Phase I/II Study of BYL719 and Nab-Paclitaxel in Subjects With Locally Recurrent or Metastatic HER-2 Negative Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: Priyanka Sharma

 
 
 
Protocol:  CBYL719XUS06T 
 
Investigator Initiated Trial 
 
 
Phase I/II Study of BYL719 and Nab-Paclitaxel in Subjects with Locally Recurrent or Metastatic 
HER-2 Negative Breast Cancer 
 
 
 
PRINCIPAL INVESTIGATOR 
Priyanka Sharma, MD 
Associate Professor of Medicine 
University of Kansas Medical Center 
2330 Shawnee Mission Parkway, Suite 210, MS 5003 
Westwood, KS 66205 
 
 
 
 
Study Drug:  
 
BYL719 (Alpelisib) 
 
 
 
Drug Protocol Number: 
CBYL719XUS06T 
 
 
IND Number:   
 
124440 
 
 
Initial Version:  
 
Version 3.0, November 10, 2014 
 
 
Modification Date:   
 
 
 
 
 
 
 
 
 
Version 4.0 - January 14, 2015 
 
 
 
 
Version 5.0 - February 20, 2015 
 
 
 
 
Version 6.0 - July 15, 2015 
 
 
 
 
Version 7.0 - August 31, 2015 
 
 
 
 
Version 8.0 - April 1, 2016 
 
 
 
 
Version 9.0 - August 22, 2016 
 
 
 
CONFIDENTIAL 
This material is the property of The University of Kansas Cancer Center.  Do not disclose or use 
except as authorized in writing by the study sponsor. 
 

IIT Protocol:  CBYL719XUS06T 
 Principal Investigator:  Priyanka Sharma, MD 
 
 
 
 
 
LIST OF KEY PERSONNEL 
 
Project Collaborating Parties:  
The University of Kansas Cancer Center 
 
 
 
 
 
Vanderbilt-Ingram Cancer Center 
 
Coordinating Center 
University of Kansas Medical Center (KUMC) / The University of 
Kansas Cancer Center (KUCC) 
 
KUCC Principal Investigator:  
Priyanka Sharma, M.D. 
 
KUCC Sub-Investigators 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biostatistician  
 
 
 
 
Vanderbilt Principal Investigator 
Vandana Abramson, M.D. 
 
 
 
 
 
2220 Pierce Ave, 777 PRB 
 
 
 
 
 
Nashville, TN 37232 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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IIT Protocol:  CBYL719XUS06T 
 Principal Investigator:  Priyanka Sharma, MD 
 
 
 
 
 
PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing complete 
and timely information, as outlined in the protocol.  It is understood that all information pertaining 
to the study will be held strictly confidential and that this confidentiality requirement applies to all 
study staff at this site. Furthermore, on behalf of the study staff and myself, I agree to maintain 
the procedures required to carry out the study in accordance with accepted GCP principles and 
to abide by the terms of this protocol. 
 
Protocol Number:  CBYL719XUS06T 
 
Protocol Title:  Phase I/II Study of BYL719 and Nab-Paclitaxel in Subjects with Locally Recurrent 
or Metastatic HER-2 Negative Breast Cancer 
 
Protocol Version and Date:  Version 9 dated 08-22-2016 
 
 
 
Principal Investigator Signature: _____________________________          
 
 
 
 
         Date 
 
 
Print Name and Title:   
  
________________________
 
 
Site Number:  001 
Site Name:  The University of Kansas Cancer Center / University of Kansas Medical Center 
 
 
 
Principal Investigator Signature: _____________________________          
 
 
 
 
         Date 
 
 
Print Name and Title:   
  
________________________
 
 
Site Number:  002 
Site Name:  Vanderbilt-Ingram Cancer Center 
 
 
 
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IIT Protocol:  CBYL719XUS06T 
 Principal Investigator:  Priyanka Sharma, MD 
 
 
 
 
 
 
TABLE OF CONTENTS 
ABBREVIATION LIST .................................................................................................................................. 6 
STUDY SCHEMA ......................................................................................................................................... 7 
STUDY SUMMARY ...................................................................................................................................... 8 
1.0 
BACKGROUND AND RATIONALE ................................................................................................ 9 
1.1 
DISEASE BACKGROUND .................................................................................................................. 9 
1.2 
BYL719 BACKGROUND AND ASSOCIATED KNOWN TOXICITIES ......................................................... 9 
1.3 
NAB-PACLITAXEL (NAB-PACLITAXEL) ............................................................................................ 12 
1.4 
RATIONALE .................................................................................................................................. 13 
1.5 
CORRELATIVE STUDIES ................................................................................................................ 13 
2.0 
STUDY OBJECTIVES ................................................................................................................... 13 
2.1 
PRIMARY OBJECTIVES .................................................................................................................. 13 
2.2 
SECONDARY OBJECTIVES ............................................................................................................. 13 
2.3 
EXPLORATORY OBJECTIVES ......................................................................................................... 13 
2.4 
ENDPOINTS .................................................................................................................................. 14 
3.0 
SUBJECT ELIGIBILITY................................................................................................................. 14 
3.1 
INCLUSION CRITERIA .................................................................................................................... 14 
3.2 
EXCLUSION CRITERIA ................................................................................................................... 16 
4.0 
TREATMENT PLAN ...................................................................................................................... 18 
4.1 
TREATMENT DOSAGE AND ADMINISTRATION .................................................................................. 18 
4.2 
BYL719 ADMINISTRATION INSTRUCTIONS ..................................................................................... 18 
4.3 
NAB-PACLITAXEL ADMINISTRATION INSTRUCTIONS ........................................................................ 20 
4.4 
DOSE MODIFICATIONS .................................................................................................................. 22 
4.5 
TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 23 
4.6 
CONCOMITANT MEDICATIONS ....................................................................................................... 30 
4.7 
DURATION OF THERAPY ................................................................................................................ 33 
4.8 
DURATION OF FOLLOW-UP ........................................................................................................... 34 
4.9 
REMOVAL OF SUBJECTS FROM PROTOCOL THERAPY ..................................................................... 34 
5.0 
STUDY PROCEDURES................................................................................................................. 34 
5.1 
SCREENING/BASELINE AND ALL STUDY PROCEDURES ................................................................... 34 
5.2 
PROCEDURES DURING TREATMENT .............................................................................................. 36 
5.3 
SCHEDULE OF EVENTS ................................................................................................................. 38 
5.4 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND STUDY ...................................................... 40 
6.0 
ADVERSE EVENTS ...................................................................................................................... 41 
6.1 
DEFINITIONS ................................................................................................................................ 41 
6.2 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ...................................................................... 43 
7.0 
DRUG INFORMATION .................................................................................................................. 46 
7.1 
BYL719 ...................................................................................................................................... 46 
7.2 
NAB-PACLITAXEL ......................................................................................................................... 46 
7.3 
DRUG ACCOUNTABILITY/SUBJECT COMPLIANCE ............................................................................ 47 
7.4 
RETURN AND RETENTION OF STUDY DRUG .................................................................................... 47 
8.0 
CORRELATIVES/SPECIAL STUDIES .......................................................................................... 48 
8.1 
SAMPLE COLLECTION FOR FUTURE BLOOD AND TISSUE CORRELATIVE STUDIES ............................. 48 
8.2 
PHARMACOKINETIC SAMPLING AND ANALYSIS ................................................................................ 48 
9.0 
MEASUREMENT OF EFFECT ...................................................................................................... 49 
 
