (letrozole or exemestane) that warrants 
cessation of the AI 
6.3.5 Patients who have received radiotherapy ≤ 2 weeks prior to starting study treatment 
 
6.3.6 Patients who have undergone major surgery ≤ 4 weeks prior to starting study 
treatment, who have not recovered from side effects of such procedure 
6.3.7 Uncontrolled diabetes (as defined by fasting glucose ≥ 140mg/dL) and/or insulin- 
dependent diabetes.  Fasting glucose measurement must be obtained at least 8 hours 
after the most recent caloric intake.  Patients currently requiring the use of 
antiglycemic agents (other than insulin) may be enrolled if fasting glucose <140mg/dL. 
6.3.8 Current need for chronic corticosteroid therapy (≥10mg of prednisone daily or an 
equivalent dose of other corticosteroid), or patients who have received systemic 
corticosteroids ≤ 2 weeks prior to starting study drug 
 
6.3.9 Current therapeutic anticoagulation with warfarin (or coumarin derivatives) 


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6.3.10 Active infection or serious underlying medical condition that would impair the patient’s 
ability to receive protocol treatment 
 
6.3.11 Clinically significant cardiac disease or impaired cardiac function, such as: 
 
Congestive heart failure requiring treatment (e.g., New York Heart Association 
Class II, III or IV) 
 
Acute coronary syndromes < 3 months prior to screening (including myocardial 
infarction, unstable angina, coronary artery bypass graft, coronary angioplasty, or 
stenting) 
 
Uncontrolled arterial hypertension defined by blood pressure > 140/100 mm Hg at 
rest (average of 3 consecutive readings) 
 
History or current evidence of unstable, clinically significant cardiac arrhythmias or 
patients that require medications with a narrow therapeutic window, atrial 
fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high- 
Grade/complete AV-blockage 
 
Corrected QT interval (QTc) > 480 msec on screening ECG 
 
6.3.12 Patients who are currently receiving medication with a known risk of prolonging the 
QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be 
discontinued or switched to a different medication prior to starting study drug 
treatment (see Section 9.6.3 and Appendix F) 
6.3.13 Impaired gastrointestinal function or poorly controlled gastrointestinal disease that 
may significantly alter the absorption of oral BYL719 (e.g. Crohn’s disease, ulcerative 
colitis, malabsorption syndrome, small bowel resection, uncontrolled nausea or 
vomiting, or grade ≥ 3 diarrhea of any etiology) based on treating physician 
assessment 
 
6.3.14 Patients may not have a “currently active” second malignancy other than non- 
melanoma skin cancers.  Patients are not considered to have a “currently active” 
malignancy if they have completed therapy and are considered by their physician to 
be at less than 30% risk of relapse. 
 
6.3.15 Patients with rapidly progressive or extensive symptomatic visceral metastatic disease 
 
7.0 
RECRUITMENT PLAN 
 
The study is open to eligible patients at Memorial Sloan Kettering Cancer Center (MSKCC) 
main campus only.  Potential research subjects will be identified by a member of the patient’s 
treatment team, the protocol investigators, or research team at MSKCC. 
Patients who are potentially eligible will be evaluated at the Breast Cancer Center at MSKCC 
main campus.  This encounter will include a discussion of the proposed treatment, the 
rationale for its use, potential risks, and alternatives.  Eligible patients who are interested in 
participating will be required to review and sign an informed consent. 
8.0 
PRETREATMENT EVALUATION 


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8.1 Physical examination within 4 weeks prior to starting treatment (including ECOG 
performance status, height, weight, temperature, blood pressure, pulse) 
8.2 Medical history within 4 weeks prior to starting treatment (including documentation of all 
prior therapies for breast cancer and complete medication list for any medications 
taken within 4 weeks prior to starting treatment, see Section 9.3 for prohibited 
concomitant medications) 
8.3 Evidence of disease (EOD) evaluation within 4 weeks prior to starting treatment 
 
o CT of chest/abdomen +/- pelvis, with oral and IV contrast unless 
contraindicated (will be a baseline measure for the study) 
o Bone scan 
o For patients with locally-advanced unresectable breast cancer, radiographic 
assessment using MRI is acceptable (may be used as a baseline measure for 
the study instead of CT, although a pretreatment CT of chest/abdomen is also 
required) 
 
8.4 Pre-treatment biopsy is required within 4 weeks prior to starting treatment, unless felt to 
put the patient at unacceptable risk.  After obtaining separate informed consent, a core 
biopsy will be obtained and processed for both targeted gene sequencing and 
proteomic analyses (Section 10.12) 
8.5 EKG within 2 weeks prior to starting treatment. 
 
8.6 Bloodwork within 2 weeks prior to starting treatment: 
 
o Complete blood count (CBC) including WBC (absolute neutrophil count 
required, remainder of differential not required), Hgb and platelet count 
o Comprehensive profile (CMP), including BUN, creatinine and liver function 
tests 
o PT/INR and PTT 
o Magnesium, amylase and lipase 
o Fasting glucose (8 hours after the most recent caloric intake) 
o Companion normal DNA for targeted gene sequencing analysis (1ml whole 
blood for correlative science, Section 10.12). 
o Plasma collection from 10 ml blood for cfDNA extraction and analysis 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 Aromatase Inhibitor  Administration 
 
This clinical trial was initially comprised of two arms, one for BYL719 in combination with 
letrozole (Arm A), and another for BYL719 in combination with exemestane (Arm B).  As of 
January 2014, the study is being amended to include two additional arms, and patients will 
no longer be enrolled onto Arms A or B.  On Arm C, patients will receive intermittent BYL719 
(7 days on, 7 days off) in combination with daily letrozole, and on Arm D, patients will receive 
intermittent BYL719 (5 days on, 2 days off) in combination with daily exemestane.  Patients 
will be eligible for only one of the two arms, Arm C or Arm D, depending on which AI 


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(letrozole or exemestane) they were taking before study enrollment (i.e., a patient who was 
taking letrozole will continue to take letrozole, and a patient who was taking exemestane will 
continue to take exemestane).  Patients will not be randomized to one of the two arms. 
 
Letrozole or exemestane will be self-administered by the study patients orally once daily.  . 
On days that patients are taking BYL719, aromatase inhibitor should be swallowed 
concomitantly with BYL719, or less than 5 minutes apart, at approximately the same time 
every day.  The recommended time of administration is approximately 9 am (+/- 2 hrs).  On a 
day of PK bloodwork, patients will take the scheduled dose in clinic.  Treatment doses for 
each AI will be fixed at the established dose (see Table 9-1 below).  There will be no dose 
escalation or dose reduction for letrozole or exemestane. 
 
Table 9-1 
 
Arm 
AI dose 
BYL719 schedule (dose per
cohort) 
A 
Letrozole 2.5mg orally once daily
Days 1-28 of 28 day cycle
B 
Exemestane 25mg orally once daily
Days 1-28 of 28 day cycle
C 
Letrozole 2.5mg orally once daily
Days 1-7, 15-21 of 28 day cycle
D 
Exemestane 25mg orally once daily
Days 1-5, 8-12, 15-19, 22-26 of 28
day cycle 
 
 
 
9.3 BYL719 Administration 
 
BYL719 will be taken orally (see Table 9-1, Table 9-2, and Section 9.4 for dose-finding 
schema).  A new bottle of medication at the appropriate dose level will be dispensed on Day 1 
of each 28-day cycle, regardless of the number of tablets remaining in the bottle from the 
previous cycle.  For patients receving treatment under Amendment 13; medication bottles will 
be dispensed on Day 1 of every other 28 day cycle such that each dispensation will provide 
enough tablets for  two cycles. Patients will be provided with an adequate supply of BYL719 
for self-administration at home until at least their next scheduled study visit.  All dosages 
prescribed and dispensed to the patient and any dose change or interruption must be 
recorded appropriately. 
Arms C and D 
 
COHORT 
BYL719 dose
+2 
350mg
+1 
300mg
0 (starting dose) 
250mg
-1 
200mg
 
 
Patients may be seen up to 7 days prior to or following the planned cycle start for the 
purpose of scheduling/conflicts. This window is also applicable to patients who are being 
seen in clinic every two cycles under Amendment 13.In the case of such changes for 


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scheduling/conflicts, BYL719 should continue to be self-administered.  Day 1 of each cycle 
will remain as every 28 days. 
 
Patients will be instructed to take BYL719 as per protocol. 
 
The following general guidelines should be followed for BYL administration: 
 
 
Patients should be instructed to take one or more tablets of BYL719 together with a 
glass of water (~250 ml or ~8 fluid ounces) daily in the morning approximately 1 hour 
after start of a light breakfast (e.g., consisting of non-grapefruit based juice, toast and 
jam) at approximately the same time each day (recommended 8AM +/1 hour), except 
on the days blood collection is scheduled at the clinic, at which time the patients 
should take their doses at the clinic. A light breakfast is defined as approximately 500 
calories, with approximately 75% from carbohydrates and approximately 25% from 
protein and/or fat. 
 
Patients should not eat for 1 hour after the administration of BYL719. 
 
If by noon the patient forgets to take the study drug (BYL719), then the dose should 
be withheld that day. Missed doses should not be made up. If, for any reason, a 
breakfast was not consumed, then the patient should still take the scheduled morning 
dose of study drug with a glass of water. 
 
Patients should be instructed to swallow the tablets and not to chew or crush them. 
 
Patients should be dosed in a staggered manner at least 1 hour before or 10 hours 
after dosing with medicinal products that may alter the pH of the upper GI tract. 
 
Patients should record if the dose was taken or not in the patient diary. 
 
If vomiting occurs during the course of treatment, no re-dosing of the patient is 
allowed before the next scheduled dose. The occurrence and frequency of any 
vomiting and/or diarrhea (or increase stool frequency) during the treatment must be 
noted in the adverse events section of the eCRF. 
 
Patients must avoid consumption of Seville orange (and juice), grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos, starfruits and cranberry juice from 7 days prior to 
the first dose of study drug and during the entire study treatment period due to 
potential CYP3A interaction. Regular orange (Citrus X sinensis) juice is allowed. 
 
On a day of scheduled fasting glucose testing, patients must be fasting overnight for at least 
8 hours prior to the blood collection.  A light breakfast should be consumed after fasting 
glucose blood draw.  BYL719 will be taken in clinic approximately 1 hour after the start of 
breakfast.  Patients should then fast for 1 hour after the administration of BYL719. 
 
Fasting glucose testing and PK sampling may be performed on the same day: fasting 
overnight for at least 8 hours fasting blood collection and pre-dose PK sample light 
breakfast 1 hour wait BYL719 oral administration post-dose PK sample at the 
appropriate time intervals (see Section 10.11). 
 
Patients will be given a medication diary to record the date and time of their BYL719 dose 
each day (Appendix H and Appendix I). 
9.4 Dose-Limiting Toxicity (DLT) Definition 


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Toxicity will be tabulated using the NCI Common Toxicity Criteria (CTCAE), version 4.0.  A 
dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as at least possibly related to the study medication, meeting any of the criteria 
listed in the table below, and occurring during Cycle 1 (≤ 28 days following the first dose of 
BYL719, including those in which the event started in Cycle 1 and the confirmation of the 
DLT occurs in a subsequent cycle).  Whenever a patient experiences toxicity that fulfills the 
criteria for a DLT, treatment with the study drug will be interrupted and the toxicity will be 
followed up (see toxicity management guidelines in Section 10). 
 
As an additional safety measure to assess for late-appearing toxicity, a confirmatory safety 
assessment will be performed at the end of Cycle 2.  If dose-limiting toxicity is observed 
between 28 days and 56 days, then safety data will be reviewed by the Principle Investigator 
and Novartis, and this information will inform the dose-finding cohorts. 
Table 9-2 
Dose-Limiting Toxicity Criteria 
 
Toxicity 
DLT criteria 
 
 
 
 
Blood and lymphatic system 
disorders 
Anemia CTCAE Grade 3 for > 14 consecutive days 
Anemia CTCAE Grade 4 
Febrile neutropenia CTCAE Grade ≥ 3 
Neutropenia CTCAE Grade 3 for > 7 consecutive days 
Neutropenia CTCAE Grade 4 
Thrombocytopenia CTCAE Grade 3 for > 7 consecutive days and/or with signs 
of clinically significant bleeding 
Thrombocytopenia CTCAE Grade 4 
 
 
 
Cardiac disorders 
Cardiac toxicity CTCAE Grade ≥ 3 or cardiac event that is symptomatic or 
requires medical intervention 
Clinical signs of cardiac disease, such as unstable angina or myocardial 
infarction, or Troponin CTCAE Grade 3 (confirmed with a repeat Troponin within 
24 hrs) 
ECG QTc interval prolonged CTCAE Grade ≥ 3 
Vascular disorders/ 
Hypertension 
Persistent hypertension CTCAE Grade ≥ 3 requiring more than one drug or more 
intensive therapy than previously 
General disorders and 
administration site conditions 
Fatigue CTCAE Grade 3 for > 7 consecutive days 
Skin and subcutaneous 
tissue disorders a: 
Rash and/or photosensitivity 
Rash or photosensitivity CTCAE Grade 3 for >7 consecutive days despite skin 
toxicity treatment, or any second or third occurrence of CTCAE Grade 3 rash 
regardless of duration 
Rash or photosensitivity CTCAE Grade 4 
 
 
 
Metabolism and nutrition 
disorders: 
Hyperglycemia b 
Hyperglycemia Grade 3(fasting plasma glucose 250 – 500mg/dL) (confirmed 
with a repeat fasting plasma glucose test within 48 hours) that does not resolve 
to grade 0 within 14 consecutive days (after initiation of oral anti-diabetic 
treatment) 
 
Hyperglycemia Grade 4 
Hyperglycemia leading to diabetic keto-acidosis, hospitalization for IV insulin 
infusion, or non-ketotic coma 
 
GI disorders a 
Diarrhea CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of anti-diarrhea therapy 
Nausea/vomiting CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of anti-emetic 
therapy 
Pancreatitis CTCAE Grade ≥ 3 
Eye disorder 
CTCAE Grade ≥ 3 


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Toxicity 
DLT criteria 
 
 
 
 
 
Blood chemistries c 
Blood bilirubin d CTCAE Grade 2 for > 7 consecutive days 
Blood bilirubin d CTCAE Grade ≥ 3 
AST or ALT CTCAE Grade ≥ 3 in conjunction with blood bilirubin d CTCAE 
Grade ≥ 2 of any duration 
AST or ALT CTCAE Grade 3 for > 7 consecutive days 
AST or ALT CTCAE Grade 4 
Serum alkaline phosphatase CTCAE Grade 4 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 3 for > 7 
consecutive days 
Serum lipase and/or serum amylase (asymptomatic) CTCAE Grade 4 
Serum creatinine CTCAE Grade 2 for > 7 consecutive days 
Serum creatinine CTCAE Grade ≥ 3 
 
 
Other hematologic and non- 
hematologic toxicities 
Any other clinically significant CTCAE ≥ Grade 3 toxicity 
Any intolerable CTCAE Grade 2 toxicity 
Apart from the criteria listed above, if a lower grade AE leads to a dose 
interruption of more than 7 consecutive days of BYL719, this AE will be 
considered as DLT 
a Patients will receive prophylactic treatment for rash with an antihistamine beginning on cycle 1 day 1.  Patients 
will not initially receive prophylactic treatment for nausea/vomiting during Cycle 1. However, prophylactic 
treatment may be initiated in all patients at the dose level where these toxicities have been observed and in all 
further patients if at least 1 patient has experienced nausea/vomiting CTCAE Grade ≥ 3 or if at least 2 patients 
experienced skin toxicity or nausea/vomiting CTCAE Grade ≥ 2 (see Section 11.2 and Table 10-2 for further 
details). Anti-emetics may be applied for treatment if the patient has experienced nausea/vomiting CTCAE 
Grade ≥ 1, at the discretion of the physician. 
bHyperglycemia occurring during corticosteroids administration will be only be considered DLT if not resolved 
within 5 days after the end of corticosteroid treatment. 
c For any hepatic toxicity CTCAE Grade 4, or CTCAE Grade 3 that does not resolve within 7 days to CTCAE 
Grade ≤ 1 (or CTCAE Grade ≤ 2 if liver infiltration with tumor present), an abdominal CT scan should be 
performed to assess if it is related to disease progression. 
d Refers to total bilirubin. 
 
9.5 Dose-Finding Phase 
 
The dose-finding phase will follow a standard 3 + 3 design.  A treatment cycle will consist of 
28 days.  Patients will continue on treatment until progression of disease or unacceptable 
toxicity. 
 
For Arms A and B, the starting dose of BYL719 for the first cohort (Cohort 0) will be 300mg 
daily, which is 75% of the MTD from the phase I study.  Treatment doses for BYL719 for 
each cohort are presented below: 
 
Table 9-3 
Dose-Finding Cohorts for Arms A and B 
 
COHORT 
BYL719 dose
+2 
400mg orally once daily (100% of MTD for single agent BYL719)
+1 
350mg orally once daily (87.5% of MTD for single agent BYL719)
0 (starting dose)
300mg orally once daily (75% of MTD for single agent BYL719)
-1 
250mg orally once daily (62.5% of MTD for single agent BYL719)
-2 
200mg orally once daily (50% of MTD for single agent BYL719)


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For Arms C and D, the starting dose of BYL719 for the first cohort (Cohort 0) will be 250mg 
daily.  Treatment doses for BYL719 for each cohort on Arms C and D are shown below: 
 
Table 9-4 
Dose-Finding Cohorts for Arms C and D 
 
COHORT 
BYL719 dose
+2 
350mg
+1 
300mg
0 (starting dose) 
250mg
-1 
200mg
 
During the dose-finding phase, a periodic teleconference will be held at least monthly with  
the primary investigator and Novartis to review toxicity data and ensure patient safety moving 
forward. 
 
Dose escalation or de-escalation schema: 
On each arm, three patients will be enrolled onto Cohort 0 at the starting BYL719 dose.  All 
patients within a cohort will be observed for toxicity for one cycle (28 days) prior to entering 
additional patients.  If a patient discontinues study participation during the first cycle (within 
28 days of starting study treatment) for reasons unrelated to an adverse event, an additional 
patient may be enrolled to replace that subject.  Between 6 and 15 patients in each arm will 
be necessary to determine the recommended phase II dose of BYL719 in combination with 
letrozole or exemestane. 
 
There will be no intrapatient dose escalation.  Intrapatient dose reductions of BYL719 will not 
be allowed during Cycle 1 (within 28 days of starting study treatment), unless a DLT has 
occurred and been counted towards informing enrollment of future cohorts of patients.  This 
is in order to accurately determine the safe and tolerable dose of BYL719 when used in 
combination with letrozole or exemestane. 
Schema for Cohort 0: 
If none of the initial three patients in Cohort 0 experience dose-limited toxicity (DLT), as 
defined above, then three new patients will be enrolled in Cohort +1 (dose escalation). 
 
If one of the initial three patients in Cohort 0 experiences DLT, then up to three additional 
patients will be treated at the same dose level.  If no more than one of six patients in Cohort 
0 experiences DLT, then three new patients will be enrolled in Cohort +1 (dose escalation). 
 
If two or more patients in Cohort 0 experience DLT, then three new patients will be enrolled 
in Cohort -1 (dose de-escalation). 
 
Schema for Cohort +1: 
If none of the initial three patients in Cohort +1 experience dose-limited toxicity (DLT), as 
defined above, then three new patients will be enrolled in Cohort +2 (dose escalation). 


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If one of the initial three patients in Cohort +1 experiences DLT, then up to three additional 
patients will be treated at the same dose level.  If no more than one of six patients in Cohort 
+1 experiences DLT, then three new patients will be enrolled in Cohort +2 (dose escalation). 
 
If two or more patients in Cohort +1 experience DLT, then the dose level in Cohort 0 will be 
re-considered as the recommended phase II dose. If only three patients were treated in 
Cohort 0, then up to three additional patients will be accrued to that dose level.  If no more 
than one of six patients in Cohort 0 experiences DLT, then that dose level will be confirmed 
as the recommended phase II dose of BYL719 in this combination. 
 
Schema for Cohort +2: 
If none or one of the initial three patients in Cohort +2 experience DLT, then up to three 
additional patients will be treated at the same dose level.  If no more than one of six patients 
in Cohort +2 experiences DLT, then that dose level will be the recommended phase II dose 
of BYL719 in this combination. 
 
If two or more patients in Cohort +2 experience DLT, then the dose studied in Cohort +1 will 
be re-considered.  If only three patients were treated in Cohort +1, then up to three additional 
patients will be accrued to that dose level.  If no more than one of six patients in Cohort +1 
experiences DLT, then that dose level will be confirmed as the recommended phase II dose 
of BYL719 in this combination. 
 
Schema for Cohort -1: 
If none or one of the initial three patients in Cohort -1 experience DLT, then up to three 
additional patients will be treated at the same dose level.   If no more than one of six patients 
in Cohort -1 experiences DLT, then that dose level will be confirmed as the recommended 
phase II dose of BYL719 in this combination.  If two or more patients in Cohort -1 experience 
DLT, then three new patients will be enrolled in Cohort -2. 
 
Schema for Cohort -2: 
If none or one of the initial three patients in Cohort -2 experience DLT, then up to three 
additional patients will be treated at the same dose level.   If no more than one of six patients 
in Cohort -2 experiences DLT, then that dose level will be confirmed as the recommended 
phase II dose of BYL719 in this combination.  If two or more patients in Cohort -2 experience 
DLT, then we will conclude that the combination is not feasible and will discontinue the 
affected arm of the trial.  If this occurs, accrual onto the unaffected arm will be halted until 
safety data is reviewed by the primary investigator and Novartis to determine whether to 
continue or close the unaffected arm of the trial. 
 
9.6 Expansion Phase 
 
As of June 2015, the recommended phase II dose of BYL719 has been determined to be 
350mg for Arm D and we are currently enrolling 10 patients to the corresponding arm in the 
expansion phase of the study. The purpose of the expansion phase is to further define the 
safety and feasibility of BYL719 daily or intermittently in combination with letrozole or 
exemestane, and to estimate efficacy. 


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Patients will be eligible for only one of the four arms depending on which AI (letrozole or 
exemestane) they were taking immediately prior to study enrollment.  Patients will not be 
randomized to one of the four arms. 
 
In the expansion phase,  BYL719 will be administered orally on the same administration 
schedule for that arm as for the dose-finding phase and at the dose established in the dose- 
finding phase of the trial.  For Arm D, the established dose is 350mg for BYL719. Patients 
will continue on treatment until progression of disease or unacceptable toxicity. 
 
In order to help ensure that the DLT rate observed among the additional 10 patients in each 
arm is consistent with the DLT rate observed at the established dose from the dose-finding 
portion, the following decision rule will be implemented for each of the two study arms.  If ≥ 4 
DLTs are seen at any time in any one expansion arm, then it is likely that the safe and 
tolerable dose determined during the dose-finding portion of the trial is too toxic. The safety 
data will then be reviewed with the primary investigator and Novartis to determine how to 
move forward.  Depending on the circumstances, we may consider de-escalating the dose of 
BYL719 to the next lower dose level and accruing 10 additional patients at that level.  The 
probability of observing at least 4 patients with a DLT in the 10 additional patients is .28 if 1 
of 6 patients were seen with a DLT in the dose-finding phase of the study.  The probability of 
observing at least 4 patients with a DLT in the 10 additional patients is .09 if 0 of 6 patients 
were seen with a DLT in the dose-finding phase of the study.
11
 
 
The two arms of the study will be monitored in tandem, and we have added an overall 
sequential global stopping rule to be applied as both expansion cohorts are accruing.  We 
include this early stopping rule across both arms because the mechanism and toxicities of 
both AIs are known to be very similar.  Our global stopping rule is based on repeated 
significance testing and serves as a global safety measure.  We assume a grade 4 toxicity 
rate of 10% as acceptable and 35% as unacceptable.  With these assumptions, if 2 of the 
first 5 patients, 3 of the first 10 patients, 4 of the first fifteen or 5 of 20 patients accrued 
experience a grade 4 toxicity, we will discontinue the entire study.  With this rule, the 
probability of discontinuing the study if the true toxicity rate is 35% is .92.  If the true toxicity 
rate is 10%, this probability is .10. 
Likewise, if two different recommended phase II doses are determined in the separate arms, 
safety data will be reviewed with the primary investigator and Novartis, and we will determine 
how to move forward.  Depending on the circumstances, we will consider reducing the dose 
of BYL719 in the unaffected arm of the trial, if felt to be appropriate to ensure patient safety. 
 
9.7 Concomitant Medications 
 
All medications (other than the study drugs) taken within 4 weeks of study treatment initiation 
and all concomitant therapy and significant non-drug therapies (including physical therapy 
and blood transfusions) administered during the study, with reasons for use, should be 
recorded. Medications include not only physician prescribed medications, but also all over- 
the counter medications, herbal medications and nutritional or vitamin supplements. 


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The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after starting study drug.  Upon enrollment, patients should be given the  
handout titled “Patient Information for BYL719 Drug and Food Interactions” (Appendix C),  
and this information should be reviewed with the patient. 
 
Patients taking medication chronically should be maintained on the same dose and schedule 
throughout the study period, as medically feasible. The days of full pharmacokinetic blood 
sampling should be representative of the other study days with regard to the use of the 
chronically administered concomitant medications. However, if a concomitant medication is 
used intermittently during the study, this medication should be avoided on the days of full 
pharmacokinetic sampling, if medically feasible. 
 
9.6.1 Permitted concomitant therapy 
In general, the use of any concomitant medication/therapies deemed necessary for the care 
of the patient is permitted, except as specifically prohibited in Section 9.6.3. 
 
Antiemetics: Use of anti-emetics is allowed. Prophylactic anti-emetics should be started  
only once the patient experienced nausea or vomiting at the discretion of the investigator 
(refer to Table 10-2 for toxicity management guidelines). It is recommended that patients use 
drugs that do not cause QT prolongation. Please note that some anti-emetics have a known 
risk for Torsades de Pointes (e.g.,chlorpromazine, droperidol, haloperidol) and are prohibited 
(refer to Section 9.6.3 and Appendix F).  Some other anti-emetics (e.g., ondansetron) are to 
be used with caution (refer to Appendix G). 
 
Bisphosphonates: The use of bisphosphonates regardless of indication is allowed provided 
patients have been on stable doses for at least 2 weeks prior to study entry. Stable dose 
should be maintained during the treatment period. Patients requiring initiation of 
bisphosphonates during the course of the study should be discontinued due to progressive 
disease unless disease progression can be completely ruled out and this is clearly 
documented in the patients’ source documentation. 
 
Oral anti-diabetics: Patients who develop diabetes mellitus during the study should be 
treated according to the ADA (American Diabetes Association) guidance (refer to Section 
10.10.3).  Patients receiving oral antidiabetics which are predominantly metabolized by 
CYP2C9 and CYP2C8, including but not limited to, repaglinide, rosiglitazone, glipizide and 
tolbutamide, must be carefully monitored for hypoglycemia as BYL719 was found to be 
moderate reversible inhibitor of these enzymes (refer to Appendix D). 
 
9.6.2 Permitted concomitant therapy requiring caution and/or action 
 
Hematopoietic growth factors: Hematopoietic growth factors (e.g. erythropoietins, G- 
colony stimulating factor (CSF) and GM-CSF) are not to be administered prophylactically. 
Use of these drugs should be reserved to patients with severe neutropenia and anemia as 
per the labeling of these agents or as dictated by local practice (see also the guidelines 
established by the American Society of Clinical Oncology). 


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Anticoagulation: Anticoagulants other than warfarin/coumarin derivates or antiaggregation 
agents may be administered under the discretion of the investigator (refer to Section 9.6.3). 
However, caution is advised when BYL719 is co-administered with anti-platelet pro-drugs 
such as clopidogrel, ticlopidine and prasugrel, which require metabolic activation by 
CYP3A4, CYP2C9 and CYP2C19.  BYL719 has the potential to inhibit these enzymes and 
may therefore decrease the metabolic activation and clinical efficacy of these pro-drugs. 
Patients using anti-platelet pro-drugs should be carefully monitored. 
 
CYP450 substrates: In vitro studies demonstrate that BYL719 is a mechanism based 
inhibitor of CYP3A4.  BYL719 may increase exposure to drugs metabolized by CYP3A4 by 
more than 5-fold. BYL719 may also inhibit the metabolic clearance of co-medications 
metabolized by CYP2C8, CYP2C9, CYP2C19, if sufficiently high BYL719 concentrations are 
achieved in vivo. Investigators, at their discretion, may administer concomitant medications 
known to be metabolized by CYP3A4/5, CYP2C8, CYP2C9 and CYP2C19 (refer to Appendix 
D).  Patients receiving such medications must be carefully monitored for potential toxicity due 
to any individual concomitant medications. Particularly, caution is advised when BYL719 is 
co-administered with drugs that are sensitive substrates for CYP3A4, CYP2C8, CYP2C9 or 
CYP2C19 and which have a narrow therapeutic index ( Appendix D, footnote 2). 
 
Opioid analgesics: Caution is advised when BYL719 is co-administered with opioid 
analgesics. Inhibition of opioid metabolism by CYP3A4 can lead to opioid toxicity, including 
fatal respiratory depression, or an enhanced risk for QTc prolongation. Patients receiving 
BYL719 and opioid analgesics should be carefully monitored. Synthetic opioids with clinically 
relevant interactions with CYP3A4 inhibitors include, but are not limited to, propoxyphene, 
fentanyl, alfentanil and sufentanil. Use of alfentanil, a sensitive CYP3A4 substrate with 
narrow therapeutic window, should be fully avoided whenever possible. The use of 
methadone or levomethadyl is prohibited (refer to Appendix F). 
 
Drugs with a conditional or possible risk to induce Torsade de Pointes (TdP):  Please 
refer to Section 9.3.3 and Appendix F for a list of prohibited QT prolonging medication.  If a 
patient, enrolled in the study, requires the concomitant use of any medication with a possible 
or conditional risk for TdP (see Appendix G for a list of such medications), then investigators, 
at their discretion, may co-administer such medications. Patients receiving such medications 
must however be monitored. 
 
Gastric protection agents: BYL719 is characterized by a pH-dependent solubility.  
Medicinal products that alter the pH of the upper gastro-intestinal tract may alter the solubility 
of BYL719 and hence its bioavailability. These agents include, but are not limited to, proton- 
pump inhibitors (e.g., omeprazole), H2-antagonists (e.g., ranitidine) and antacids. BYL719 
should preferably be dosed in a staggered manner, i.e., at least 1 hour before or 10 hours 
after dosing with a gastric protection agent. Note that some proton pump inhibitors may 
possibly inhibit BCRP (refer to Appendix E).  The treatment with BCRP inhibitors should be 
kept as short as possible or, if possible, fully avoided. 
 
BCRP Inhibitors: BYL719 was identified as a substrate for the human BCRP. Co- 
administration of BYL719 with BCRP inhibitors may possibly increase systemic exposure 


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and/or alter tissue uptake of oral BYL719. The treatment with BCRP inhibitors should be kept 
as short as possible or, if possible, fully avoided. See Appendix E for a list of BCRP 
inhibitors. 
 
Palliative radiotherapy: Local radiotherapy for analgesic purposes or for lytic lesions at risk 
of fracture may be carried out if required. Whenever possible, these patients should have a 
tumor assessment of the lesion(s) before they actually receive the radiotherapy in order to 
rule out progression of disease. In case of disease progression, patients should discontinue 
treatment and be removed from the study. No dose modification of study treatment is needed 
during radiotherapy. 
 
Steroids:  Chronic administration of corticosteroids (> 5 days) can induce CYP3A4.  Due to 
this and concern for hyperglycemia, steroids should be used briefly and with caution. 
Patients who have a current need for chronic corticosteroid therapy at the time of screening 
(≥10mg of prednisone daily or an equivalent dose of other corticosteroid) are not eligible to 
enroll. 
 
9.6.3 Prohibited concomitant therapy 
 
Other investigational and antineoplastic therapies: Other investigational therapies must 
not be used while the patient is on the study. Systemic anticancer therapy (chemotherapy, 
biologic) other than the study treatments must not be given to patients while the patient is on 
the study medication. If such agents are required for a patient then the patient must be 
discontinued from the study. 
 
Drugs with a known risk for Torsades de Pointes (TdP): If a patient, enrolled in the study, 
requires the concomitant use of any medication included in Appendix F entitled “List of 
Prohibited QT prolonging drugs” (i.e., drugs that are generally accepted by the Qtdrugs.org 
Advisory Board of the Arizona CERT to have a known risk of causing TdP), BYL719 
administration must be interrupted as long as the patient requires therapy with the QT 
prolonging agent. Note that Appendix D also includes drugs that are substrates for CYP3A 
and CYP2C with a possible or conditional risk for TdP. If the patient requires long term 
therapy with such a QT prolonging agent, leading to study treatment interruption of > 21  
days, the patient must be permanently discontinued from BYL719. 
 
Herbal medications: Herbal preparations/medications are not allowed throughout the study. 
These herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng. Patients should stop using these herbal medications 7 days prior to first dose of 
study drug. 
 
Warfarin and coumarin derivates: Therapeutic doses of warfarin sodium (Coumadin®) or 
any other coumarin-derivative anticoagulants are not permitted. Warfarin has a narrow 
therapeutic range and BYL719 is a possible inhibitor of CYP2C8 and 2C9, the major 
metabolizing enzyme of warfarin.  Therapeutic anticoagulation may be accomplished using 
low-molecular weight heparin. 