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IIT Protocol:  CBYL719XUS06T 
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9.1 
ANTITUMOR EFFECT- SOLID TUMORS ............................................................................................ 49 
9.2 
RESPONSE CRITERIA .................................................................................................................... 51 
9.3 
DURATION OF RESPONSE ............................................................................................................. 52 
10.0 
DATA AND SAFETY MONITORING ............................................................................................. 53 
10.1 
OVERSIGHT AND MONITORING PLAN ............................................................................................. 53 
10.2 
REVIEW AND OVERSIGHT REQUIREMENTS ..................................................................................... 53 
11.0 
REGULATORY CONSIDERATIONS ............................................................................................ 54 
11.1 
PROTOCOL REVIEW AND AMENDMENTS ......................................................................................... 54 
11.2 
INFORMED CONSENT .................................................................................................................... 54 
11.3 
ETHICS AND GOOD CLINICAL PRACTICE (GCP) ............................................................................. 54 
12.0 
REGISTRATION PROCEDURES ................................................................................................. 55 
12.1 
GENERAL GUIDELINES FOR KUCC AND OTHER PARTICIPATING ORGANIZATIONS ........................... 55 
12.2 
REGISTRATION PROCESS FOR KUCC AND OTHER PARTICIPATING CENTERS .................................. 55 
13.0 
STUDY MANAGEMENT ................................................................................................................ 56 
13.1 
INVESTIGATOR FILES AND RETENTION OF DOCUMENTS .................................................................. 56 
13.2 
CASE REPORT FORMS.................................................................................................................. 56 
13.3 
STUDY MONITORING .................................................................................................................... 56 
14.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 57 
14.1 
STUDY DESIGN/SAMPLE SIZE AND ACCRUAL ................................................................................. 57 
14.2 
DATA ANALYSES PLANS ............................................................................................................... 58 
15.0 
REFERENCES ............................................................................................................................... 59 
16.0 
APPENDICES ................................................................................................................................ 61 
APPENDIX A. PERFORMANCE STATUS ..................................................................................................... 61 
APPENDIX B: LIST OF CONCOMITANT MEDICATIONS ................................................................................. 62 
APPENDIX C: SPECIMEN COLLECTION FOR CORRELATIVE STUDIES .......................................................... 67 
(SERUM, PLASMA, AND BUFFY COAT) ......................................................................................................... 67 
APPENDIX D: GUIDELINES FOR MANAGEMENT OF DIARRHEA .................................................................... 68 
APPENDIX E: SUMMARIES OF CHANGES .................................................................................................. 71 
 
 
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ABBREVIATION LIST 
 
AE 
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
AST 
 
Aspartate Aminotransferase 
BCRP  
Breast Cancer Reactive Protein 
BUN 
 
Blood Urea Nitrogen 
CBC 
 
Complete Blood Count 
CBR 
 
Clinical Benefit Rate 
CMP  
Comprehensive Metabolic Panel 
CR 
 
Complete Response 
CT 
 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB  
Data and Safety Monitoring Board 
EGFR  
Epidermal Growth Factor Receptor 
ER 
 
Estrogen Receptor 
FU 
 
Follow-Up Visit 
IULN  
Institutional Upper Limit of Normal 
HSC 
 
Human Subjects Committee 
ICF 
 
Informed Consent Form 
IRB 
 
Institutional Review Board 
KUMC  
University of Kansas Medical Center 
KUCC  
The University of Kansas Cancer Center 
LD 
 
Longest Diameter 
MBC  
Metastatic Breast Cancer 
MRI 
 
Magnetic Resonance Imaging 
MTD 
 
Maximum Tolerated Dose 
ORR  
Overall Response Rate 
OS 
 
Overall Survival 
PD 
 
Progressive Disease; Pharmacodynamics 
PET 
 
Positron Emission Tomography 
PFS 
 
Progression Free Survival 
PI 
 
Principal Investigator 
PI3K 
 
Phosphatidylinositol-3-Kinase 
PK 
 
Pharmacokinetics 
p.o. 
 
Per Os/By Mouth/Orally 
PR 
 
Partial Response 
PgR 
 
Progesterone Receptor 
QD 
 
Daily  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPTD  
Recommended Phase II Dose 
SAE 
 
Serious Adverse Event 
SD 
 
Stable Disease 
TNBC  
Triple Negative Breast Cancer 
WOCBP 
Woman of Child Bearing Potential 
 
  
 
 
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IIT Protocol:  CBYL719XUS06T 
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STUDY SCHEMA  
Phase I: Standard 3+3 dose escalation of BYL19 combined with 100 mg/m2 Nab-Paclitaxel 
 
 
 
Phase II: BYL719/alpelisib RPTD Used To Assess Endpoints 
 
 
 
 
 
 
 
 
 
 
 
Start at 250 
mg BYL719 
Treat 3 
subjects 
Number 
of DLTs 
0/3 
1/3 
2/3-3/3 
De-escalate to next 
lower dose level of 
BYL719 if N<6 
 
Recruit 3 more 
subjects at 
same dose  
 
Escalate to next 
higher dose level of 
BYL719 if N<6 
1/6 
Number of DLTs 
MTD 
Identified 
STOP 
Next lower dose 
level already has 6 
subjects treated 
Next higher dose 
level already has 6 
subjects treated 
≥ 2/6 
 
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STUDY SUMMARY 
Title 
Phase I/II Study of BYL719 and Nab-Paclitaxel in Subjects With Locally 
Recurrent or Metastatic HER-2 Negative Breast Cancer 
Short Title 
Study of BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic 
HER-2 Negative Breast Cancer 
Phase 
I/II 
Methodology 
Open-Label 
Study Duration 
3 years 
Study Center(s) 
The University of Kansas Cancer Center and Vanderbilt-Ingram Cancer 
Center 
Objectives 
Primary Objectives: 
• 
For Phase I, determine the recommended phase II dose (RPTD) 
of BYL719/alpelisib + Nab-Paclitaxel to be used in combination 
for treatment of advanced HER-2 negative breast cancer 
• 
For Phase II, assess ORR 
Secondary Objectives: 
• 
Assess pharmacokinetics of BYL719/alpelisib when administered 
with Nab-Paclitaxel 
• 
Assess pharmacokinetics of Nab-Paclitaxel when administered 
with BYL719/alpelisib 
• 
Determine the Clinical Benefit Rate (CBR) 
• 
Progression-Free Survival (PFS) and Overall Survival (OS) 
Exploratory Objective: 
• 
Investigate the correlation of PI3K aberration with response 
Number of Subjects 
Approximately 54 (18 in Phase I, 36 in Phase II) 
Diagnosis and Main 
Inclusion Criteria 
• 
Histologically-proven HER-2 negative breast cancer, which at the 
time of study is either stage III (locally advanced) disease not 
amenable to curative therapy or stage IV disease. 
• 
Demonstration of adequate bone marrow, kidney and hepatic 
function. Minimum criteria include: ANC > 1500/uL platelet count 
> 100,000/u/L, hemoglobin  > 9 g/dL, serum creatinine < 1.5 
mg/dL, transaminases < 2X IULN, total bilirubin < 1.5 mg/dL 
Study Product(s), Dose, 
Route, Regimen 
250-350 mg BYL719/alpelisib once daily on days 1-28 every 28 days 
plus 100 mg/m2 Nab-Paclitaxel intravenous on days 1,8, and 15 of every 
28 day cycle. 
Duration of Administration 
6, 28 day cycles of BYL719/alpelisib plus Nab-Paclitaxel after which 
Nab-Paclitaxel can be stopped and subjects will be allowed to take 
BYL719/alpelisib dosed continuously until disease 
progression/unacceptable toxicity. 
Interim Monitoring 
We will employ the following Bayesian sequential monitoring rule for 
toxicity during the Phase II portion of the study. We will stop the study if 
P (toxicity > 33% / data from the trial) > 0.95. This decision rule gives the 
following stopping rule. We assume a uniform prior distribution for the 
toxicity rate. Stop the study if [ # of subjects with toxicity / # of subjects 
evaluated ] ≥ 4/6, 5/7, 6/9, 7/11, 8/13, 9/16, 10/18, 11/20, 12/23, 13/25, 
14/28, 15/30. 
Statistical Methodology 
Phase I: Standard 3+3 design for Phase I portion with three dose levels 
of BYL719/alpelisib (250 mg, 300 mg, 350 mg) and one level of Nab-
Paclitaxel (100 mg/m2), Phase II study is designed according to Simon’s 
two stage Minimax design to detect an improvement in ORR from 20% to 
40% (alpha 0.05 and power of 0.8). 
 
 
 
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IIT Protocol:  CBYL719XUS06T 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Breast cancer is the most common cancer and the second leading cause of cancer-related 
death in American women, with 232,340 new cases of breast cancer expected to be diagnosed 
in the year 2013[1]. Despite clinical advances in treatment of breast cancer over the last 
decade, up to 30% of women with early-stage, non-metastatic breast cancer at diagnosis will 
develop distant metastatic disease and 40,000 women still die as a result of breast cancer 
annually in the United States[1, 2]. The median survival for metastatic breast cancer (MBC) is 
18-24 months though this varies widely based on tumor subtype, site(s) of metastatic 
involvement and burden of metastatic disease. Chemotherapy (usually a sequential single 
agent) remains the backbone of systemic treatment for subjects with HER-2 negative MBC. 
Although a majority of subjects with MBC respond to systemic chemotherapy, eventually all 
subjects will progress with a median time to progression of 3-7 months[3, 4]. While the exact 
mechanism for resistance or failure of systemic chemotherapy in MBC remain largely unclear, 
evidence suggests that the phosphatidylinositol-3-kinase (PI3K) pathway may play a role in 
primary and/or acquired resistance[5]. 
1.2 
BYL719/Alpelisib Background and Associated Known Toxicities 
 
The PI3K Pathway 
 
PI3K signaling regulates diverse cellular 
functions, including cell proliferation, survival, 
translational regulation of protein synthesis, 
glucose metabolism, cell migration and 
angiogenesis[6]. Constitutive activation of PI3K 
signaling is known to be a critical step in 
mediating the transforming potential of 
oncogenes and tumor suppressors in many 
tumor types[7]. Resistance to a variety of 
therapeutic interventions including 
chemotherapy, hormonal therapy and anti-HER2 
therapies can also be linked to constitutive 
activation of the PI3K pathway[8]. Moreover, 
preliminary data suggest that activation of the 
PI3K pathway may be a predictor or poor 
prognostic outcome in many cancers. The 
dysregulation of the PI3K signaling pathway is 
implicated in many human cancers[9-13] and 
includes the inactivation of the PTEN tumor 
suppressor gene[14], amplification/overexpression or activating mutations of some receptor 
tyrosine kinases (e.g., erbB3, erbB2, EGFR), and amplification of genomic regions containing 
AKT or PIK3CA genes[11, 15]. A schematic representation of these PI3K components is shown 
in Figure 1. Together these observations suggest that the PI3K pathway could be a critical 
therapeutic target for the treatment of subjects with advanced solid malignancies who often 
have limited therapeutic options beyond institutional standard of care. 
 
 
 
Figure 1: The PI3K pathway regulates numerous cellular 
activities and overexpression of these proteins has been 
associated with a variety of cancers. 
 
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PI3K Aberrations in Breast Cancer 
 
Recent data shows that mutations/deregulations in the PI3K pathway are common in breast 
cancer. Gain-of-function mutations in oncogenes such as PIK3CA (encoding the catalytic 
subunit p110α have been observed in about 10% to 40% of BC subjects and are commonly 
observed in HR-positive (HR+) and triple-negative breast cancer (TNBC)[16, 17]. In activation of 
the tumor suppressor gene PTEN via loss-of-function mutations, gene deletion or transcriptional 
downregulation also leads to PI3K pathway activation and has been reported in 15-48% of BC 
subjects[18, 19]. Alternately, the PI3K pathway can be activated through various receptor 
classes or cross-talk with other pathways. For example, in HER-2 negative BC, specifically 
TNBC, the PI3K pathway appears to be modulated by the human epidermal growth factor 
receptor (EGFR). Preclinical models have demonstrated that EGFR signaling through the PI3K 
pathway leads to a higher level of Akt phosphorylation in TNBC cell lines[20-22]. Profiling of 
residual tumor tissue after neoadjuvant chemotherapy in subjects with TNBC revealed that 40% 
of the residual tumors demonstrated an aberration in PI3K/mTOR pathway, making it the most 
targetable aberration in chemoresistant TNBC[23]. Interestingly, TNBC cell lines have also been 
associated with lower expression of PTEN which correlates with increased activation of AKT 
and portends a favorable response to PI3K inhibition. Indeed, cell lines which are wild type for 
PIK3CA but have lost PTEN expression can be sensitive to a PI3K inhibitor[24] (Novartis 
internal data). These agents, therefore, represent an intriguing class of targeted anti-cancer 
therapy for subjects with HER-2 negative BC. The epidemiology data reported so far presents 
modest variation, however, based on these numbers, approximately 40% of TNBC subjects and 
40% of HER-2/HR+ BC subjects, respectively, should harbor a constitutively activated PI3K 
pathway (defined as mutation in the PIK3CA gene and/or PTEN gene and/or loss of PTEN 
expression by immunohistochemistry). The metastatic HER-2 negative population is likely to be 
enriched for subjects/tumors with PI3K pathway aberrations, making this an attractive target to 
test in the metastatic setting. 
 