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Opioid analgesics: See Section 9.3.2 for opioid analgesics to be used with caution.  Use of 
alfentanil, a sensitive CYP3A4 substrate with narrow therapeutic window, should be fully 
avoided whenever possible. The use of methadone or levomethadyl is prohibited. 


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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 Evaluation Summary 
 
Table 10-1 Evaluation Summary Chart 
 
 
Pre- 
a 
Rx 
 
Cycle 1 
Day 1 
 
Cycle 1
Day 8 
(+/- 3 
days)
Cycle 1
Day 15 
(+/- 3 
days) 
Cycle 2
Day 1 
(+/- 3 
days) 
Cycle 2 
Day 15 
(+/- 3 
days) 
Cycle 3+ 
Day 1 
(+/- 7 
days)h 
 
End of Rx 
(within 28 
days)b 
Letrozole or 
Exemestane
Continuous daily dosing, Days 1-28 
BYL719, Arm A/B 
Continuous daily dosing, Days 1-28 
BYL719, Arm C 
Days 1-7, 15-21 of 28 day cycle 
BYL719, Arm D 
Days 1-5, 8-12, 15-19, 22-26 of 28 day cycle 
Tumor biops   
y 
X 
 
 
X 
 
 
 
X
History and physical 
X 
X 
X
X
X
X
X 
X
Toxicity assessment  
X 
X
X
X
X
X 
X
Assessment of 
Concomitant 
Medications 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Complete blood 
count (CBC) 
X 
X 
 
X 
X 
X 
X 
X 
Comprehensive 
metabolic panel 
(CMP) 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Magnesium, 
amylase, lipase 
X 
X 
 
X 
X 
X 
X 
X 
PT/INR and PTT 
X 
 
 
Fasting glucose 
X 
X 
 
X 
X 
X 
X 
X 
Tumor markers 
(CA15-3 and CEA) 
 
X 
 
 
X 
 
X 
X 
Blood draw for 
companion normal 
DN  c 
A 
 
X 
 
 
 
 
 
 
 
Blood draw for 
plasma collection 
(cfDNA) 
X 
X 
 
X 
X 
 
X 
 
X 
X 
j 
EKG 
X 
X 
 
X 
X 
X 
d 
X 
X 
EOD evaluatio   
n 
X 
 
 
 
 
 
d 
X 
e
X 
Research PK 
 
X 
 
X 
X 
X 
f 
X 
 
Estradio g 
l 
X 
 
 
 
 
 
d 
X 
 
 
a 
See Section 8 for required time frames for pre-treatment studies 
b 
Pre-treatment and Day 15 on-treatment biopsies will be required, unless felt to put the patient at 
unacceptable risk (note: patients with bone-only metastases will have a pre-treatment biopsy 
only).  See Section 10.12 for processing.  The tumor biopsy is not required to be scheduled on 
the same day as the MD visit.  While every attempt will be made to schedule the on-treatment 
tumor biopsy on Day 15, the exact timing of the research biopsy will be at the discretion of the 
investigators. All patients may be asked to undergo an optional tumor biopsy at progression, with 
the exact timing to be at the discretion of the investigator and patie nt (not necessarily within 28 


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10.2 Cycle 1 Day 1 
 
10.2.1 MD visit, with history and physical examination, including weight, blood pressure, 
pulse, ECOG performance status, and updated medication list.  Concurrent 
medications will be reviewed for potential drug-drug interactions with study 
medication (see Section 9.6). 
10.2.2 Toxicity will be assessed and the type, severity, timing, and relationship of each 
adverse event to therapy will be determined as per the NCI Common Toxicity Criteria, 
version 4.0. 
 
10.2.3 Fasting bloodwork prior to taking BYL719 in clinic on this day (if screening bloodwork 
was not performed within 72 hours of dosing).  A light breakfast may be consumed 
after fasting plasma glucose draw.  BYL719 may be administered 1 hour after 
breakfast.  Patients should fast for 1 hour after the administration of BYL719. 
Bloodwork results do not need to be resulted prior to dosing on this day; however, all 
bloodwork must be reviewed and the patient contacted within 24 hours (excluding 
weekends and holidays) if an abnormality is detected which would affect dosing.  If a 
patient is being screened and starting treatment on the same day, then results of 
CBC, CMP and fasting glucose must be reviewed prior to enrollment and initiation of 
treatment. 
 
o CBC, including WBC (differential not required), Hgb and platelet count 
o CMP, including BUN, creatinine and liver function tests 
o Magnesium, amylase and lipase 
o Fasting glucose 
o PT/INR and PTT 
o Tumor markers (CA 15-3 and CEA) 
o Plasma collection from 10 ml blood for cfDNA extraction  analysis 
10.2.4 EKG will be performed (if screening EKG was not performed within 72 hours of 
dosing).  EKG must be reviewed prior to dosing. 
days of last dose of BYL719), although a 2 week window is allowed. 
c 
Companion normal DNA for targeted gene sequencing analysis (1ml whole blood for correlative 
science, Section 10.12) 
d 
Day 1 +/- 7 days of Cycle 3, Cycle 5, and then every 3rd cycle (Cycle 8, Cycle 11, etc) 
e 
If EOD not already performed in the last 28 days 
f 
Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 8 and Cycle 10 for letrozole arm (Arm A) and Cycle 3 only 
for exemestane arm (Arm B) 
g 
Estradiol to be tested only on women who are recei vi ng pharmacologic ovarian suppression 
h 
Patients on study under Amendment 13 will have relevant blood and cfDNA collection every other 
cycle (+/- 7 days). 
i 
Patients on study under Amendment 13 will have EOD evaluations will be preformed every 16 
weeks +/-  4 weeks from their last scan. 
j 
Patients on study under Amendment 13 will have EKG evaluations every 4 cycles.  EKG eval uations 
may be preformed more frequently at the discretion of the MD. 


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10.2.5 PK bloodwork for research purposes (see schedule in Section 10.11). 
 
10.2.6 Patients will be prescribed or advised to take an over the counter antihistamine daily, 
unless contraindicated for that specific patient. Initiation of anti-histamine therapy is 
recommended but not required at the start of BYL719 therapy. 
10.3 Cycle 1 Day 8 (+/- 3 days) 
 
10.3.1 MD visit, with history and physical examination, including weight, blood pressure, 
pulse, ECOG performance status, and updated medication list.  Concurrent 
medications will be reviewed for potential drug-drug interactions with study 
medication (see Section 9.6). 
 
10.3.2 Research blood draw for plasma collection from 10ml blood for cfDNA extrac tion and 
analysis 
 
10.4 Cycle 1 Day 15 (+/- 3 days) 
 
10.4.1 MD visit, with history and physical examination, including weight, blood pressure, 
pulse, ECOG performance status, and patient drug diary review. 
10.4.2 Toxicity will be assessed and the type, severity, timing, and relationship of each 
adverse event to therapy will be determined as per the NCI Common Toxicity Criteria, 
version 4.0. 
 
10.4.3 Fasting bloodwork prior to taking BYL719 in clinic on this day.  A light breakfast may 
be consumed after fasting plasma glucose draw.  BYL719 may be administered 1 
hour after breakfast.  Patients should fast for 1 hour after the administration of 
BYL719.  Bloodwork results do not need to be resulted prior to dosing on this day 
(because BYL719 dosing is continuous); however, all bloodwork must be reviewed 
and the patient contacted within 24 hours (excluding weekends and holidays) if an 
abnormality is detected which would affect dosing. 
 
o CBC, including WBC (differential not required), Hgb and platelet count 
o CMP, including BUN, creatinine and liver function tests 
o Magnesium, amylase and lipase 
o Fasting glucose 
o Plasma collection from 10 ml blood for cfDNA extraction and analysis 
10.4.4 EKG will be performed and reviewed prior to dosing. 
 
10.4.5 PK bloodwork for research purposes (see schedule in Section 10.11). 
 
10.4.6 Day 15 on-treatment tumor biopsy will be required, unless felt to put the patient at 
unacceptable risk (note: patients with bone-only metastases will have a pre-treatment 
biopsy only).  This biopsy is for research purposes.  After obtaining separate informed 
consent, a core biopsy will be obtained and processed for proteomic analysis (Section 
10.12).  The tumor biopsy should be taken 2-8 hours after the BYL719 dose             
on that day.  The tumor biopsy is not required to be scheduled on the same day as 


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the MD visit.  While every attempt will be made to schedule the tumor biopsy on Day 
15, the exact timing of the research biopsy will be at the discretion of the 
investigators. 
 
 
 
10.5 Cycle 2 Day 1 (+/- 3 days) 
 
10.5.1 MD visit, with history and physical examination, including weight, blood pressure, 
pulse, ECOG performance status, patient drug diary review, and updated medication 
list.  Concurrent medications will be reviewed for potential drug-drug interactions with 
study medication (see Section 9.6). 
 
10.5.2 Toxicity will be assessed and the type, severity, timing, and relationship of each 
adverse event to therapy will be determined as per the NCI Common Toxicity Criteria, 
version 4.0. 
 
10.5.3 Fasting bloodwork prior to taking BYL719 in clinic on this day.  A light breakfast may 
be consumed after fasting plasma glucose draw.  BYL719 may be administered 1 
hour after breakfast.  Patients should fast for 1 hour after the administration of 
BYL719.  Bloodwork results do not need to be resulted prior to dosing on this day 
(because BYL719 dosing is continuous); however, all bloodwork must be reviewed 
and the patient contacted within 24 hours (excluding weekends and holidays) if an 
abnormality is detected which would affect dosing. 
 
o CBC, including WBC (differential not required), Hgb and platelet count 
o CMP, including BUN, creatinine and liver function tests 
o Magnesium, amylase and lipase 
o Fasting glucose 
o Tumor markers (CA 15-3 and CEA) 
o Plasma collection from 10 ml blood for cfDNA extraction and analysis 
 
10.5.4 EKG will be performed and reviewed prior to dosing. 
 
10.5.5 PK bloodwork for research purposes (see schedule in Section 10.11). 
 
10.6 Cycle 2 Day 15 (+/- 3 days) 
 
10.6.1 MD visit, with history and physical examination, including weight, blood pressure, 
pulse, ECOG performance status, and patient drug diary review. 
 
10.6.2 Toxicity will be assessed and the type, severity, timing, and relationship of each 
adverse event to therapy will be determined as per the NCI Common Toxicity Criteria, 
version 4.0. 
10.6.3 Fasting bloodwork prior to taking BYL719 in clinic on this day.  A light breakfast may 
be consumed after fasting plasma glucose draw.  BYL719 may be administered 1 
hour after breakfast.  Patients should fast for 1 hour after the administration of 
BYL719.  Bloodwork results do not need to be resulted prior to dosing on this day 


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(because BYL719 dosing is continuous); however, all bloodwork must be reviewed 
and the patient contacted within 24 hours (excluding weekends and holidays) if an 
abnormality is detected which would affect dosing. 
 
o CBC, including WBC (differential not required), Hgb and platelet count 
o CMP, including BUN, creatinine and liver function tests 
o Magnesium, amylase and lipase 
o Fasting glucose 
10.6.4 EKG will be performed and reviewed prior to dosing. 
 
10.6.5 PK bloodwork for research purposes (see schedule in Section 10.11). 
 
10.7 Subsequent Cycles (Cycle 3+) Day 1 (+/- 7 days) 
 
10.7.1 One MD clinic visit per cycle, with history and physical examination, including weight, 
blood pressure, pulse, ECOG performance status, patient drug diary review, and 
updated medication list.  Concurrent medications will be reviewed for potential drug- 
drug interactions with study medication (see Section 9.6). 
 
10.7.2 Toxicity will be assessed and the type, severity, timing, and relationship of each 
adverse event to therapy will be determined as per the NCI Common Toxicity Criteria, 
version 4.0. 
 
10.7.3 Fasting bloodwork prior to taking BYL719 in clinic on this day.  A light breakfast may 
be consumed after fasting plasma glucose draw.  BYL719 may be administered 1 
hour after breakfast.  Patients should fast for 1 hour after the administration of 
BYL719.  Bloodwork results do not need to be resulted prior to dosing on this day 
(because BYL719 dosing is continuous); however, all bloodwork must be reviewed 
and the patient contacted within 24 hours (excluding weekends and holidays) if an 
abnormality is detected which would affect dosing. 
 
o CBC, including WBC (differential not required), Hgb and platelet count 
o CMP, including BUN, creatinine and liver function tests 
o Magnesium, amylase and lipase 
o Fasting glucose 
o Tumor markers (CA 15-3 and CEA) 
o Plasma collection from 10 ml blood for cfDNA extraction and analysis 
 
10.7.4 EKG will be performed and reviewed on Day 1 +/- 7 days of Cycle 3, Cycle 5, and 
then every 3rd cycle (Cycle 8, Cycle 11, etc). 
 
10.7.5 PK bloodwork for research purposes (for specified cycles only, see schedule in 
Section 10.11). 
10.7.6 Estradiol will be performed Day 1 +/- 7 days of Cycle 3, Cycle 5, and then every 3rd 
cycle (Cycle 8, Cycle 11, etc) thereafter, for patients who are receiving pharmacologic 
ovarian suppression 
10.7.7 Patients who are on study under Amendment 13 will present for one MD visit every 
other cycle. Patient’s will complete all assessments per Section 10.1. 


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10.8 End of Treatment (within 28 days of last dose of BYL719) 
 
10.8.1 MD visit, with history and physical examination, including weight, blood pressure, 
pulse, ECOG performance status, and final patient drug diary review. 
 
10.8.2 Toxicity will be assessed and the type, severity, timing, and relationship of each 
adverse event to therapy will be determined as per the NCI Common Toxicity Criteria, 
version 4.0. 
10.8.3 Fasting bloodwork (if not already performed in the last 28 days). 
 
o CBC, including WBC (differential not required), Hgb and platelet count 
o CMP, including BUN, creatinine and liver function tests 
o Magnesium, amylase and lipase 
o Fasting glucose 
o Tumor markers (CA 15-3 and CEA) 
o Plasma collection from 10 ml blood for cfDNA extraction and analysis 
 
10.8.4 EKG will be performed (if not already performed in the last 28 days). 
 
10.8.5 All patients may be asked to undergo an optional tumor biopsy at progression, with 
the exact timing to be at the discretion of the investigator and patient (not necessarily 
within 28 days of last dose of BYL719), although a 2 week window is allowed. 
 
10.9 Evidence of Disease (EOD) Evaluation 
 
Patients on all study arms will have an evidence of disease (EOD) evaluation at baseline, 
consisting of CT of chest/abdomen +/- pelvis (with oral and IV contrast unless 
contraindicated) and a bone scan.  Patients will then have EOD evaluation with CT of 
chest/abdomen +/- pelvis every two cycles (8 weeks) for the first four cycles (16 weeks) of 
study treatment (Day 1 +/- 7 days of Cycle 3 and Cycle 5), and then every 3
rd cycle (12 
weeks) thereafter (Day 1 +/- 7 days of Cycle 8, Cycle 11, etc).  EOD evaluation will occur 
every 16 weeks +/- 4 weeks from the last evaluation for patients who  are on study under 
Amendment 13. EOD evaluation will also be performed at the end of study treatment, if not 
already performed in the last 28 days.  A bone scan may also be performed per investigator 
discretion.  In patients without bone-only disease, bone scans may be repeated in the event 
of clinical suspicion of progression of existing bone lesions, the development of new bone 
lesions, and in the assessment of a complete response, if any disease was evident at 
screening.  For patients with locally-advanced unresectable breast cancer, radiographic 
assessments using MRI scans are acceptable to evaluate response, and a CT scan of 
chest/abdomen is not required. 
 
It remains to be determined whether FDG-PET response accurately predicts tumor response 
to PI3K/AKT pathway inhibitors.  Glucose metabolism is regulated through PI3K/AKT 
signaling. Inhibition of the PI3K/AKT pathway therefore inhibits glucose uptake on FDG-PET. 
Although FDG-PET may be a pharmacodynamic marker of pathway inhibition, clinical 
correlation with tumor response has not been confirmed.  Therefore, CT imaging (+/- bone 
scan) is the preferred approach at this time. 


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RECIST criteria version 1.1 will be used to evaluate therapeutic response.  With the 
development of progressive disease, patients will be removed from the study.  For equivocal 
findings of progression (e.g., very small and uncertain new lesions, cystic changes or 
necrosis in existing lesions, or other such equivocal findings), treatment may continue until 
the next scheduled assessment at the discretion of the treating physician.  If, at the next 
scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
 
 
10.10 Toxicity Management 
 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation time points 
during the study. All AEs and SAEs whether volunteered by the patient, discovered by the 
study personnel during questioning, or detected through physical examination, laboratory 
test, or other means will be recorded in the patient’s medical history and on the appropriate 
AE or SAE CRDB page. Each recorded AE or SAE will be described by its duration (i.e., start 
and end dates), severity, and suspected relationship to the protocol treatment. Since this 
trial’s primary outcome is to measure safety and feasibility of the intervention by assessing 
toxicity to determine the MTD by measuring experiences of DLT, suspected relationships or 
attributions of adverse events will only be collected if assessed as grade ≥2. Additionally all 
laboratory toxicities will be collected for assessment if the results are considered grades ≥2. 
 