Overview of BYL719/Alpelisib 
 
BYL719/Alpelisib is an oral, class I PI3Kα-specific inhibitor belonging to the 2-aminothiazole 
class of compounds. BYL719/alpelisib strongly inhibits the PI3Kα isoform (both the p110α wild 
type and p110α mutation+) and is significantly less active against the other class I isoforms β, δ, 
and γ. In addition, it is inactive against the majority of other kinases. Targeting the alpha isoform 
of PI3K is expected to reduce the potential for inducing treatment-related toxicity and improve 
the therapeutic window over inhibitors with less isoform specificity. In vitro, BYL719/alpelisib has 
been shown to inhibit the proliferation of cell lines harboring PIK3CA mutations. 
 
BYL Preclinical Efficacy in Breast Cancer Cell Lines 
 
Several preclinical studies have demonstrated activity of class I PI3K inhibitors in HR+/HER-2 
negative and basal-like/TNBC cell lines[25-27]. In xenograft models, PI3K/AKT inhibitors 
demonstrated activity against basal-like cancers and luminal breast cancer[28]. 
 
Pharmacodynamics of BYL719/Alpelisib 
 
 
  
 
 
 
 
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Nonclinical PK and Metabolism of BYL719/Alpelisib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Safety of BYL719/Alpelisib [CBYL719X2101] 
 
 
 
 
 
 
 
 
 
 
 
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1.3 
Nab-Paclitaxel (Nab-Paclitaxel) 
Taxanes are very active therapeutic agents in both early and advanced stage TNBC. Nab-
Paclitaxel is a solvent-free, nanoparticle, albumin-based paclitaxel with activity in breast cancer. 
Nab-Paclitaxel was developed to take advantage of the antitumor activity of paclitaxel while 
decreasing or eliminating the toxicities typically associated with the solvent (Cremophor) used to 
administer the most common formulation of paclitaxel[29]. A phase III trial of Nab-Paclitaxel 
administered every three weeks in MBC showed improved response rates and time to 
progression (TTP) compared to solvent-based paclitaxel given every three weeks. Weekly Nab-
Paclitaxel (150 mg/m2) and every three-week Nab-Paclitaxel (300 mg/m2) were found to have 
improved response rates and improved TTP compared to docetaxel in terms of efficacy. Nab-
Paclitaxel is an approved chemotherapy for the treatment of advanced stage breast cancer and 
has demonstrated activity even in subjects with tumor progression on traditional paclitaxel[30]. 
 
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Due to its formulation, Nab-Paclitaxel also does not require steroid premedication and has a 
short infusion time, which makes it easy to combine with other agents[31]. 
1.4 
Rationale 
Although taxanes are effective early on in advanced stage breast cancer, resistance often 
develops. While the exact mechanism(s) underlying the development of treatment resistance 
towards taxanes remain largely unknown, it has been demonstrated that activation of the 
PI3K/Akt pathway confers resistance to paclitaxel[32] and that increased Akt activity may be an 
early compensatory mechanism of resistance to chemotherapy[33]. Additionally, in preclinical 
models, concomitant inhibition of the PI3K pathway enhances the efficacy of taxanes as 
compared to each agent given separately[32]. This provides a rationale for studying a 
combination of a taxane with PI3K inhibitor in breast cancer. An ongoing randomized phase II 
study is evaluating a Class I PI3K inhibitor (BKM120) in combination with paclitaxel in the first 
line setting in HER-2 negative MBC (NCT01572727). However, taxanes are often used beyond 
first line setting in MBC, thus, providing a rationale for studying a combination of PI3K inhibitor 
and a taxane beyond the first line setting. We propose a phase Ib/II study of BYL719/alpelisib 
(PI3Kα-specific inhibitor) in combination with Nab-Paclitaxel.  
1.5 
Correlative Studies 
 
 
  
 
  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 For Phase I, determine the Recommended Phase II Dose (RPTD) of 
BYL719/alpelisib + Nab-Paclitaxel to be used in combination for treatment of 
advanced HER-2 negative breast cancer 
2.1.2 For Phase II, assess Overall Response Rate (ORR) of subjects treated at the 
RPTD 
2.2 
Secondary Objectives  
2.2.1 Determine Clinical Benefit Rate (CBR) at 16 weeks of study treatment for 
subjects treated at the RPTD 
2.2.2 Assess PK of BYL719/alpelisib when administered with Nab-Paclitaxel 
2.2.3 Assess the PK of Nab-Paclitaxel when administered with BYL719/alpelisib 
2.2.4 Determine Progression-Free Survival (PFS) and Overall Survival (OS) 
2.3 
Exploratory Objectives 
2.3.1 Investigate the correlation of PI3K aberrations with clinical response 
 
 
 
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2.4 
Endpoints 
 
Primary Endpoints: Recommended Phase II Dose of BYL719/alpelisib in combination 
with Nab-Paclitaxel (Phase I); Overall Response Rate of treated subjects (Phase II) 
according to RECIST v1.1 criteria 
 
Secondary Endpoints: Phase II: Percentage of subjects that have achieved complete 
response, partial response or stable disease as a result of treatment (CBR), PK of 
BYL719/alpelisib and Nab-Paclitaxel individually when given in combination, average 
progression free survival (PFS) and overall survival (OS) time in days 
 
Exploratory Endpoints: Assessment of molecular status of subject tumor tissue (archival 
primary tumor, metastatic tumor or new pre-treatment tumor biopsies), including 
PIK3CA, PTEN and KRAS mutations, PTEN protein expression by IHC, PI3K 
amplification and Akt phosphorylation  
 
3.0 
SUBJECT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
 
3.1.1 Ability to understand and the willingness to sign a written Informed Consent 
Form. 
3.1.2 Age ≥ 18 years  
3.1.3 Histologically proven HER-2 negative breast cancer (HER-2 negative defined as 
HER IHC 0 or 1+ and/or HER-2 FISH negative); HER-2 negative breast cancer 
includes hormone positive (ER and/or PR positive) breast cancer and TNBC 
3.1.4 HER-2 negative breast cancer that at the time of study entry is either stage III 
(locally advanced) disease not amenable to curative therapy or stage IV disease. 
Histological confirmation of recurrent/metastatic disease is encouraged but not 
required if clinical evidence of stage IV disease is available 
3.1.5 Have measurable (defined as at least one lesion that can be accurately 
measured in at least one dimension [longest diameter to be recorded] with 
minimum lesion size of ≥ 2 cm on conventional measurement techniques or ≥ 1 
cm on spiral computed tomography (CT) scan 
3.1.6 No limitations to number of prior chemotherapies for metastatic disease. 
Treatment with prior taxanes (except Nab-Paclitaxel) is allowed as long as it has 
been 6 months or more since exposure to prior taxane. 
NOTE:  For subjects who are, or who have previously received endocrine 
therapy for breast cancer, the treating investigator will decide how many days 
should pass between the last dose of endocrine therapy and the first dose of 
study treatment. 
3.1.7 All patients should have received at least one line of chemotherapy in either the 
advanced or adjuvant setting and hormonal therapy (where appropriate) 
3.1.8 Performance status of 2 or better as per ECOG criteria (See Appendix A for 
details) 
 
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3.1.9 Subject is able to swallow and retain oral medicines 
3.1.10 Adequate marrow and organ function as defined below (labs must be performed 
within 14 days of subject registration) 
• 
Absolute neutrophil count ≥ 1500/uL 
• 
Platelets 100,000/uL (no transfusion allowed within 2 weeks) 
• 
Hemoglobin > 9 g/dL (which may be reached by transfusion) 
• 
Total bilirubin within normal range or ≤ 1.5X IULN if liver metastases are 
present or total bilirubin ≤ 3.0X IULN with direct bilirubin within normal 
range in subjects with well-documented Gilbert’s Syndrome, which is 
defined as presence of unconjugated hyperbilirubinemia with normal 
results from CBC (including normal reticulocyte count and blood smear), 
normal liver function test results and absence of other contributing 
disease processes at the time of diagnosis 
• 
AST(SGOT)/ALT(SPGT) ≤ 2.5X IULN or ≤ 5X IULN if liver metastases are 
present 
• 
Serum creatinine ≤ 1.5X IULN 
• 
INR ≤ 1.5 
• 
Fasting plasma glucose ≤ 140 mg/dL or 7.8 mmol/L  
(NOTE:  Fasting whole blood glucose testing is acceptable if fasting 
plasma glucose is not feasible.) 
• 
HBA1c ≤ 8% 
• 
Potassium, calcium (corrected for serum albumin) and magnesium within 
IULN 
• 
Serum Amylase < 2 x ULN and serum lipase within normal limits 
3.1.11 IV bisphosphate and denosumab for bony metastatic disease will be allowed 
3.1.12 Prior palliative radiation therapy to bony metastases is allowed. There should be 
a minimum of 14 days between the end of radiation treatment and start of study 
treatment 
3.1.13 Subjects with previously treated brain metastases who are free of CNS 
symptoms and are > 3 months from treatment of brain metastases are eligible 
Subjects should be > 2 weeks from prior systemic chemotherapy for breast 
cancer AND should have recovered to Grade 1 or better (except alopecia) from 
related side effects of any prior antineoplastic therapy prior to study entry  
NOTE:  For subjects who are, or who have previously received endocrine 
therapy for breast cancer, the treating investigator will decide how many days 
should pass between the last dose of endocrine therapy and the first dose of 
study treatment. 
3.1.14 Women of child bearing potential (WOCBP) and their partners must agree to use 
adequate contraception (barrier method of birth control; abstinence) prior to study 
entry, for the duration of study participation, and for 90 days following completion 
of therapy. After confirmation of negative pregnancy test at screening, should a 
WOCBP become pregnant or suspect that she is pregnant while participating in 
 
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this study, she should inform her treating physician and the investigator 
immediately. 
• 
WOCBP are defined as any females (regardless of sexual orientation, 
having undergone tubal ligation, or remaining celibate by choice) who 
meet the following criteria: 
o Have not undergone a hysterectomy or bilateral oophorectomy 
OR 
o Have not been naturally postmenopausal for at least 12 
consecutive months (i.e. has had menses at any time in the 
preceding 12 consecutive months) 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
3.2.1 Subject has any other medical or psychiatric disorder that, in the opinion of the 
treating physician, would contraindicate the use of drugs in this protocol or place 
the subject at undue risk for treatment complications 
3.2.2 Subject is pregnant or lactating 
3.2.3 Subject has previously been treated with Nab-Paclitaxel  
NOTE:  Subjects who have had previous treatment with Nab-Paclitaxel will NOT 
be excluded if given in the adjuvant or neoadjuvant setting   
Only in the metastatic setting, will subjects previously treated with Nab-Paclitaxel 
be excluded from this trial.  Exceptions may be made for subjects who 
discontinued treatment with a previous Nab-Paclitaxel inhibitor for reasons other 
than progression and as long as it has been > 12 months since discontinuation of 
the previous Nab-Paclitaxel. This exception will require prior approval from the 
study PI at KUMC. 
3.2.4 Subject has inflammatory breast cancer 
3.2.5 Subject has a known hypersensitivity to any of the excipients of Nab-Paclitaxel or 
BYL719/alpelisib 
3.2.6 Subject has a concurrent malignancy or malignancy within 3 years of study 
enrollment (with the exception of adequately treated, basal or squamous cell 
carcinoma, non-melanomatous skin cancer or curatively resected cervical 
cancer) 
3.2.7 Subject has clinically manifest diabetes mellitus or documented steroid-induced 
diabetes mellitus 
3.2.8 Subject has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g. ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel 
resection) 
3.2.9 Subject is classified into Child-Pugh class C 
3.2.10 Subject has a known history of HIV infection (testing not mandatory) 
3.2.11 Subject has active, uncontrolled infection 
 
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3.2.12 Subject has symptomatic/untreated CNS disease 
3.2.13 Subject has ≥ Grade 2 peripheral neuropathy 
3.2.14 Subject has active cardiac disease or a history of cardiac dysfunction including 
any of the following: 
• 
Unstable angina pectoris within 6 months prior to study entry 
• 
Symptomatic peritonitis 
• 
Documented myocardial infarction within 6 months prior to study entry 
• 
History of documented congestive heart failure (New York Heart 
Association functional classification III-IV) 
• 
Documented cardiomyopathy 
• 
Subject has a Left Ventricular Ejection Fraction (LVEF) < 50% as 
determined by Multiple Gated Acquisition (MUGA) scan or 
echocardiogram (ECHO) 
• 
Subject has any of the following cardiac conduction abnormalities 
• 
Ventricular arrhythmias except for benign premature ventricular 
contractions 
• 
Supraventricular and nodal arrhythmias requiring a pacemaker or not 
controlled with medicine 
• 
Conduction abnormality requiring a pacemaker 
• 
Other cardiac arrhythmia not controlled with medication 
3.2.15 Subject has a QTcF > 480 msec on the screening ECG (using the QTcF formula) 
3.2.16 Subject is currently receiving treatment with a medication that has a known risk 
to prolong the QT interval or induce Torsades de Pointes and the treatment 
cannot be discontinued or switched to a different medication prior to 
randomization 
3.2.17 Subject has had major surgery within 14 days prior to starting study drug or has 
not recovered from major side effects 
3.2.18 Subject is currently receiving or has received systemic corticosteroids ≤ 2 weeks 
prior to starting study drug or who have not fully recovered from side effects of 
such treatment 
3.2.19 Subject is currently receiving treatment with drugs known to be moderate or 
strong inhibitors or inducers of isoenzyme CYP3A. The subject must have 
discontinued strong inducers for at least one week and must have discontinued 
strong inhibitors before the start of treatment 
3.2.20 Subject is currently receiving warfarin or other coumarin-derived anti-coagulant 
for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular 
weight heparin (LMWH), or fondaparinux is allowed 
3.2.21 Subject has received previous treatment with a PI3K inhibitor. Exceptions may be 
made for subjects who discontinued treatment with a previous PI3K inhibitor for 
reasons other than toxicity or progression and as long as it has been > 12 
 