Toxicity will be assessed using the NCI Common Toxicity Criteria, version 4.0, unless 
otherwise specified.  The type, severity, timing and relationship of each adverse event will be 
documented.  Criteria for defining dose-limiting toxicities (DLTs) are defined in Section 9.3. 
Criteria for defining serious adverse events (SAEs) are defined in Section 17.2. 
 
10.10.1 Toxicity Follow-up 
 
Whenever a patient experiences toxicity that fulfills the criteria for a dose limiting toxicity 
(DLT) or serious adverse event (SAE), treatment with the study drug will be interrupted and 
the toxicity will be followed up.  Patients whose treatment is interrupted or permanently 
discontinued due to a DLT, other adverse event, or clinically significant laboratory value,  
must be followed up at least once a week (or more frequently if clinically indicated) for 4 
weeks, and subsequently at approximately 4 week intervals, until resolution or stabilization of 
the event, whichever comes first.  Clinic visits may include physical examination, assessment 
of residual toxicity, and blood tests (including CBC and CMP).  Appropriate clinical experts 
(such as cardiologists or dermatologists, etc) should be consulted as deemed necessary. 
10.10.2 Dose Reductions and Dose Delays 
 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to allow the patient to continue the study treatment.  All dose 
modifications should be based on the worst preceding toxicity (NCI Common Toxicity 
Criteria, version 4.0). 
 
Prior to completion of Cycle 1, treatment (either BYL719 or AI or both) can be held for up to 7 
days for any reason, and then resumed at the same dose.  After completion of Cycle 1, 


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treatment (either BYL719 or AI or both) can be held for up to 3 weeks for any reason, and 
then resumed at the same dose.  The investigator may remove any patient from study for 
any toxicity if he/she believes that it is in the best interest of the patient to discontinue study 
treatment. 
 
Intrapatient dose reductions of BYL719 will not be allowed during Cycle 1 (within 28 days of 
starting study treatment), unless a DLT has occurred and been counted.  This is in order to 
accurately determine the safe and tolerable dose of BYL719 when used in combination with 
letrozole or exemestane. 
 
BYL719 dose modification guidelines for toxicities considered at least possibly related to the 
study treatment are outlined in Table 10-2 below.  If a patient experiences unacceptable 
toxicity that fails to resolve after a maximum BYL719 dose delay of 21 consecutive days,  
then the patient should be discontinued from the study treatment.  In exceptional situations, if 
the patient is clearly benefiting from the study treatment (i.e., stable disease, partial 
response, complete response), and in the opinion of the investigator no safety concerns are 
present, the patient may remain on the study treatment.  Patients who discontinue from the 
study for a study-related adverse event or an abnormal laboratory value must be followed as 
described in Section 10.10.1. 
 
For each patient, a maximum of two dose reductions (minimum dose of BYL719 for this  
study is 200mg daily on Arm A and Arm B, and 150mg intermittently on Arm C and Arm D) 
will be allowed after which the patient will be discontinued from the study treatment. Dose 
reduction for BYL719 means treatment at the next lower dose level of BYL719 (e.g., 300mg 
daily if the prior dose was 350mg daily, and 250mg daily if the prior dose was 300mg daily).  
In addition, a patient must discontinue treatment if, after treatment is resumed at a lower 
dose, the same toxicity reoccurs with the same or worse severity. If, after interruption of 
treatment and resolution, treatment is resumed at the same dose following the criteria in 
Table 10-2, and the same toxicity reoccurs with the same severity, next treatment re-initiation 
must resume at the next lower dose level irrespective of duration. 
 
There will be no intrapatient dose escalation for BYL719.  For each patient, once a dose level 
reduction of BYL719 has occurred, the dose level may not be re-escalated during  
subsequent treatment cycles with the study drug. 
 
There will be no dose escalation or dose reduction for letrozole or exemestane. 
For specific guidelines related to hyperglycemia, see Section 10.10.3. 
 
Table 10-2 
Criteria for interruption and re-initiation BYL719 treatment 
 
Recommended Dose Modifications for BYL719 
  Worst Toxicity CTCAE v4.03 Grade (unless 
otherwise specified) 
Recommended Dose Modifications any time during a cycle of 
therapy 
BLOOD AND LYMPHATIC SYSTEM DISORDER 
  Anemia 
Grade 1 (Hgb < LLN-10.0 g/dL) 
 
 
Grade 2 (Hgb < 10.0 g/dL - 8.0 g/dL) 
 
Maintain dose level of BYL719. 
 
 
Maintain dose level of BYL719. 


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  Recommended Dose Modifications for BYL719 
  Worst Toxicity CTCAE v4.03 Grade (unless 
otherwise specified) 
Recommended Dose Modifications any time during a cycle of 
therapy 
  
Grade 3 (Hgb < 8.0 g/dL); transfusion indicated 
 
 
 
Grade 4 (Life threatening consequences; urgent 
intervention indicated) 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1 or baseline 
- If resolved in ≤ 14 days, then maintain dose level of BYL719. 
- If resolved in > 14 days, then ↓ 1 dose level a of BYL719. 
 
Discontinue study treatment. 
  ANC decreased (Neutropenia) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
 
 
Grade 4 (ANC < 0.5 x 109/L) 
 
Maintain dose level of BYL719. 
Maintain dose level of BYL719. 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then maintain dose level of BYL719. 
- If resolved in > 7 days, then ↓ 1 dose level a of BYL719. 
 
Omit dose of BYL719 until resolved to CTCAE ≤ Grade 1, then ↓ 1 
dose level a of BYL719. 
  Febrile neutropenia 
Grade 3 (ANC < 1.0 x 109/L, single temperature 
of > 38.3°C or a sustained temperature of ≥ 
38.0°C) 
 
 
Grade 4 
 
Omit dose of BYL719, then 
- If resolved by ≤ 7 days, then ↓ 1 dose level a of BYL719. 
- If not resolved within 7 days discontinue patient from study 
treatment. 
 
Discontinue study treatment.
  Platelet count decreased (Thrombocytopenia)
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Grade 3 (PLT < 50 - 25 x 109/L ) 
 
Grade 4 (PLT < 25 x 109/L ) 
 
Maintain dose level of BYL719. 
Maintain dose level of BYL719. 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then maintain dose level of BYL719. 
- If resolved in > 7 days, then ↓ 1 dose level a of BYL719. 
 
Discontinue study treatment. 
  Bleeding 
Any bleeding (related to BYL719) resulting in 
platelet transfusion 
 
Omit dose of BYL719 until no further bleeding has been observed. 
Continuation of study treatment may be considered. 
CARDIAC DISORDERS 
 
QTcF > 500 ms (≥ 
Grade 3) 
or > 60 ms change from baseline 
on at least two separate ECGs 
First Occurrence: 
-Interrupt BYL719 
-Perform a repeat ECG within one hour of the fi rst QTcF of 
> 500 ms or >60ms from baseline 
- If QTcF remains > 500 ms or >60ms from baseli ne, repeat 
ECG as clinically indicated until the QTcF returns to < 480 
ms. 
-Seek cardiol ogist input; address electrolytes, calcium and 
magnesium abnormalities; concomitant medication must 
be reviewed. 
Once QTcF prolongation has resolved, BYL719 may be 
restarted at a one lower dose level 
 
Second  Occurrence: 
Permanently discontinue BYL719 treatment 
  Cardiac disorders - others 
Grade 1 and 2 
 
Maintain dose level of BYL719. 


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  Recommended Dose Modifications for BYL719 
  Worst Toxicity CTCAE v4.03 Grade (unless 
otherwise specified) 
Recommended Dose Modifications any time during a cycle of 
therapy 
 
Grade ≥ 3 
Discontinue study treatment.
VASCULAR DISORDERS 
  Hypertension 
Persistent hypertension CTCAE Grade 3 
requiring more than one drug or more intensive 
therapy than previously 
 
Persistent hypertension CTCAE Grade 4 
requiring more than one drug or more intensive 
therapy than previously 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, then ↓ 1 
dose level a of BYL719. 
 
Discontinue study treatment. 
INVESTIGATIONS – RENAL 
  Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Grade 2 (> 1.5 - 3.0 x ULN) 
 
 
 
Grade ≥ 3 (> 3.0 x ULN) 
 
Maintain dose level of BYL719. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1 or 
baseline, then 
- If resolved in ≤ 7 days, then maintain dose level of BYL719. 
- If resolved in > 7 days, then ↓ 1 dose level a of BYL719. 
 
Discontinue study treatment. 
INVESTIGATIONS – HEPATIC 
  Blood Bilirubin b (for patients with Gilbert 
Syndrome these dose modifications apply to 
changes in direct bilirubin only) 
Grade 1 (> ULN – 1.5 x ULN) 
Grade 2 (>1.5 – 3.0 x ULN) 
 
Grade ≥ 3 (> 3.0 x ULN) 
 
 
 
Maintain dose level of BYL719. 
 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then maintain dose level of BYL719. 
- If resolved in > 7 days, then ↓ 1 dose level a of BYL719. 
 
Discontinue study treatment. 
 
Note: If CTCAE Grade 3 or 4 hyper-bilirubinemia is due to the 
indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g. 
review of peripheral blood smear and haptoglobin determination), 
then ↓ 1 dose level a of BYL719 and continue treatment at the 
discretion of the Investigator. 
  AST or ALT 
Grade 1 (> ULN - 3 x ULN) 
Grade 2 (> 3 - 5.0 x ULN) 
Grade 3 (> 5.0 - 20.0 x ULN) 
 
 
 
 
 
 
 
 
Grade 4 (> 20.0 x ULN) 
 
Maintain dose level of BYL719. 
Maintain dose level of BYL719. 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1 (or CTCAE 
Grade ≤ 2 in case of liver metastasis), then 
- If resolved in ≤ 7 days, then maintain dose level of BYL719. 
- If resolved in > 7 days, then ↓ 1 dose level a of BYL719. 
 
Note: If BYL719 is held for hepatic toxicity, then letrozole or 
exemestane should be also held until hepatic toxicity resolves to 
CTCAE ≤ Grade 1 (or CTCAE Grade ≤ 2 in case of liver metastasis). 
 
Discontinue study treatment.
METABOLISM AND NUTRITION DISORDERS
  Fasting Plasma Glucose 
Please refer to the guidelines for study drug-induced hyperglycemia 
provided in Section 10.10.3 


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  Recommended Dose Modifications for BYL719 
  Worst Toxicity CTCAE v4.03 Grade (unless 
otherwise specified) 
Recommended Dose Modifications any time during a cycle of 
therapy 
  Amylase and/or lipase elevation 
Grade 2 (> 1.5 - 2.0 x ULN) 
 
Grade 3 (> 2.0 - 5.0 x ULN) 
 
 
 
Grade 4 (> 5.0 x ULN) 
 
Maintain dose level of BYL719. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 2, then 
- If resolved in ≤ 7 days, maintain dose level of BYL719. 
- If resolved in > 7 days, then ↓ 1 dose level a of BYL719. 
 
Discontinue study treatment. 
 
Note: A CT scan or other imaging study to assess the pancreas, 
liver, and gallbladder must be performed within 1 week of the first 
occurrence of any CTCAE ≥ Grade 3 of amylase and/or lipase. If 
asymptomatic CTCAE Grade 2 elevations of lipase and/or amylase 
occur again at the reduced dose, patients will be discontinued 
permanently from study treatment. 
NERVOUS SYSTEM DISORDERS 
  Neurotoxicity 
Grade 1 
 
Grade 2 
 
 
Grade ≥ 3 or second occurrence of Grade 2 
 
Maintain dose level of BYL719. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, then 
resume treatment at the same dose level. 
 
Discontinue study treatment. 
GI DISORDERS 
  Pancreatitis 
Grade ≥ 3 
 
Discontinue study treatment. 
  Diarrhea 
Grade 1 
 
Grade 2 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
Maintain dose level of BYL719, but initiate anti-diarrhea treatment. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, initiate 
anti-diarrhea treatment, then maintain dose level of BYL719. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, initiate 
anti-diarrhea treatment, then 
- If resolved in ≤ 48 hours, maintain dose level of BYL719. 
- If resolved in > 48 hours, then ↓ 1 dose level a of BYL719. 
 
For 2nd occurrence of diarrhea CTCAE Grade 3 for > 48 hours 
despite the use of anti-diarrhea treatment, discontinue study 
treatment. 
 
Discontinue study treatment. 
 
Note: Antidiarrheal medication is recommended at the first sign of 
abdominal cramping, loose stools or overt diarrhea. 
  Nausea/Vomiting 
Grade 1 
 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
 
Grade 4 
 
Maintain dose level of BYL719, but initiate anti-emetic treatment 
(see Section 9.6.1). 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, initiate 
anti-emetic treatment (see Section 9.6.1), then maintain dose level 
of BYL719. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, initiate 
anti-emetic treatment (see Section 9.6.1), then 
- If resolved in ≤ 48 hours, maintain dose level of BYL719. 
- If resolved in > 48 hours, then ↓ 1 dose level a of BYL719. 
 
Discontinue study treatment. 
SKIN and SUBCUTANEOUS DISORDERS 


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  Recommended Dose Modifications for BYL719 
  Worst Toxicity CTCAE v4.03 Grade (unless 
otherwise specified) 
Recommended Dose Modifications any time during a cycle of 
therapy 
  Rash/ photosensitivity 
Please refer to the guidelines for study drug-induced hyperglycemia
provided in Section 10.10.4 


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  Recommended Dose Modifications for BYL719 
  Worst Toxicity CTCAE v4.03 Grade (unless 
otherwise specified) 
Recommended Dose Modifications any time during a cycle of 
therapy 
GENERAL DISORDERS 
  Fatigue 
Grade 1 or 2 
 
Grade 3 
 
Maintain dose level of BYL719. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain dose level of BYL719. 
- If resolved in 7 days, discontinue patient from study treatment.
OTHER ADVERSE EVENTS 
 
Grade 1 or 2 
 
 
Grade 3 
 
 
Grade 4 
Maintain dose level of BYL719. For intolerable grade 2 toxicity, may
omit dose of BYL719 until resolved. 
 
Omit dose of BYL719 until resolved to CTCAE Grade ≤ 1, then ↓ 
dose level of BYL719. 
 
Discontinue study treatment. 
 
Note: These are general guidelines. The investigator may omit 
dose of BYL719, ↓ dose level of BYL719 or remove any patient from 
study for any toxicity, if he/she believes that it is in the best interest 
of the patient. 
 
All dose modifications should be based on the worst preceding toxicity. Once a dose has been reduced it will not 
be increased at a later time even if there is no toxicity. Patients who require more than two dose reductions of 
BYL719 will be discontinued from study drug treatment. 
 
If a patient requires a dose delay of > 21 consecutive days of BYL719 then the patient must be discontinued from 
the study treatment. Patients who discontinue from the study for a study-related adverse event or an abnormal 
laboratory value must be followed at least once a week for 4 weeks and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first, except specifically mentioned. 
 
For patients on either Arm C, receiving BYL719 on days 1 -7 and 15-21 of a 28 day cycle, or arm D, receiving 
BYL719 on days 1-5, 8-12, 15-19, 22-26, omitted days will be counted from the date of decision to omit therapy. 
For example, for a patient on Arm C whose BYL719 is omitted at cycle 2 day 20, but whose toxicity resol ves at 
cycle 2 day 27, therapy will be resumed at Cycle 3 day 1. That is, the study treatment calendar will continue 
unchanged irregardless of treatment omissions. For a patient on Arm D whose BYL719 is omitted beginning cycle 
2 day 15, but whose toxicity resolves at cycle 2 day 20, the patient will still not receive treatment on days 20    
and 21 as per the unchanged study treatment calendar. Any issues arising in the setting of therapy held for 
toxicity will be discussed between the Principal Investigator and Novartis. 
 
a Dose reduction for BYL719 means treatment at the next lower dose level of BYL719 (e.g., 250mg daily if the prior dose 
was 300mg daily, and 200mg daily if the prior dose was 250mg daily). 
b Refers to total bilirubin 
c Refer to the guidelines for study drug-induced hyperglycemia provided in Section 10.10.3. 
10.10.3 Hyperglycemia Management 
 
PI3K is a key component of the insulin signaling pathway.  Therefore, hyperglycemia may be 
a marker of BYL719 activity on its intended target. 
 