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months since discontinuation of the previous PI3K inhibitor. This exception will 
require prior approval from the study PI at KUMC.   
3.2.22 Subjects who have received an investigational agent within 30 days OR within 5 
half-lives of the investigational agent (whichever is shorter) prior to the possible 
enrollment date on this study. 
3.2.23 Subject with history of acute within one year of study entry or past medical 
history of chronic pancreatitis.  
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
• 
Standard 3+3 design for Phase I portion with three dose levels of 
BYL719/alpelisib (250 mg, 300 mg, 350 mg PO Q day D1-28 every 28 days) and 
one dose level of Nab-Paclitaxel (100 mg/m2 IV D1,8,15 +/- 1 day every 28 days) 
• 
If starting dose of 250 mg of BYL719/alpelisib is not tolerated, it is permissible to 
lower the starting dose to 200 mg 
 
 
 
Table 1: Dose Escalation Scheme 
 
 
 
 
 
• 
Required study treatment will continue for a minimum of 6 cycles in subjects with 
stable disease/PR/CR). In subjects with stable disease/PR/CR after 6 cycles of 
treatment, subjects can either continue both study drugs until disease 
progression/unacceptable toxicity or Nab-Paclitaxel can be stopped (at the 
discretion of the treating physician) but subjects will continue BYL719/alpelisib 
until disease progression/unacceptable toxicity. Potential dose modifications for 
Nab-Paclitaxel will be specified in more detail in section 5.5. Growth factor 
support will be allowed at the discretion of the treating physician. 
 
Drug 
Premedications 
Dose 
Route 
Schedule 
Cycle Length 
BYL719/alpelisib 
None 
250 mg, 300 
mg, or 350 
mg 
Oral 
D1 to 28, 
every 28 days 
4 weeks (28 
days) 
Nab-Paclitaxel 
Benadryl 25 mg 
to 50 mg PO/IV; 
Tylenol 650 mg 
PO, Zofran 4 mg 
IV 
100 mg/m2 
Benadryl can 
be PO/IV; 
Tylenol is PO, 
Zofran is IV 
D1, 8, and 15 
+/- 1 day 
every 28 days 
4 weeks (28 
days) 
 
4.2 
BYL719/Alpelisib Administration Instructions 
BYL719/alpelisib tablets will be supplied by Novartis Pharmaceuticals. The tablets will be 
administered orally on a daily schedule (QD). At each visit, responsible site personnel will 
ensure that the appropriate dose of each study drug is administered at the clinic and will provide 
the subject with the correct amount of BYL719/alpelisib for subsequent dosing. Subjects will be 
instructed to return unused BYL719/alpelisib study drug to the site at each visit. 
 
 
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The following guidelines should be followed for BYL719/alpelisib administration: 
• 
Subjects should be instructed to take one or more tablets of BYL719/alpelisib together 
with a glass of water (~250 ml or ~8 fluid ounces) daily in the morning approximately 1 
hour after start of breakfast (not including grapefruit or grapefruit-based juice) at 
approximately the same time each day (recommended 8AM +/- 1 hour), except on days 
that blood collection is scheduled at the clinic; subjects will take their doses at clinic on 
those days. There are no restrictions on the composition or caloric intake of the 
breakfast meal. 
• 
Subjects should not eat for 1 hour after the administration of BYL719/alpelisib. 
• 
If by noon the subject forgets to take the study drug (BYL719/alpelisib), 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 subject should still take the scheduled morning 
dose of study drug with a glass of water. If this happens on days of PK sampling, it 
should be documented in the eCRF. 
• 
Subjects should be instructed to swallow the tablets and not to chew or crush them. 
• 
Subjects 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. 
• 
Subjects should record if the dose was taken or not in the subject diary. 
• 
If vomiting occurs during the course of treatment, no re-dosing of the subject is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting/diarrhea 
(or increase in stool frequency) within the 24 hours post-dosing on that day must be 
noted in a separate section of the eCRF. 
• 
Subjects 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 the potential 
CYP3A interaction. Regular orange (Citrus X sinensis) juice is allowed. 
 
On the days of Nab-Paclitaxel administration, BYL719/alpelisib should be taken 1 hour prior to 
the infusion of Nab-Paclitaxel. 
 
• FPG Monitoring: On the days of FPG monitoring, subjects must be fasting overnight for 
at least 8 hours prior to the blood collection. Breakfast may be consumed after FPG 
draw. BYL719/alpelisib may be administered 1 hour after the start of breakfast. Subjects 
should continue to fast for 1 hour after the administration on the days of Nab-Paclitaxel 
administration. 
o NOTE:  Fasting whole blood glucose testing is acceptable if fasting plasma 
glucose is not feasible. 
• PK Sampling: On the days of PK sampling, subjects must be fasting overnight for at 
least 8 hours prior to breakfast to achieve light fed conditions. Pre-dose PK sample 
should be collected just prior to BYL719/alpelisib intake. BYL719/alpelisib should be 
consumed/taken 1 hour prior to the Nab-Paclitaxel administration on the days of Nab-
Paclitaxel administration. 
• Any doses that are missed should be skipped and should not be replaced or made up 
during the next scheduled dosing or on a subsequent day, whichever applies 
• Subjects must avoid consumption of grapefruit, grapefruit juice (Citrus paradise) and 
Seville orange juice (Citrus aurantium) during the entire study and preferably 7 days 
before the first dose of study medications due to potential CYP3A4 interaction with the 
study drug combination. Regular orange juice (Citrus sinensis) is allowed. 
• Subjects should be instructed to swallow the tablets whole and not to chew or crush 
them. 
 