In the BYL719 single agent first-in-human study, hyperglycemia occurred in 24/50 patients 
(48%), in a dose-related fashion. At a dose of 270 mg daily, one patient experienced 
hyperglycemia CTCAE Grade 1, but no Grade 3/4 hyperglycemia was reported. At the MTD 
of 400mg daily, 10/16 (62%) of patients experienced hyperglycemia, among them 4 (25%) 
with Grade 3/4 hyperglycemia. In the majority of patients, hyperglycemia could be managed 
by administration of oral anti-diabetic drugs such as metformin or glimepiride. Occasionally 
treatment with insulin was required. 
 
No hyperglycemia or related metabolic abnormalities have been noted in a large phase III 
studies of letrozole and exemestane. 


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Patients with controlled, non-insulin-dependent diabetes may be enrolled if fasting glucose 
<140mg/dL, even if currently requiring the use of anti-hyperglycemic agents (other than 
insulin).  We are including these patients with well-controlled diabetes because we anticipate 
that they will be familiar with glucose management, and thus able to manage hyperglycemia 
associated with BYL719 potentially better than those patients without a prior diagnosis of 
diabetes. 
 
Fasting glucose levels will be obtained at selected study visits during each cycle as shown in 
Table 10-1.  For the purposes of dose delay decisions, glucose measurements should be in a 
fasted state, defined as a level obtained at least 8 hours after the most recent caloric    
intake. 
 
Any patient experiencing hyperglycemia will be managed per the guidelines in the table below, 
and per standard medical practice for sequelae of hyperglycemia such as dehydration and 
acidosis. 
 
Grade 4 hyperglycemia must be reported to the MSKCC IRB and Novartis.  See Section 17.2 
for reporting requirements. 
 
Table 10.3 Hyperglycemia Management 
 
 
The below are guidelines that may be modified at the discretion of the Principal 
Investigator. 
 
Management of steroid-induced hyperglycemia and resultant decisions regarding dose- 
reduction are also at the discretion of the Principal Investigator. 
 
For any hyperglycemia ≥ grade 1, if, upon recheck of the fasting plasma glucose, 
hyperglycemia is not present or is of a lower grade than the initial value, the patient 
should be managed as per guidelines for the more severe toxicity.  For example, if a 
patient has a fasting glucose in the grade 2 range, and on recheck is grade 1, the patient 
should be managed as if she has a grade 2 toxicity.  However, if the initial value would 
result in a DLT, and the repeat value is in a lower-grade range, determination of DLT is at 
the discretion of the Principal Investigator. 
 
Should a patient experience toxicity during the resolution of a prior, higher-grade toxicity, 
the patient should continue to be managed as per the guidelines for the higher-grade 
toxicity.  For example, if the patient experiences grade 3 hyperglycemia on day 1, and 
this improves to a value within grade 2 hyperglycemia on day 5, the patient should 
continue being management as for grade 3 hyperglycemia rather than switch to 
management for grade 2 hyperglycemia. 


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Severity 
Dose  adjustment and management recommendations 
Grade 1 (> ULN - 160 mg/dL) [> 
ULN - 8.9 mmol/L] 
confirmed within 48 hours 
Continue BYL719 dosing and maintain the current dose level 
As per investigator’s discretion, initiate or intensify medication with 
appropriat e anti-diabetic treatment such as oral anti -hyperglycemic 
therapy (e.g. metformin) 
Check fasting glucose as clinically indicated and at least weekly for 
8 weeks 
Asymptomatic grade 2 (>160 - 250 
mg/dL) [> 
8.9 - 13.9 mmol/L] 
Maintain dose level and re-check within 24 hours: if grade worsens 
or improves, follow specific recomm endations; if grading 
is 
confirmed: 
Continue BYL719 dosing. 
Initiate or intensify medication with appropriate anti- di abetic   
treatment such as oral anti-hyperglycemic therapy (e.g. metformin) as 
per investigator’s discretion; consider adding a second oral agent if  
no improvement aft er several days 
Monitor fasting glucose as clinically indicated and at least 
weekly until fasting glucose resol ves to ≤ Grade 1 
If fasting glucose does not resol ve to ≤ Grade 1 within 14 days 
after institution of appropriate anti-di abetic treatment, reduce 
BYL719 by 1 dose level 
Continue with anti-diabetic treatment and check fasting glucose at 
least weekly for 8 weeks, then continue checking at least every 2 
weeks 
Asymptomatic grade 3 (> 250 - 500 
mg/dL) [> 
13.9 - 27. 8 mmol/L] 
 
Or Grade 2 with signs or symptoms 
of hyperglycemia (e.g., mental status 
changes, excessive thirst, polyuria) 
Omit BYL719 and re-check within 24 hours: if grade worsens or 
improves, follow specific recommendations. If gradi ng is confirmed: 
Omit BYL719 dosing. 
Consider adm inistering intravenous hydration and intervention 
for electrolyte/ketoacidosis/hyperosmolar disturbances as 
clinically  appropriate 
Initiate or intensify medication with appropriate anti- di abetic 
treatment (consider addi ng insulin) as per investigator’s 
discretion. 
Monitor fasting glucose as clinically indicated and at least 
twice weekly until fasting glucose resol ves to ≤ Grade 1 
If fasting glucose resolves to Grade1 within 14 days, then re-start 
BYL719 and reduce 1 dose level 
If fasting glucose doesn’t resolve to Grade1 within 14 days, 
then discontinue patient from BYL719 
Continue with anti-diabetic treatment and check fasting glucose at 
least weekly for 8 weeks, then continue checking at least every 2 
weeks 


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Grade 4 (> 500 mg/dL) [≥ 27. 8 
mmol/L] 
 
Or Grade 3 with signs or symptoms of 
hyperglycemia (for ex., mental status 
changes, excessive thirst, polyuria) 
Omit BYL719, initiate or intensify medication with appropriate anti- 
diabetic treatment (consider adding insulin), re-check within 24 
hours.  If grade improves then follow specific grade 
recommendations. 
 
If fasting glucoses confirmed at Grade 4: 
Discontinue patient from BYL719 
A diabetologist consultation should always be considered. 
Based on current experience, hyperglycemia usually resolves within a few days after BYL719 omission; 
temporary omission of BYL719 may be considered as clinically indicated to improve control of hyperglycemia. 
Special attention should be paid to 
the risk of hypoglycemia in patients interrupting BYL719 treatment and receiving insulin or sulfonylurea. 
For all grades : instruct patient to follow dietary guidelines according to local and/or institutional st andards for 
management of diabetes mellitus (such as those provided by the American Diabetes Association) during the 
study 
 
10.10.4 Rash Management Guidelines 
 
 
BYL719 can be associated with maculopapular rash, as discussed in Section 3.7 above. 
The below are recommendations that have been developed to guide meticulous 
management of this toxicity and may be modified at the discretion of the Principal 
Investigator.  Discussion or formal consultation with dermatology is recommended with 
rash of any grade. 
 
 
Grade (CTCAE v4.0) 
Dose  adjustment and management recommendations 
Grade 1 
 
Maintain BYL719 dosing. 
 
Augment antihistamine dosing or consider alternate/additional agent(s) 
(e.g. hydroxyzine 25 mg bid, non-sedating regimen) for at least 28 days 
 
Consider topical corticosteroid preparation bid for affected areas for at 
least 28 days. 
Grade 2 
 
Maintain BYL719 dosing. 
 
Consider augmenting antihistamine dosing or consider 
alternate/additional agent(s)  (e.g. non-sedating regimen during the 
daytime and sedating at QHS such as hydroxyzine 25 mg AM and noon 
followed by diphenhydramine 25 -50 mg QHS) for at least 28 days. 
 
Consider topical corticosteroid preparation bid for affected areas for at 
least 28 days. 
 
Oral corticosteroid (recommend prednisone 10mg PO TID for 10 days). 
If rash resolves to Grade 0 -1 within 10 days, oral corticosteroid may be 
discontinued, tapered dosing not needed.  If oral prednisone 
administered continuously for >10 days, tapered dosing is indicated. 
Intravenous steroid administration can be substituted for oral 
administration. 
 
If rash is not grade ≤1 within 14 days of optimal medical management, 
consider increasing steroid duration, with taper) 


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Grade  3/intolerable 
Grade 2 
 
Hold BYL719 dosing until rash resolved to Grade 0 -1 and consider 
dermatology consult for skin biopsy and photographs. 
 
Initiate antihistamine dosing. Recommend non-sedating regimen during 
the daytime and sedating at QHS (e.g. hydroxyzine 25 mg AM and noon 
followed by diphenhydramine 25 -50 mg QHS) for at least 28 days. 
 
Topical corticosteroid preparation bid for affected areas for at least 28 
days. 
 
Oral corticosteroid (recommend prednisone 10mg PO TID for 10 days). 
If rash resolves to Grade 0 -1 within 10 days (and does not recur with 
redosing; see below for guideline on rechallenge), oral corticosteroid 
may be discontinued, tapered dosing not needed.  If oral prednisone 
administered continuously for >10 days, tapered dosing is indicated. 
Intravenous steroid administration can be substituted for oral 
administration. 
 
If rash is not grade ≤1 in 14 days, continue or readminister oral 
corticosteroid until resolved and BYL719 is restarted. 
 
A dose reduction of one dose level is recommended if this is a second 
occurrence.  Dose reduction is not necessary followin g the fi rst 
occurrence of Gr 3 or intolerable Gr 2 rash. 
 
Upon rechallenge with BYL719 (once rash Grade ≤1), continue oral 
corticosteroid for at least 48 hours.  If rash and/or pruritus do not recur in 
48 hours, discontinue corticosteroid dosing.   Antihistamine regimen 
should be continued. 
Grade 4 
 
Permanently discontinue BYL719 and consider a dermatology consult. 
 
Treatment of rash should follow guidelines for Grade 3/intolerable Grade 
2 rash above with the exception of rechallenge and with any additional 
measures needed.  (BYL719 should be permanently discontinued.) 
 
10.10.5 Pneumonitis Management Guidelines 
 
If the pneumonitis is confirmed to be study drug related (BYL719 + Exemestane or Letrozole), 
BYL719 must be discontinued as well as the combination drug if the relationship is suspected, 
regardless of the grade. 
 
As per the new guidance, the table can be summarized as hereafter: 


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Pneumonitis 
 
Required Investigations 
Management of 
Pneumonitis 
Study Treatment 
Modification 
Any Grade 
 
 
 
 
 
 
Obtain appropriate 
imaging (e.g. high 
resolution CT scan) 
 
Consider broncho‐ 
alveolar lavage (BAL) 
and biopsy if clinically 
appropriate 
 
Infectious causes of 
interstitial lung disease 
should be ruled out 
 
 
 
 
 
Follow institutional 
practice for management 
of pneumonitis (e.g. 
treatment with high  
dose  corticosteroids; 
concurrent antibiotic 
therapy if infectious 
causes are suspected). 
 
Consultation with a 
pulmonologist is highly 
recommended 
 
Immediately 
interrupt both 
BYL719 and 
Exemestane or 
Letrozole for any 
case of suspected 
pneumonitis. 
 
For all patients with 
confirmed  pneumonitis 
 
BYL719 should be 
permanently 
discontinued 
 
Exemestane or 
Letrozole should be 
permanently 
discontinued if 
suspected to be 
etiologically  related 
to the pneumonitis 
 
 
Additional follow‐up for selected toxicities 
Management of pneumonitis in patients receiving BYL719 
 
All patients will be routinely asked about and observed for the occurrence of adverse events 
including new or changed pulmonary symptoms (consistent with lung abnormalities). Patients 
who are suspected to have developed pneumonitis should suspend study treatment (BYL719 
and Exemestane or Letrozole) immediately and undergo appropriate imaging (high resolution 
CT scan); and broncho-alveolar lavage and biopsy should be considered if clinically 
appropriate. Infectious causes of interstitial lung disease should be ruled out. Investigators 
should follow institutional practice for management of pneumonitis which generally includes 
treatment with high dose corticosteroids; antibiotic therapy should be administered 
concurrently if infectious causes are suspected. Consultation with a pulmonologist is highly 
recommended for any pneumonitis case during the study treatment. BYL719 and any other 
drug (if suspected to be etiologically related to the AE of pneumonitis) should be permanently 
discontinued in all patients with confirmed pneumonitis. 
 
10.11 Pharmacokinetics 
 
Pharmacokinetic (PK) sampling will be more intensive for the letrozole arm.  Letrozole is 
considered to be a sensitive substrate for CYP3A4.  BYL719 is likely to decrease letrozole 
clearance via its potent irreversible inhibition of CYP3A4, with a potential considerable 
increase in both letrozole systemic drug exposure and its elimination half-life. The increase in 
the elimination half-life is expected to delay the attainment of steady-state, which may only  
be reached after several weeks.  Although letrozole is not known to have serious toxicities 


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(potential toxicities include hot flashes, arthralgias, fatigue, and bone density loss over time), 
pharmacokinetic sampling has been designed to carefully evaluate the potential drug-drug 
interaction with BYL719. 
 
In contrast, the risk for drug-drug interaction in the exemestane arm is considerably lower.  In 
a clinical pharmacokinetic study, the specific inhibition of CYP 3A4 by ketoconazole showed 
no significant effects on the pharmacokinetics of exemestane.  This data suggest that the 
fractional clearance of exemestane via CYP3A4 is not significant and therefore the impact of 
BYL719, a potent CYP3A4 inhibitor, on the oral drug clearance of exemestane can be 
considered low.  Also, in vitro evidence showed that exemestane is metabolized not only 
through CYP3A4 but that alternative metabolic pathways such as aldoketoreductases exist. 
Exemestane does not inhibit any of the major CYP isoenzymes, indicating a low risk to affect 
BYL719 clearance.  In addition, the available preclinical metabolism data of BYL79 indicate 
that CYP450 enzymes are unlikely to play a major role in BYL719 metabolism. 
 
PK blood samples will be collected from all patients in the study. The sampling regimen 
assumes that both BYL719 and letrozole will be swallowed concomitantly, or less than 5 
minutes apart; and both drugs will be taken at the same time every day. 
The exact clock time of dosing as well as actual sample collection date and time and any 
sampling problems must be noted on appropriate source documentation.  When patients 
come for the pre-dose PK (except for Cycle 1, Day 1) it should be noted when BYL719 and 
letrozole were taken the day before. 
At the specified time points, 2.0 mL of blood will be collected in tubes containing EDTA. 
Plasma sample will be collected for BYL719 concentration measurement. Refer to the 
Laboratory Manual for detailed instructions for the collection, handling, and shipping of PK 
samples.  Plasma concentrations of BYL719 will be measured by a laboratory designated by 
Novartis using a validated high-performance liquid chromatography (HPLC) method with 
tandem mass spectrometry (LC/MS/MS). Samples will be shipped for analysis to Novartis, 
Basel. 
1. Please see laboratory manual for details regarding collection, shipping, and 
processing of PK samples. 
2. Samples are to be stored at a minimum –70° Celsius until ready for 
shipment/analysis. 
 
 
Pharmacokinetic (PK) sampling will be performed according to the table below for all study 
Arms.  Also, if a patient experiences an adverse event that is related to BYL719, it is 
recommended to collect a blood sample for BYL719 PK. 
 
Table 10-4 
Pharmacokinetic  sampling 
 
 
Arms A and C 
(Letrozole + BYL719) 
Arm A 
Sample 
Number 
Arms B and D 
(Exemestane + 
BYL719) 
Arm B 
Sample 
Number 
Cycle 1 Day 1 
Predose 
US101A
Predose
US130B


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30 min ± 6 min post dose 
1 hr ± 15 min post dose 
2 hr ± 15 min post dose 
3 hr ± 15 min post dose 
4 hr ± 15 min post dose 
8 hr ± 1 hr post dose 
US102A 
US103A 
US104A 
US105A 
US106A 
US107A 
1 hr ± 15 min post dose 
6 hr ± 30 min post dose 
US131B 
US132B 
Cycle 1 Day 15 
Predose 
US108A
Predose
US133B
Cycle 2 Day 1 
Predose 
30 min ± 6 min post dose 
1 hr ± 15 min post dose 
2 hr ± 15 min post dose 
3 hr ± 15 min post dose 
4 hr ± 15 min post dose 
8 hr ± 1 hr post dose 
US109A 
US110A 
US111A 
US112A 
US113A 
US114A 
US115A 
Predose
1 hr ± 15 min post dose 
US134B 
US135B 
Cycle 2 Day 15 
Predose 
US116A
Predose
1 hr ± 15 min post dose 
US136B
US137B 
Cycle 3 Day 1 
Predose 
US117A
Predose
1 hr ± 15 min post dose 
US138B 
US139B 
Cycle 4 Day 1 
Predose 
US118A
Predose
US140B
Cycle 5 Day 1 
Predose 
US119A
No PK
 
Cycle 6 Day 1 
Predose 
US120A
No PK
 
Cycle 8 Day 1 
Predose 
US121A
No PK
 
Cycle 10 Day 1 
Predose 
US122A
No PK
 
 
Unscheduled 
US1000A+
Unscheduled 
US1000B+
 
 
 
10.12 Biopsy Specimen Processing and Analysis and Cell-free DNA (cfDNA) Studies 
 
Pre-treatment, Day 15 on-treatment, and optional at-progression biopsies will be obtained to 
further define the biology of AI-resistance in metastatic ER+ breast cancer, and to evaluate 
predictive and pharmacodynamic biomarkers of treatment with BYL719.  Pre-treatment and 
Day 15 on-treatment biopsies will be required, unless felt to put the patient at unacceptable 
risk (note: patients with bone-only metastases will have a pre-treatment biopsy only). 
Patients will also be asked for their permission to store tissue for future use.  All patients may 
be asked to undergo an optional tumor biopsy at progression, with the exact timing to be at 
the discretion of the investigator and patient (not necessarily within 28 days of last dose of 
BYL719), although a 2 week window is allowed 


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For retrospective feasibility and observational studies, tissue use at MSKCC is governed by 
the Human Biospecimen Utilization Committee (HBUC). The HBUC has trans -departmental 
and multidisciplinary representation. The HBUC reviews tissue-related applications for 
Exemptions for Existing Data (formerly Waiver of Authorization).The applicant will be asked 
to include information on the availability of the specific material that is being requested in the 
bank and its heritage, including information on the curation, the consent linked to the 
specimen (if any), and rarity of the resource including frequency of available and quantity of 
material. 
Certain archived specimens have been obtained for specific purposes – for example, to 
determine protocol eligibility based on expression of a biologic determinant, or for 
pharmacodynamic assessments in association with a clinical trial. In the frozen specimen 
archive these purposes have been appropriately flagged in the specimen annotations, so that 
review committees and bank curators do not mistakenly authorize the use of such specimens 
for other than the purposes for which they were acquired. 
 
Specimens will not be released if there is a concern with respect to amount of tumor 
available (i.e. a small tumor embedded in a single block); or if the request would deplete the 
MSKCC archive, unless MSKCC is specifically requested to do so by the patient. The HBUC 
will give special consideration to tissues requested for correlative analysis as part of a clinical 
trial, or to develop a tissue bank at an academic institution, cooperative group or corporate 
entity. In cases where specimens reside in local repositories curated by PI’s of specific 
procurement protocols, the PI’s are under the same obligation to seek HBUC (and other 
necessary) approval for use of the resource in their own studies as other investigators in the 
Center. This is so, because specimen resources are ultimately institutional resources, 
wherever they are stored and by whatever means they are ascertained. Approval of such 
studies by the HBUC will be by the same criteria as noted above. Special care should attend 
review of requests where approval would exhaust the resource. 
In cases where specimens are needed fresh and will be used prospectively, the individual 
investigator needs to write an IRB biospecimen protocol. This protocol is fast-tracked through 
departmental and Research Council review and is reviewed at IRB by the expedited review 
process. This protocol is only for research that will be done on biospecimens obtained under 
specifically identified banking protocols and their informed consent and research 
authorization. The consent and research authorization for the use of the biospecimens will be 
waived as per 45 CFR 46.116(d) and 45 CFR 164.512(i)(2)(ii). 
Pre-treatment biopsy will be performed within 4 weeks prior to starting treatment.  A 
metastatic site is preferred to a primary breast tumor site, when safely accessible.  When 
multiple sites of metastatic disease are safely accessible, a biopsy of a bone metastasis is 
not preferred, because processing may interfere with the proteomic analysis.  In patients 
with bone-only metastases, a pre-treatment biopsy of a bone metastasis will still be 
informative for targeted sequencing analysis and immunohistochemistry for PTEN loss 
(however, patients with bone-only metastases will not undergo a Day 15 on-treatment 
biopsy, because processing may interfere with the proteomic analysis).  After obtaining 
separate informed consent, a core biopsy will be obtained by surgery or interventional 
radiology and processed for both targeted gene sequencing and proteomic analyses.  The 


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core will be divided into a frozen sample and paraffin blocks.  For gene sequencing, we will 
also obtain a blood sample for a normal tissue comparison. 
 
The following information must be provided in the IR referral at the time of a biopsy request: 
1. 
Protocol number 
2. 
Target of biopsy:  Is there a specific target to be biopsied, or is decision left to the IR 
attending to choose? (highly recommended if possible) 
3. 
Specimen required:   FNA, core biopsy, or IR attending decides (example: “at least 
five 18-20 gauge cores”) 
4. 
Specimen handling information 
5. 
Time frame :  First available date, within a time period, or a fixed date 
6. 
Is this a single biopsy or will a second “post treatment” biopsy be needed.  If a second 
biopsy is needed, then IR needs to know the date range of the second biopsy for 
scheduling. 
7. 
Name and pager number of the specimen contact person 
 
An appropriate example of a request is; “Protocol xx-xxx, Right adrenal mass, 4 cores in 
formalin to go to surgical pathology, 1 core to be flash frozen by RSA Joe XX b1234, 
pretreatment biopsy requested for first week of August. Post treatment biopsy to be done one 
week after the first biopsy” 
 
At-progression biopsy may be performed on patients, with tissue preferably obtained from  
the same site as prior pre-treatment and/or on-treatment biopsy.  At progression biopsy will 
be sent for genomic sequencing and/or proteomic evaluation, with utilization of tissue to be at 
the discretion of the investigators. 
 
In collaboration with Dr. Michael Berger (Department of Pathology), as we plan to perform 
massively parallel sequencing12  of all exons corresponding to 230 cancer genes, including all 
currently druggable or “actionable” somatic mutations as well as additional oncogenes and 
tumor suppressor genes shown to have strong associations with cancer genesis and 
progression. The technique used to sequence exons of genes of interest
13  and the technical 
implementation of an oncogene screening profile14  have been described previously. A small 
amount of tumor tissue is required for this sequencing platform (25ug of gross tissue, 
minimum 500ng DNA).  Exonic DNA will be captured via solution-based hybrid selection12  
and sequenced on the Illumina HiSeq platform. The sequencing data will be analyzed for 
base mutations, insertions, deletions, copy number alterations and genomic rearrangements 
in all target genes, with germ-line DNA (whole blood) serving as a reference.  Corroborating 
studies in cell lines will be performed in the lab of Dr. Sarat Chandarlapaty (HOPP) in order  
to evaluate the biological plausibility of potential hits. 
 
This approach has recently been used with success to identify genomic alterations  
underlying both drug sensitivity and resistance.  In breast cancer, we have piloted this 
approach on a panel of 22 prospectively collected HER2 amplified metastatic tumors 
(MSKCC IRB # 06-163, Chandarlapaty - PI) and have identified several mutations which may 
confer resistance to HER2-targeted therapy.  Also using this platform, a TSC2 mutation was 
identified in a patient at MSKCC with advanced bladder cancer who had an uniquely  
favorable response to treatment with rapamycin on a clinical trial (personal communication, 
David Solit). In a patient with BRAF-mutated melanoma who developed acquired resistance 


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to vemurafenib, a MEK1 mutation was identified in the post-treatment sample that proved to 
confer resistance to RAF inhibition with further corroborating studies.
14    These results 
highlight the ability of a targeted, next generation sequencing approach to identify 
mechanisms of drug sensitivity and resistance. 
 
In order to determine if pharmacodynamic markers of PI3K pathway hyperactivation and 
inhibition (e.g. P-AKT, P-S6, P-4EBP) predict for PFS, we will also perform proteomic 
analysis of pre-treatment and on-treatment biopsies.  When possible, Day 15 on-treatment 
biopsies should be performed from the same tumor site as the pre-treatment biopsies.  The 
levels of pathway protein expression and their activation will be determined by Collaborative 
Enzyme Enhanced Reactive-immunoassay (CEER, Promethius Biosciences). CEER can be 
performed in a multiplexed fashion directly on clinical samples that may be available in 
limited amounts.  This phosphoproteomic assay utilizes the formation of unique immuno- 
complexes between capture antibodies (Abs) printed on a nitrocellulose microarray surface, 
the target molecule (in cell lysate reacted with the slide), and two independent detector-Abs. 
One of the detector-Abs is conjugated to glucose oxidase (GO), and the other is conjugated 
to Horse Radish Peroxidase (HRP). Target detection requires the presence of both detector- 
Abs and the enzyme channeling event between GO and HRP will not occur unless both Abs 
are in close proximity.  Using this assay, receptor tyrosine kinases and downstream pathway 
proteins can be detected at the single cell level (sensitivity of about 100 zeptomoles). 
Intrapatient percent change in quantitative PI3K pathway activation signature will be scored 
and compared to percent tumor volume change at 8 week CT scan.  The Spearman's rank 
correlation of intrapatient percent change in PI3K pathway activation signature (measured as 
a continuous variable) with percent tumor volume change at 8 week CT scan (measured as a 
continuous variable) will be calculated to evaluate whether pharmacodynamic markers of 
PI3K pathway inhibition are predictive of response to therapy.We will also perform 
immunohistochemistry on a paraffin block to evaluate for PTEN loss. This may be performed 
on archival primary tumor block or archival metastatic tumor if not enough tumor is available 
from the pre-treatment metastatic biopsy.  PTEN will be scored as 0 (PTEN loss), 1 or 2, as 
previously described for breast cancer tissue by Dr. Tari King at MSKCC14.  Specifically, the 
cytoplasmic and/or nuclear immunoreaction will be scored based on intensity whereby a 
score of 2 = positive (equal in intensity to normal epithelial cells), a score of 1 = weak 
(reduced intensity as compared with normal epithelial cells), and a score of 0 = negative (no 
immunoreaction).15 
Sequencing data will be analyzed for base mutations, insertions, deletions, and copy number 
alterations.  Corroborating studies in cell lines will be performed in the lab in order to  
evaluate the biological plausibility of potential hits. Results of correlative studies will be 
primarily descriptive and provide the preliminary evidence necessary to recommend specific 
biomarkers for future clinical study or new drug development. 
 
Tumor specimen macrodissection will be performed in the MSK clinical pathology 
department.  Immunohistochemistry for PTEN will be performed in the lab of Dr. Tari King 
(Department of Surgery, Breast Service).  DNA isolation and targeted sequencing analysis 
will be performed in the lab of Dr. Michael Berger (Department of Pathology).  Proteomic 
analyses and corroborating studies in cell lines will be performed in the lab of Dr. Sarat 
Chandarlapaty (Department of Medicine, HOPP). 


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The detection of tumor derived fragments of DNA in a blood sample provides the opportunity 
for relatively non-invasive serial assessment of the genetic alterations harbored in the tumor. 
Optimally the analysis of cfDNA will be used to determine tumor mutation status for patients 
in whom a biopsy is not feasible and serial assessment for new genetic alterations that occur 
during tumor progression and therapeutic resistance (Forshew, Murtaza et al. 2012; Misale, 
Yaeger et al. 2012; Murtaza, Dawson et al. 2013).  Small studies have begun to examine the 
clinical utility of cfDNA; quantitatively as a prognostic biomarker and specifically as a 
surrogate for tumor burden and response to treatment by quantifying known somatic 
mutations identified in the tumor (Spindler, Pallisgaard et al. 2012; Dawson, Tsui et al. 2013). 
Incorporation of formal testing for its predictive utility in prospective studies examining 
pathway inhibition with targeted therapy is currently under investigation. 
 
cfDNA will be extracted and quantified by qPCR under the direction of Dr. Mary Ellen 
Moynahan (Department of Medicine, Jasin Lab) at intervals designated in Table 10-1. Known 
PIK3CA mutations will be serially quantified by dPCR in the Genomic Core Facility. 
Additional mutations identified by targeted exome sequencing will undergo dPCR assay 
design and validation. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Potential BYL719 toxicities are listed below.  Definitions of dose limiting toxicities (DLTs) are 
provided in Section 9.3.  Toxicity management guidelines are provided in Section 10.10. 
Definitions of serious adverse events, and reporting requirements are provided in Section 
17.2. 
Percentages below refer to adverse events reported to date in the ongoing phase I single- 
agent study (n=50).  For details on preclinical and clinical experience, please refer to Section 
3.5.1 and Section 3.5.2 of this protocol and the current BYL719 Investigator’s Brochure (IB). 
Cardiovascular: hypertension (2%) 
Endocrine: hyperglycemia (46%) 
 
Gastrointestinal: nausea (34%), decreased appetite (34%), diarrhea (32%), vomiting 
(24%), dyspepsia (14%), dysgeusia (12%) 
 
Hepatic: ALT increase (4%), AST increase (4%), alkaline phosphatase increase (2%) 
Skin: skin toxicity including rash (28%) 
Miscellaneous: fatigue (24%), weight decrease (14%), asthenia (10%) 
 
There is also noted to be a rare but serious risk of hypersensitivity. One patient with colon 
cancer on the ongoing single-agent phase I study experienced hypersensitivity which was 
considered possibly drug related. The patient was hospitalized 12 days after start of 
treatment with 400 mg BYL719 daily, with generalized rash, pyrexia and prickly sensation. 
The study medication was temporarily interrupted and the patient received treatment with 
hydrocortisone and piriton. When treatment was restarted 2 days later, the allergic reaction 
(which included reddening of skin, pyrexia, and prickling sensation) reoccurred on the same 


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day and resolved again following treatment with hydrocortisone and piriton. This event was 
considered serious and unexpected, and an investigator notification was issued. 
 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The primary objective of this study is to determine the recommended phase II dose of 
BYL719 when administered in combination with either letrozole or exemestane.  As of 
January 2014, this trial is being amended such that an additional primary objective is to 
determine the recommended phase II dose of BYL719 administered in a 7 day on, 7 day off 
schedule, in combination with letrozole, and the recommended phase II dose of BYL719 
administered on a 5 day on, 2 day off schedule, in combination with exemestane.  All 
patients who receive at least one dose of BYL719 will be evaluable for toxicity assessment. 
See Section 9.3 for the definitions of dose limiting toxicities and Section 9.4 for the dose- 
finding schema. 
 
In order to estimate the efficacy of BYL719 plus letrozole or exemestane (a secondary 
endpoint), we will calculate the following for each arm separately in the expansion cohort 
only: 
a. Progression-free survival (PFS) will be examined using Kaplan-Meier methods. 
b. Overall response rate (ORR = complete response (CR) plus partial response (PR)) 
will be calculated with an exact confidence interval. 
c. Clinical benefit rate at 16 weeks (CBR = CR + PR + stable disease) will be 
calculated with an exact confidence interval. 
d. Time to treatment failure (TTF) will be examined using Kaplan-Meier methods. 
 
The RECIST criteria version 1.1 will be used to evaluate therapeutic response.  All patients 
who receive at least one week of BYL719 in combination with letrozole or exemestane will be 
evaluable for response.  Patients with measurable or non-measurable lesions are included in 
this study.  Measurable lesions are defined as those that can be measured accurately in at 
least one diameter, that is ≥ 20mm using conventional imaging techniques (including 
incremental CT) or ≥ 10mm using spiral CT equipment.  Non-measurable lesions include 
bony metastases, leptomeningeal disease, ascites, pleural/pericardial effusions,  
inflammatory breast cancer, lymphangitic carcinomatosis, and heavily calcified and 
cystic/necrotic lesions. 
Patients will have an evidence of disease (EOD) evaluation at baseline, consisting of CT of 
chest/abdomen +/- pelvis (with oral and IV contrast unless contraindicated) and a bone scan. 
Patients will then have EOD evaluation with CT of chest/abdomen +/- pelvis every two cycles 
(8 weeks) for the first four cycles (16 weeks) of study treatment (Day 1 +/- 7 days of Cycle 3 
and Cycle 5), and then every 3rd cycle (12 weeks) thereafter (Day 1 +/- 7 days of Cycle 8, 
Cycle 11, etc). EOD evaluation will occur every 4th cycle (16 weeks) +/- 4 weeks from the last 
evaluation for patients who are on study under Amendment 13. A bone scan will also be 
performed if the baseline bone scan showed evidence of osseous metastatic disease 
(otherwise, a bone scan is not required, but may be obtained at the investigator’s discretion if 
clinically indicated).  For patients with locally-advanced unresectable breast cancer, 
radiographic assessments using MRI scans are acceptable to evaluate response, and a CT 
scan of chest/abdomen is not required. 