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• If vomiting occurs during the course of treatment, no re-dosing of the subject is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting and/or 
diarrhea (or increase in stool frequency) should be noted. In addition, on the days of full 
PK sampling, the onset time of any episodes of vomiting and diarrhea (or increased stool 
frequency) within the first 4 hours post-dosing on that day should also be noted. 
4.3 
Nab-Paclitaxel Administration Instructions 
Nab-Paclitaxel will be obtained from each center’s commercial supply. Nab-Paclitaxel is 
supplied as a sterile lyophilized powder for reconstitution before use. Avoid errors, read 
entire preparation instructions prior to reconstitution. 
 
1. Aseptically, reconstitute each vial by injecting 20 ml of 0.9% sodium chloride 
injection, USP. 
 
2. Slowly inject the 20 ml of 0.9% sodium chloride injection, USP, over a minimum of 1 
minute, using the sterile syringe to direct the solution flow onto the inside wall of the 
vial. 
 
3. DO NOT INJECT the 0.9% sodium chloride injection, USP, directly onto the 
lyophilized cake as this will result in foaming. 
 
4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to 
ensure proper wetting of the lyophilized cake/powder. 
 
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs. Avoid generation of foam. 
 
6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam 
subsides. Each mL of the reconstituted formulation will contain 5 mg/mL Nab-
Paclitaxel. Calculate the exact total dosing volume of 5 mg/mL suspension required 
for the subject: Dosing volume (mL) = Total dose (mg)/5 (mg/mL). 
 
The reconstituted suspension should be milky and homogenous without visible 
particulates. If particulates or settling are visible, the vial should be gently inverted again 
to ensure complete resuspension prior to use. Discard the reconstituted suspension if 
precipitates are observed. Discard any unused portion. 
 
Inject the appropriate amount of reconstituted Nab-Paclitaxel into an empty, sterile 
intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type 
intravenous bag]. The use of specialized DEHP-free solution containers or 
administration sets is not necessary to prepare or administer Nab-Paclitaxel infusions. 
The use of an in-line filter is not recommended. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. 
 
Dose-Limiting Toxicity (DLT) AND Maximally Tolerated Dose (MTD) 
Toxicity will be assessed using the NCI CTCAE, version 4.03 unless otherwise specified. A DLT 
is defined as an AE or abnormal laboratory value assessed as at least possibly related to the 
study medication, which occurs ≤ 28 days following the first dose of BYL719/alpelisib (Cycle 1) 
and meets any of the criteria listed in Table 3. Whenever a subject experiences toxicity that 
 
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fulfills the criteria for a DLT, treatment with the study drug will be stopped and the toxicity will be 
followed. For the purposes of dose escalation and determination of the MTD, the evaluation 
period for DLTs will be during the first cycle.  Toxicity monitoring in the Phase I will follow the 
stopping rules in the 3+3 design.  Toxicity monitoring in the Phase II will follow the Bayesian 
Sequential Monitoring design as described in section 13.3.   
 
Recommended Phase 2 dose (RP2D) 
The Recommended Phase 2 dose (RP2D) is defined as the next lower dose level below MTD 
(dose at which patients experienced a DLT). 
 
Table 3: Criteria For Determining Dose-Limiting Toxicities 
 
Toxicity 
DLT criteria 
Blood and lymphatic 
system disorders 
Grade 4 neutropenia lasting for > 7 days or CTCAE Grade 4 neutropenia associated 
with fever (> 38.5oC) 
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 
Fatigue CTCAE Grade 3 for > 7 consecutive days 
Skin and subcutaneous 
tissue disorders; Rash 
and Photosensitivity 
Rash or photosensitivity CTCAE Grade 3 for > 7 consecutive days despite skin 
toxicity treatment 
Rash or photosensitivity CTCAE Grade 4 
Metabolism and nutrition 
disorders: Hyperglycemiab 
Hyperglycemia Grade 2 (FPG 200-250 mg/dL) [11.2-13.8 mmol/L] confirmed with a 
repeat FPG within 24 hrs that does not resolve to Grade 0 (FPG < 160 mg/dL) [< 
7.8mmol/L] within 14 consecutive days after initiation of oral anti-diabetic treatment. 
Hyperglycemia Grade 3 (FPG 250-399 mg/dL)[13.9-22.2 mmol/L] confirmed with a 
repeat FPG within 24 hrs (whether related to use of steroid therapy or not); lasting > 
72 hrs despite adequate antidiabetic therapy. 
Hyperglycemia Grade 4 (FPG > 400 mg/dL) [> 22.3 mmol/L] 
Hyperglycemia leading to diabetic keto-acidosis, hospitalization for IV insulin 
infusion, or non-ketotic coma 
 
NOTE:  Fasting whole blood glucose testing is acceptable if fasting plasma glucose 
is not feasible. 
GI disordersa 
Diarrhea CTCAE Grade > 3 for > 48 hrs despite the use of anti-diarrhea therapy 
Nausea/vomiting CTCAE Grade > 3 for > 48hrs despite the use of anti-emetic 
therapy 
Pancreatitis CTCAE Grade > 3 
Eye disorders 
CTCAE Grade > 3 
 
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Investigationsc 
Blood bilirubind CTCAE Grade > 3 
AST or ALT CTCAE Grade > 3, in conjunction with blood bilirubind 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 > 3 
Platelet count CTCAE Grade 3 for > 7 consecutive days and/or signs of bleeding 
Platelet count CTCAE Grade 4 
Hypomagnesemia CTCAE Grade 3 for > 3 consecutive days and not correctable with 
supplements or symptomatic 
Hypomagnesemia CTCAE Grade 4 
Other hematologic and 
non-hematologic toxicities 
> Grade 3 mood alteratione 
Any other CTCAE > Grade 3 toxicity except lymphocyte count decrease 
(lymphocytopenia) CTCAE Grade > 3 unless clinically significant 
a Subjects will not initially receive prophylactic treatment for skin toxicity or nausea/vomiting for BYL719/alpelisib 
during Cycle 1.  However, prophylactic treatment may be initiated in all subjects at the dose level where these 
toxicities have been observed and in all further subjects if at least 1 (one) subject has experienced skin toxicity or 
nausea/vomiting CTCAE Grade > 3 or if at least 2 (two) subjects experienced skin toxicity or nausea/vomiting 
CTCAE Grade > 2.  However anti-emetics may be applied for treatment if the subject has experienced 
nausea/vomiting CTCAE Grade    > 1 at the discretion of the physician. 
b Not according to CTCAE v4.03.  Of note: Hyperglycemia occurring during corticosteroids administration will be 
only considered a DLT if not resolved within 2 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.  If baseline laboratory value is elevated (or decreased) prior to 
drug therapy, an increase (or decrease) will not be considered a DLT unless there is a worsening by at least 2 
toxicity grades. 
d Refers to total bilirubin 
e To be assessed for DLT status by physical examination and subject history 
 
NOTE: Apart from criteria listed above, if a lower grade AE leads to a dose interruption of more than 7 consecutive 
days of BYL719/alpelisib, this AE may be considered as a DLT. 
 