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For equivocal findings of progression (e.g., very small and uncertain new lesions, cystic 
changes or necrosis in existing lesions, or other such equivocal findings), treatment may 
continue until the next scheduled assessment at the discretion of the treating physician.  If, at 
the next scheduled assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
Criteria for removal from the study are: 
 
 
Progressive disease 
 
Unacceptable toxicity 
 
Three or more consecutive weeks of a delay in treatment due to toxicities 
 
Intercurrent, non-cancer related illness that prevents continuation of protocol therapy 
or follow-up 
 
Major protocol violation that would render the patient inevaluable for safety/toxicity 
 
Repeated non-compliance by the patient with protocol requirements 
 
Changes in the patient’s condition or study drug related toxicity such that, in the 
opinion of the investigator, continued participation in the protocol would compromise 
the patient’s well-being 
 
Withdrawal of the patient’s consent for any reason 
 
Termination of the clinical trial by the investigator or Novartis, the drug manufacturer 
 
14.1 
BIOSTATISTICS 
 
This is a single institution phase I study of BYL719 in combination with letrozole or 
exemestane, with a dose-finding phase and an expansion phase.  The primary objective is to 
determine the recommended phase II dose of BYL719 when administered in combination 
with either letrozole or exemestane to patients with HR+ locally-advanced or metastatic 
breast cancer.  As of January 2014, this trial is being amended such that an additional 
primary objective is to determine the recommended phase II dose of BYL719 administered in 
a 7 day on, 7 day off schedule, in combination with letrozole, and the recommended phase II 
dose of BYL719 administered on a 5 day on, 2 day off schedule, in combination with 
exemestane. 
 
This clinical trial was initially comprised of two arms, one for BYL719 in combination with 
letrozole (Arm A) and another for BYL719 in combination with exemestane (Arm B).  As of 
January 2014, Arms A and B will no longer accrue patients and the study will be amended to 
include Arms C and D.  Arm C will involve letrozole with BYL719 given on days 1-7 and 15- 
21 of a 28 day cycle.  Arm D will involve exemestane with BYL719 given on days 1-5, 8-12, 
15-19, 22-26 of a 28 day cycle.  Anastrozole will not be evaluated in this study because 
anastrozole is a non-steroidal AI similar to letrozole.  Arms C and D employ distinct 
aromatase inhibitors for clarity throughout clinical care.  However, given the similar toxicity 
profile seen with both aromatase inhibitors with continuously dosed BYL719 (Arms A and B), 
results from either arm are felt to be generalizable to either aromatase inhibitor. 


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The dose-finding phase will require 4 to 24 patients for each arm that will accrue patients 
(Arm C and Arm D), and the expansion phase will require 10 patients for each arm.  We 
anticipate ~38 patients total across both arms, and we estimate an accrual rate of at least 2 
patients per month, with a total time of two years to complete the study. 
 
14.2 Dose-Finding Phase 
The purpose of the dose-finding portion of the study is to determine the recommended phase 
II dose of BYL719 in combination with a fixed dose of either letrozole or exemestane.  For 
Arm A and Arm B, the five proposed doses of BYL719 are 200mg, 250mg, 300mg, 350mg or 
400mg.  For Arms C and D, the five proposed doses of BYL719 are 150mg, 200mg, 250mg, 
300mg, and 350mg. 
 
The plans for dose escalation or de-escalation consist of entering patients in cohorts of three. 
The specific details are given in Section 9.4.  Dose-limiting toxicities are defined in Section 
9.3. All patients within a cohort will be observed for toxicity for one cycle (28 days) prior to 
entering patients at the next dose level.  If a patient discontinues study participation during 
the first cycle (within 28 days of starting study treatment) for reasons unrelated to an adverse 
event or disease progression, an additional patient may be enrolled to replace that subject. 
We expect this early dropout to be a rare event, occurring 5% of the time, and will be 
examined closely as a source for potential bias.  Otherwise, all patients who receive at least 
one dose of BYL719 in combination with letrozole or exemestane will be evaluable for toxicity.  
All patients who receive at least one week of BYL719 in combination with letrozole or 
exemestane will be evaluable for response. 
The probability that dose escalation or de-escalation will occur at any stage during this 
portion of the study is a function of the underlying DLT rate at the current dose level.  This 
probability can be calculated as the sum of the binomial probabilities of the following two 
outcomes that would permit escalation to occur: 
1. No DLT observed in the first three patients. 
2. One DLT is observed in the first three patients followed by no DLT observed in 
three additional patients at the same dose level. 
 
The true risk of toxicity is expected to be in the range of 10%-40%.  The following table 
shows the corresponding probabilities of dose escalation: 
 
True Risk of Toxicity 
.10
.20
.30
.40
Probability of Escalation 
.91
.71
.49
.31
 
These numbers show that the probability of escalating to the next dose level is large when 
the underlying true toxicity rate is small and the probability of escalating decreases 
appropriately as the true toxicity rate increases. 
 
Between 2-6 patients will be treated at each dose level.  Assuming 4 dose levels, this portion 
of the trial will require a minimum of 4 and a maximum of 24 patients for each arm.  If 2 or 
more patients in the lowest dose cohort (Cohort -2 for Arms A and B, and Cohort -1 for Arms 
C and D) for either arm experience DLT, then we will conclude that the combination is not 


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feasible and will discontinue the affected arm of the trial.  If this occurs, accrual onto the 
unaffected arm will be halted until safety data is reviewed by the primary investigator and 
Novartis to determine whether to continue or close the unaffected arm of the trial. 
 
We expect both arms (Arm C and Arm D) to accrue simultaneously, as letrozole is typically 
given first-line for HR+ metastatic breast cancer, while exemestane is more often used in the 
second-line setting.  With an expected accrual rate of at least 2 patients per month, it is 
expected that the dose-finding portion of the trial will take less than 1 year.  This allows each 
3-patient cohort to be observed for 28 days, the length of time for treatment with one cycle of 
therapy, prior to additional patients being accrued. 
 
14.3 Expansion Phase 
In the expansion portion of the study, 10 additional patients will be enrolled in each arm, Arm 
C and Arm D, in order to further define the safety and feasibility of BYL719 in combination 
with letrozole or exemestane at the established dose from the dose-finding phase, and to 
estimate the efficacy of this combination. 
 
In order to help ensure that the DLT rate observed among the additional 10 patients in each 
arm is consistent with the DLT rate observed at the established dose from the dose-finding 
portion, the following decision rule will be implemented for each of the two study arms.  If ≥ 4 
DLTs are seen at any time in any one expansion arm, then it is likely that the safe and 
tolerable dose determined during the first portion of the trial is too toxic. The safety data will 
then be reviewed with the primary investigator and Novartis to determine how to move 
forward.  Depending on the circumstances, we may consider de-escalating the dose of 
BYL719 to the next lower dose level and accruing 10 additional patients  at that level.  The 
probability of observing at least 4 patients with a DLT in the 10 additional patients is .28 if 1 
of 6 patients were seen with a DLT in the dose-finding phase of the study.  The probability of 
observing at least 4 patients with a DLT in the 10 additional patients is .09 if 0 of 6 patients 
were seen with a DLT in the dose-finding phase of the study.
11  The below table provides 
additional details on the probability of observing at least 1 to 9 patients with DLTs in the 
expansion cohort of 10 patients given that 0 or 1 patient in the initial dose-finding cohort of 6 
patients had a DLT.11 
 
 
 
 
DLTs in expansion cohort 
DLTs in dose- 
finding cohort 
1 DLT 
(of 10) 
2 
DLTs 
3
DLTs 
4
DLTs 
5
DLTs 
6
DLTs 
7 
DLTs 
8 
DLTs 
9
DLTs 
0 (of 6) 
0.59 
0.33
0.18
0.09
0.04
0.02
0.01 
<0.01
<0.01
1(of 6) 
0.85 
0.64
0.44
0.28
0.16
0.08
0.04 
0.01
0.01
 
The two arms of the study will be monitored in tandem, and we have added an overall 
sequential global stopping rule to be applied as both expansion cohorts are accruing.  We 
include this early stopping rule across both arms because the mechanism and toxicities of 
both AIs are known to be very similar.  Our global stopping rule is based on repeated 
significance testing and serves as a global safety measure.  We assume a grade 4 toxicity 
rate of 10% as acceptable and 35% as unacceptable.  With these assumptions, if 2 of the 


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first 5 patients, 3 of the first 10 patients, 4 of the first fifteen or 5 of 20 patients accrued 
experience a grade 4 toxicity, we will discontinue the entire study.  With this rule, the 
probability of discontinuing the study if the true toxicity rate is 35% is .92.  If the true toxicity 
rate is 10%, this probability is .10. 
 
14.4 Secondary Objectives 
There are several planned secondary analyses.  Selected non-hematologic and hematologic 
toxicities will be described, as measured by the NCI Common Toxicity Criteria, version 4.0, 
with the maximum grade over all cycles used as the summary measure per patient. 
 
In order to estimate the efficacy of BYL719 plus letrozole or exemestane, we will calculate 
the following for each arm, Arm C and Arm D separately in the expansion cohort only: 
a. Progression-free survival (PFS) will be examined using Kaplan-Meier methods. 
b. Overall response rate (ORR = complete response (CR) plus partial response (PR)) 
will be calculated with an exact confidence interval. 
c. Clinical benefit rate (CBR = CR + PR + stable disease at 16 weeks) will be 
calculated with an exact confidence interval. 
d. Time to treatment failure (TTF) will be examined using Kaplan-Meier methods. 
Pharmacokinetic parameters such as AUC and Cmax  of daily BYL719 will be calculated. 
14.5 Exploratory Objectives 
Correlative studies examining patient and clinical factors correlated with BYL719 sensitivity 
will be done using next generation sequencing and fine copy number analysis of  pre- 
treatment biopsies, as well as proteomic analysis of pre-treatment and on-treatment biopsies. 
cfDNA analysis in plasma obtained at baseline, Cycle 1 day 1, Cycle 1 day 8, Cycle 1 day 15 
and at each subsequent treatment cycle will be performed to assess for a correlation  
between mutant allele quantification and response to BYL719.We feel that combining the 
letrozole and exemestane arms for these exploratory analyses is reasonable given their 
similar mechanisms of action at the level of the breast cancer cell.  The correlative studies  
will be primarily descriptive and provide the preliminary evidence necessary to recommend 
BYL719 and specific biomarkers for future clinical study. 
 
cfDNA extraction from 2-6 ml plasma obtained at the time of routine blood draws has been 
feasible in patients with metastatic breast cancer according to ongoing study, MSKCC IRB 
#13-050, Moynahan – PI.  DNA quantity and integrity is assessed by qPCR and uniformly  
has yielded amplifiable fragments suitable for dPCR and small amplicon library construction. 
We anticipate that this approach will be informative for patients with tumors harboring a 
PIK3CA mutation and exploratory for patients whose tumors harbor potential driver mutations 
for which additional dPCR assays will be designed (Dawson, Tsui et al. 2013). 
 
The protocol consent form asks participants for permission to discuss their research findings 
if their samples are used in an HBUC or Biospecimen project and an incidental finding is 
made that may be critical to their preventative care.  If a participant agrees to be contacted, 
the participant will not be told the specific results of the research test, but will be informed 
that their samples were used in a project and a potential risk was uncovered.  If the 
participant is interested in further discussion of the research findings, the participant will be 


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asked to come into MSKCC Clinical Genetics Service for counseling and specific genetic 
testing. 
 
Based on our ongoing experience with our tumor biopsy study to evaluate molecular 
mechanisms of resistance in patients with HER2+ disease (MSKCC IRB # 06-163, 
Chandarlapaty - PI), we anticipate that it will be feasible to obtain a pre-treatment biopsy in at 
least 80% of patients (~30 patients assuming total accrual of 38 patients).  Due to logistical 
issues, such as lack of sufficient viable cells in the biopsy sample, it is possible that a viable 
pre-treatment biopsy sample may not be obtained in several patients. 
 
In order to determine if pharmacodynamic markers of PI3K pathway hyperactivation and 
inhibition predict for PFS, proteomic analysis of pre-treatment and Day 15 on-treatment 
biopsies will be performed.  The Spearman's rank correlation of intrapatient percent change 
in PI3K pathway activation signature (measured as a continuous variable) with percent tumor 
volume change at 8 week CT scan (measured as a continuous variable) will be calculated to 
evaluate whether pharmacodynamic markers of PI3K pathway inhibition are predictive of 
response to therapy. 
 
We anticipate that it will be feasible to obtain a Day 15 on-treatment biopsy in at least 50% of 
patients (~19 patients assuming total accrual of 38 patients). 
 
To evaluate mechanisms of AI resistance, the analysis will include pre-treatment tumor 
biopsies obtained in patients who had POD on an AI at the time of study consent, on- 
treatment biopsies, as well as optional post-progression biopsies.  We estimate that this will 
include about half of patients in the dose-finding phase (because those with stable disease 
will be excluded), and all patients in the expansion phase who have a viable pre-treatment 
biopsy sample. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 


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15.3 
Randomization 
 
Randomization will not be necessary for this study.  Patients will be eligible for only one of  
the two arms depending on which AI (letrozole or exemestane) they were taking before study 
enrollment.  Patients will not be randomized to one of the two arms. 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the study team. 
 
The Clinical Research Database (CRDB) will be used for data collection.  The data will be 
reported to the institution (IRB) and the drug manufacturer (Novartis) as appropriate. 
 
Tumor slides will be stored in the breast surgery laboratory.  Results from laboratory studies 
will include photomicrographs of IHC studies, computer files of sequencing data, and 
computer files from microarray analyses.  These files will be stores on the Department of 
Medicine server.  Documentation linking patient identifiers and patient samples and results 
will be securely maintained in the CRDB with access limited to study investigators. 
It is estimated that 2 patients will be accrued per month and it will take up to two years to 
accrue. 
16.2 
Quality Assurance 
 
Routine registration reports will be generated to monitor patient accruals and completeness 
of registration data.  Routine data quality reports will be generated to assess missing data 
and inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/learningabout/patientsafety/dsm -guidelines /page1.    The 
DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research.  The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet at: 
http://smskpsps9/dept/ocr/OCR%20W 
ebsite%20Documents/Clinical%20Research%20Qualit   
y%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.p  
df. 


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There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff  
education on clinical research QA) and departmental procedures for quality control, plus  
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs.  The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side  
effects.  Alternative treatment options, including non-protocol treatment options, will be 
discussed with the patient.  It will be reviewed that participation in this clinical trial is voluntary 
and that the patient may withdraw consent at any time.  The study is designed with careful 
safety monitoring for toxicity including physician visits approximately every 4 weeks and 
approximately every 8 weeks at minimum for patients on study under Amendment 13 of the 
protocol.  Every effort will be made to keep study records private.  Neither the patient’s name 
nor anything else that could identify the patient will be used in any reports or publications that 
result from this study.  Trained staff at Memorial Sloan-Kettering Cancer Center, the Food 
and Drug Administration, or the drug manufacturer, Novartis, will be able to review the 
medical records if necessary.  The financial costs of the study will be discussed with the 
patient; BYL719 will be provided free of charge.  The cost of the pharmacokinetic studies and 
correlative research on tumor biopsies will be covered by RNB. 
17.2 
Privacy 
 
Medical information is confidential. The participant’s personal identity will not be used in 
reports that are written about the research. The MSKCC IRB/PB will review all requests for 
research performed involving biospecimens ascertained through this protocol. Blo od and 
tissue samples will be stored with a code linked to the patient’s medical record. With the 
permission of the IRB/PB, research studies on cellular, genetic, immunologic, or other 
features of tumor or normal samples may be performed with no names attached to the 
samples but linked by codes to personal identifiers. The results of any research using blood 
or tissues will not be placed in the medical record. 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
The consent also indicates that samples and genetic information collected may be shared 
with other qualified researchers. Such information will not include identifying information such 
as name. It is also stated in the consent and Research Authorization that research data (e.g. 
genomic sequence) may be placed into databases monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 


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The requirements for submission of genotype/phenotype data into the NIH GWAS Repository 
(or any other public database) will be outlined in the biospecimen analysis application, i.e. 
IRB Biospecimen Correlative Protocol. 
 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is any undesirable sign, symptom or medical condition occurring after 
starting study drug (BYL719), even if the event is not considered to be related to study drug. 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected, recorded and followed as appropriate.   Medical conditions/diseases 
present before starting study treatment are only considered adverse events if they worsen 
after starting study treatment (any procedures specified in the protocol). Adverse events 
occurring before starting study treatment but after signing the informed consent form are 
recorded. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms or require therapy, and are recorded. 
 
A serious adverse event (SAE) is an undesirable sign, symptom or medical condition which: 
1. is fatal or life-threatening, 
2. required or prolonged hospitalization, 
3. results in persistent or significant disability/incapacity, 
4. constitutes a congenital anomaly or a birth defect, or 
5. is medically significant, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, 
• treatment, which was elective or pre-planned, for a pre-existing condition that did 
not worsen, 
• treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission. 
 
Any serious adverse event occurring after the patient has provided informed consent, has 
started taking the study medication, and until 30 daysafter the patient has stopped study 
participation must be reported. This includes the period in which the study protocol interferes 
with the standard medical treatment given to a patient (e.g. treatment withdrawal during 
washout period, change in treatment to a fixed dose of concomitant medication). The period 
after discontinuing study drug may be extended if there is a strong suspicion that the drug 
has not yet been eliminated. 
Hyperglycemia is an adverse event of interest.  Grade 3 or 4 hyperglycemia must be 
reported to the IRB and Novartis. 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. 


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The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number and title 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
17.2.1 
 
The principal investigator has the obligation to report all serious adverse events to the IRB, 
FDA (all correspondence with the FDA must go through the MSKCC IND Office), and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
 
SAEs will be reported to Novartis concurrent to MSKCC CRDB SAE Report Form using the 
MSKCC CRDB SAE Report Form. 
 
The investigator must complete the SAE Report Form and Novartis SAE fax coversheet in 
English, assess the relationship to study treatment and send the initial completed SAE  
Report Form and Novartis SAE coversheet by fax 1.888.299.4565 within 24 hours of learning 
of its occurrence (excluding weekends and holidays) to the local Novartis DS&E Department. 
The investigator must then ensure that the form and coversheet are accurately and fully 
completed with follow-up information and fax those to Novartis DS&E Department within 2 to 
3 calendar days for deaths or life-threatening events and 5 calendar days for other serious 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-027 A(15) 
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adverse events. The original and the duplicate copies of the SAE Report Form, Novartis SAE 
coversheet, and the fax confirmation sheet must be kept at the study site. 
 
Follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or discontinued study participation. 
The SAE Report Form, Novartis SAE coversheet, and fax confirmation sheet must be 
retained. 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
Subjects currently enrolled onto Arms A and B will continue on Arms A and B.  They will be 
re-consented with the revised Arm A and B consents which will reflect our updated toxicity 
profile. 


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19.0 
REFERENCES 
 
1. Smith IE and Dowsett M.  Aromatase inhibitors in breast cancer. 2003  New England 
Journal of Medicine, 348:2431-2442. 
 
2. Kalinsky K, Jacks LM, Heguy A, et al.  PIK3CA mutation associates with improved 
outcome in breast cancer. 2009  Clinical Cancer Research, 15:5049-5059. 
 
3. Crowder RJ, Phommaly C, Tao Y, et al.  PIK3CA and PIK3CB inhibition produce synthetic 
lethality when combined with estrogen deprivation in estrogen receptor positive breast 
cancer.  2009  Cancer Research, 69;3955-3962. 
4. Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al.  Hyperactivation of 
phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen 
receptor-positive human breast cancer.  2010  The Journal of Clinical Investigation, 
120:2406–2413. 
5. Miller TW, Balko JM, and Arteaga CL.  Phosphatidylinositol 3-kinase and antiestrogen 
resistance in breast cancer.  2011  Journal of Clinical Oncology, 29:4452-4461. 
6. Bachelot T, Bourgier C, Cropet C, et al.  Randomized phase II trial of everolimus in 
combination with tamoxifen in patients with hormone receptor-positive, human epidermal 
growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase 
inhibitors: a GINECO study.  2012  Journal of Clinical Oncology, [2012 May 7, Published 
online ahead of print]. 
 
7. Baselga J, Campone M, Piccart M, et al.  Everolimus in postmenopausal hormone- 
receptor-positive advanced breast cancer.  2012  New England Journal of Medicine, 
366:520-529. 
8. Fleming GF, Ma CX, Huo D, et al.  Phase II trial of temsirolimus in patients with metastatic 
breast cancer.  2012  Breast Cancer Research and Treatment, [2012 Jan 13, Published 
online ahead of print]. 
 
9. Chandarlapaty S, Sawai A, Scaltriti, et al.  AKT inhibition relieves feedback suppression of 
receptor tyrosine kinase expression and activity.  2011  Cancer Cell, 19:58-71. 
 
10. Juric D, Rodon J, Gonzalez-Angulo AM, et al.  BYL719, a next generation PI3K alpha 
specific inhibitor: preliminary safety, PK, and efficacy results from the first-in-human study 
[abstract].  In: Proceedings of the 103rd  Annual Meeting of the American Association for 
Cancer Research; 2012 Mar 31-Apr 4; Chicago, Illinois.  Philadelphia (PA): AACR; 2012. 
Abstract nr CT-01. 
11. Gonen M. A Bayesian evaluation of enrolling additional patients at the maximum 
tolerated dose in phase I trials.  2005  Contemporary Clinical Trials, 26:131-40. 
12. Wagle N, Berger MF, Davis MJ, et al.  High-throughput detection of actionable genomic 
alterations in clinical tumor samples by targeted, massively parallel sequencing.  2012 
Cancer Discovery 2:82-93. 


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13. Gnirke A, Melnikov A, Maguire J, et al. Solution hybrid selection with ultra-long 
oligonucleotides for massively parallel targeted sequencing. 2009  Nature Biotechnology, 
27:182-189. 
 
14. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition 
in melanoma by tumor genomic profiling.  2011 Journal of Clinical Oncology, 29:3085-3096. 
 
15. Sakr RA, Barbashina V, Morrogh M, et al. Protocol for PTEN expression by 
immunohistochemistry in formalin-fixed paraffin-embedded human breast carcinoma.  2010 
Applied Immunohistochemistry & Molecular Morphology, 18:371-374. 
20.0 
APPENDICES 
 
Appendix A:  Patient BYL719 Drug Diary (Letrozole) (attached separately) 
 
Appendix B:  Patient BYL719 Drug Diary (Exemestane) (attached separately) 
 
Appendix C:  Patient Information for BYL719 Drug and Food Interactions 
(attached separately) 


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Appendix D:  List of CYP450 Substrates to Be Used With Caution* 
 
 
CYP 2C8 
CYP 2C9 
CYP 2C19 
CYP 3A** 
 
Amodiaquine 
Acenocoum arol 
Clopidogrel 
Alfentanil 1,2 
Ergotami ne 2 
Ceri vastatin 
Celecoxi b 
Diazepam 
Alpha- 
dihydroergocryptine 1 
Everolimus 
1
 
Repaglinide 
Diclofenac 
Esoprazole 
Alprazolam 
Felodipine 
1
 
Rosiglitazone 
Glipizide 
Lansoprazole 
Amlodipine 
Fentanyl 2 
Torasemide 
Irbesartan 
Moclobemide 
Aplavi roc 
Fluticasone 1 
 
Losartan 
Omeprazole 
Aprepitant 1 
Indinavir 1 
 
Phenytoin 2 
Pantoprazole 
Aripiprazole 
Lopinavi r 1 
 
Piroxicam 
Phenobarbitone 
Atorvastatin 
Lovastatin 1 
 
S-ibuprofen 
Phenytoin 2 
Boceprevir 
Maraviroc 1 
 
Sulfamethoxazol e 
Proguanil 
Brecanavir 
Midazolam 
1
 
 
Tolbutam ide 
Rabeprazole 
Brotizolam 1 
Ni fedipine 
 
Torasemide 
S-mephenytoin 
Budesoni de 1 
Nisoldipine 
 
 
 
Buspirone 1 
Nitrendipi ne 
 
 
 
capravirine 
Perospirone 1 
 
 
 
casopitant 
Quinine 
 
 
 
Conivaptan 1 
Saquinavi r 1 
 
 
 
Cyclosporine 
2
 
Sildenafil 
1
 
 
 
 
Dari fenaci n 1 
Sim vastatin 1 
 
 
 
Darunavir 1 
Sirolimus 1,2 
 
 
 
Diazepam 
Telaprevir 
 
 
 
Diergotami ne 2 
Tipranavir 1 
 
 
 
Diltiazem 
Tol vaptan 
 
 
 
Ebastine 1 
Triazolam 1 
 
 
 
Eletriptan 
1
 
Verapamil 
 
 
 
Eplerenone 1 
 
* This  database of  CYP  substrates  was  compiled from the  Indiana University  School of Medicine’s 
“Clinically Relevant” Table, and from (Zhou et al 2009) 
** CYP3A substrates were compiled from the Indiana University School of Medicine’s “Clinically
Relevant” Table and supplement ed by the FDA’s “Guidance for Industry, Drug Interaction Studies” and
the University of Washington’s Drug Interaction Dat abase. 
1.   Sensitive  substrates:  Drugs  whose  plasma  AUC  values  have  been  shown  to  increase  5-fold  or 
higher when co-administered with a potent inhibitor of the respective enzyme. 
2.   Substrates  with  narrow  therapeutic  i ndex  (NTI):  Drugs  whose  ex posure-response  indicates  that 
increases in their exposure levels  by  the concomitant use of potent  inhibitors may l ead to serious 
safety concerns (e.g. TdP). 


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Appendix E:  List of BRCP Inhibitors to Be Used With Caution 
 
 
 
Diketopiperazines 
P-glycoprotein inhibitors 
Fumitremorgin C 
Elacridar (GF-120918) 
Tryprostatin A 
Tariquidar (XR-9576) 
Indolyl diketopiperazines 
Biricodar 
Steroid(-like) compounds 
Flavonoids 
Corticosterone 
Chrysin 
Digoxin 
Biochanin A 
Beclometasone 
Benzoflavone 
6 α-Meth ylprednisolone 
6-Prenylchrysin 
Dexamethasone 
Tectochrysin 
Triamcinolone 
Naringenin 
Mometasone 
Quercetin 
Ciclesonide 
Acacetin 
Antivirals 
Kaempferol 
Nelfinavir 
Silymarin 
Lopinavir 
Hesperetin 
Delavirudine 
Daidzein 
Efavirenz 
Resveratrol 
Saquinavir 
Genistein 
Atazanavir 
Naringenin-7-glucoside 
Immunosupressants 
3´,4´,7-Trimethoxyflavone 
Sirolimus 
Eupatin 
Ciclosprin A 
Azoles: 
(Dihydro)pyridines 
Pantoprazole 
Niguldipine 
Omeprazole 
Nicardipine 
Oxfendazole 
Nitrendipine 
Ketoconazole 
Dipyridamole 
Itraconazole 
Nimodipine 
Estrogens, estrogen agonists, estrogen antagonists 
Nifedipine 
17-ß-estradiol 
 
Diethylstilbestrol 
 
Toremifene 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
Page 79 of 82
 
 
 
 
List of moderate and strong CYP3A4 and CYP2C8 inducers and 
inhibitors 
 
Category 
Drug Name 
Strong CYP3A Inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravi r, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nel finavir, 
posaconazole, rit onavir, saquinavi r, telaprevi r, telithromycin, tipranavir, 
troleandomycin,  voriconazole 
Strong CYP3A Inducers 
Avasimibe1,2, carbamazepi ne, mitotane, phenobarbital, phenytoin, 
rifabutin, ri fampin (rifampicin)2, St. John's wort (hypericum perforatum )2 
Moderate CYP3A Inhibit ors 
Amprenavi r, aprepitant, atazanavir, casopitant, cimetidine, 
ciprofloxacin, cyclosporine, darunavir, diltiazem, dronedarone, 
erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus 
paradisi fruit juice), imatinib, Schisandra sphenanthera1, tofisopam, 
verapam il 
Moderate CYP3A Inducers 
Bosentan, efavi renz, etravirine, genistein, modafinil, nafcillin, ritonavir, 
tal viraline, thioridazine, tipranavi r 
Strong and moderate 
CYP2C8 inhibit ors 
Gemfibrozil (strong), defasirox (moderate) 
Strong and moderate 
CYP2C8 inducers 
rifampin (rifampicin)2 
1.     Herbal product 
2.     P-gp inducer 
All QT-prolonging drugs listed in Table 5 are prohibited for all patients fro m 
screening through permanent discont inuat ion of study treatment. Table 5  lists 
drugs with a known risk for TdP as well as CYP3A and CYP2C substrates (with a 
possible or condit ional risk for TdP). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
Page 80 of 82
 
 
 
 
Appendix F: List of prohibited QT prolonging drugs 
 
Drug 
QT risk* 
Comment 
Amiodarone 
known risk 
Females>Males, TdP risk regarded as low 
Amitriptyline 
conditional risk 
Risk of TdP with overdosage. Substrate of CYP2C19 
Arsenic trioxide 
known risk 
 
Astemizole 
known risk 
No Longer available in U.S. Substrate for 3 A4 
Bepridil 
known risk 
Females>Males 
Chloroquine 
known risk 
Chlorpromazine 
known risk 
Cisapride 
known risk 
No longer available in the U.S.; available in Mexico. 
Substrate for 3A4 
Citalopram 
known risk 
 
Clarithromycin 
known risk 
Substrate for 3A4 
Clomipramine 
conditional risk 
Disopyramide 
known risk 
Females>Males 
Dofetilide 
known risk 
Domperidone 
known risk 
Not available in the U.S. 
Dronedarone 
possible risk 
Substrate for 3A4 
Droperidol 
known risk 
Erythromycin 
known risk 
Females>Males. Substrate for 3A4 
Drug 
QT risk* 
Comment 
Flecainide 
known risk 
 
Halofantrine 
known risk 
Females>Males 
Haloperidol 
known risk 
When given intravenously or at higher-than- recommended 
doses, risk of sudden death, QT prolongation and torsades 
increases. Substrate for 3A4 
Ibutilide 
known risk 
Females>Males 
Levomethadyl 
known risk 
Not available in the U.S. 
Mesoridazine 
known risk 
Methadone 
known risk 
Females>Males. Substrate for 3A4 
Moxifloxacin 
known risk 
 
Pentamidine 
known risk 
Females>Males 
Pimozide 
known risk 
Females>Males. Substrate for 3A4 
Probucol 
known risk 
No longer available in U.S. 
Procainamide 
known risk 
Quetiapine 
possible risk 
Substrate for 3A4 
Quinidine 
known risk 
Females>Males. Substrate for 3A4 
Ritonavir 
conditional risk 
Substrate for 3A4 
Sotalol 
known risk 
Females>Males 
Sparfloxacin 
known risk 
Tacrolimus 
possible risk 
Substrate for 3A4 
Telithromycin 
possible risk 
Substrate for 3A4 
Terfenadine 
known risk 
No longer available in U.S.Substrate for 3A4 
Thioridazine 
known risk 
Trazodone 
conditional risk 
Substrate for 3A4 
Vandetanib 
known risk 
Vardenafil 
possible risk 
Substrate for 3A4 
* Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
Page 81 of 82
 
 
 
 
 
 
 
Appendix G: List of QT prolonging drugs to be used with caution 
 
Patients receiving any study treatment  may use  the fo llowing medicat ions but 
should  be mo nitored closely. 
 
Drug 
QT risk* 
Comment 
Alfuzosin 
poss ible risk 
 
Amantadine 
poss ible risk 
Atazanavir 
poss ible risk 
 
Azithromycin 
poss ible risk 
Rare reports 
Chloral hydrate 
poss ible risk 
Ciprofloxacin 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Clozapine 
poss ible risk 
Desipramine 
conditional risk 
Risk of TdP with overdosage 
Diphenhydramine 
conditional risk 
Risk of QT increase/TdP in overdosages 
Dolasetron 
poss ible risk 
 
Doxepin 
conditional risk 
Eribulin 
poss ible risk 
 
Escitalopram 
poss ible risk 
Drug 
QT risk* 
Comment 
Famotidine 
poss ible risk 
Felbamate 
poss ible risk 
Fingolimod 
poss ible risk 
Fluconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Fluoxetine 
conditional risk 
Foscarnet 
poss ible risk 
Fosphenytoin 
poss ible risk 
 
Galantamine 
conditional risk 
Gatifloxacin 
poss ible risk 
Gemifloxacin 
poss ible risk 
Granisetron 
poss ible risk 
 
Imipramine 
conditional risk 
Risk of TdP in overdosage 
Indapamide 
poss ible risk 
 
Isradipine 
poss ible risk 
Itraconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Ketoconazole 
conditional risk 
Drug metabolism inhibitor 
Levofloxacin 
poss ible risk 
Lithium 
poss ible risk 
 
Moexipril/HCTZ 
poss ible risk 
Nicardipine 
poss ible risk 
Nortriptyline 
conditional risk 
Octreotide 
poss ible risk 
 
Ofloxacin 
poss ible risk 
Ondansetron 
poss ible risk 
Oxytocin 
poss ible risk 
Paliperidone 
poss ible risk 
 
Paroxetine 
conditional risk 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-027 A(15) 
Approval date: 09-Oct-2018 
Page 82 of 82
 
 
 
 
 
Perflutren lipid 
microspheres 
poss ible risk 
 
Protriptyline 
conditional risk 
 
Ranolazine 
poss ible risk 
Risperidone 
poss ible risk 
Roxithromycin* 
poss ible risk 
*not available in the United States 
Sertindole 
poss ible risk 
 
Sertraline 
conditional risk 
Solifenacin 
conditional risk 
Tizanidine 
poss ible risk 
Trimethoprim-Sulfa 
conditional risk 
Trimipramine 
conditional risk 
 
Venlafaxine 
poss ible risk 
Voriconazole 
poss ible risk 
 
Ziprasidone 
poss ible risk 
* Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
 
 
Appendix H:  Patient BYL719 Drug Diary (Letrozole, Arm C) (attached separately) 
 
Appendix I:  Patient BYL719 Drug Diary (Exemestane, Arm D) (attached separately)