Follow up for toxicity 
 
Subjects whose treatment is delayed or permanently discontinued due to an AE or clinically 
significant laboratory value must be followed up with at least once a week (or more frequently if 
required by institutional practices, or if clinically indicated) for 4 weeks, and subsequently at 
approximately 4 week intervals until resolution or stabilization of the event, whichever comes 
first. All subjects must be followed for AEs and SAEs for 30 days following the last doses of 
BYL719/alpelisib. Subjects exhibiting hypomagnesaemia, hypocalcaemia, and/or hypokalemia 
should receive electrolyte replacement as indicated by national and institutional guidelines and 
must be followed until laboratory values have normalized or as clinically indicated.  
4.4 
Dose Modifications 
4.4.1 Dose modifications 
For subjects who do not tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to allow the subject to continue the study 
treatment. All dose modifications should be based on the worst preceding toxicity 
 
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(CTCAE version 4.03). If a subject experiences a DLT, study treatment should be 
interrupted and the toxicity should be followed. 
4.4.2 Treatment Interruption and Treatment Discontinuation 
At the discretion of the investigator, a one week delay prior to starting a new 
cycle maybe requested to accommodate patient travel or schedule burdens. 
The criteria for dose modifications of BYL719/alpelisib for toxicities considered at 
least “possibly-related” to the study medication treatment are outlined in Table 4. 
If a subject requires a dose delay of > 28 consecutive days of BYL719/alpelisib, 
then the subject should be discontinued from the study treatment. In exceptional 
situations, if the subject is clearly benefitting 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 subject may remain on the 
study treatment. Subjects who discontinue from the study for a study-related AE 
or an abnormal laboratory value must be followed. 
For each subject, a maximum of two (2) dose reductions will be allowed after 
which the subject will be discontinued from the study treatment. In addition, a 
subject 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 4 and the same toxicity reoccurs with the same severity, next 
treatment re-initiation must resume at the next lower dose level irrespective of 
duration. 
For each subject, once a dose level reduction of BYL719/alpelisib has occurred, 
the dose level may not be re-escalated during subsequent treatment cycles with 
the study drugs. Dose reduction for BYL719/alpelisib means treatment at the 
next lower, previously tested respective dose level of BYL719/alpelisib. 
4.5 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each subject 
will be assessed for the development of toxicity according to the Schedule of Events table 
contained within Section 6.4. Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTACAE), version 4.03. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity. 
 
 
 
 
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Table 4: Dose Adjustment and Management Recommendations: BYL719/alpelisib 
 
Adverse Drug Reaction 
Severity 
Dose Adjustment and Management 
Recommendations 
Hematology 
ANC < 500/uL without 
fever and/or platelets < 
75000/uL 
Hold BYL719/alpelisib until ANC is > 500/uL and 
platelet count is > 75,000/uL. If treatment delay is 
< 7 days, restart at same dose.  If treatment delay 
is > 7 days drop 1 dose level. 
ANC < 1000/uL with 
fever ( > 38.3oC) or 
sustained fever > 38 oC 
for more than 1 hour 
Hold BYL719/alpelisib until ANC is > 1000/uL. If 
treatment delay is < 7 days, restart at same dose. 
If treatment delay is > 7 days, drop 1 dose level. 
Cardiac – QTc prolongation 
QTcF > 500 ms (> 
Grade 3) or > 60 ms 
change from baseline 
on at least two separate 
ECGs.  
First Occurrence: 
Omit BYL719/alpelisib 
Perform a repeat ECG within one hour of the first 
QTcF of > 500 ms or > 60 ms from baseline.  If 
QTcF remains > 500 ms or > 60 ms from 
baseline, repeat ECG as clinically indicated, but at 
least once a day until the QTcF returns to < 480 
ms. 
Seek cardiologist input, address electrolytes, 
calcium and magnesium abnormalities; 
concomitant medication must be reviewed.  Once 
QTcF prolongation has resolved, BYL719/alpelisib 
may be restarted at the next lowest dose. 
Second Occurrence: 
Permanently discontinue subject from 
BYL719/alpelisib 
Cardiac – Left Ventricular 
systolic dysfunction 
Asymptomatic, resting 
ejection fraction 40-
50%; or 10-20% drop 
from baseline 
Maintain dose level and continue BYL719/alpelisib 
with caution;  
Repeat LVEF within 4 weeks or as clinically 
appropriate 
Symptomatic, 
responsive to 
intervention, ejection 
fraction 20-39% or > 
20% drop from baseline 
Omit BYL719/alpelisib until resolved (subject is 
asymptomatic, has a resting ejection fraction > 
40% and < 20 % decrease from baseline), then 
drop 1 (one) dose level 
Refractory or poorly 
controlled, ejection 
fraction < 20% 
Permanently discontinue subject from 
BYL719/alpelisib 
Cardiac Events 
(other than QTc prolongation or 
left ventricular systolic 
dysfunction) 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to < Grade 1, then lower 
1 (one) dose level 
Grade 4 
Permanently discontinue subject from 
BYL719/alpelisib 
Diarrhea 
Please see Appendix G for 
guidelines for study drug-
induced diarrhea management 
Grade 1 
Maintain dose level 
Grade 2 
Omit dose until resolved to < Grade 1, then restart 
at same dose. 
> Grade 3 
Omit dose until resolved to < Grade 1, then drop 1 
(one) dose level. 
Eye disorders 
> 3 ocular/vision 
symptoms interfering 
with activities of daily 
life or requiring 
medication intervention 
Discontinue subject from BYL719/alpelisib 
 
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Hepatic – bilirubin 
(*For subjects with Gilbert 
Syndrome; these dose 
modifications apply to changes 
in direct bilirubin only) 
Grade 1 (>IULN – 1.5 x 
IULN) 
Maintain dose level with LFTs* monitored as per 
protocol 
Grade 2 (> 1.5 – 3.0 x 
IULN) with ALT or AST 
< 3.0 x IULN)  
Omit dose until resolved to < Grade 1, then: if 
treatment delay is < 7 days, restart at same dose. 
If resolved in > 7 days, drop 1 (one) dose level. 
Grade 3 (> 3.0 - 10.0 x 
IULN) with ALT or AST 
< 3.0 x IULN)  
Omit dose until resolved to < Grade 1, then: if 
treatment delay is < 7 days, restart at same dose. 
If resolved in > 7 days, discontinue subject from 
BYL719/alpelisib 
Grade 4 (>10.0 x IULN) 
Permanently discontinue BYL719/alpelisib 
Hepatic – AST or ALT 
Grade 1 (> IULN – 3.0 x 
IULN) 
Maintain dose level with LFTs monitored per 
protocol 
Grade 2 (>3.0 – 5.0 x 
IULN) without total 
bilirubin elevation to > 
2.0 X IULN 
Omit dose until resolved to < Grade 1. If treatment 
delay is < 7 days, restart at same dose. If 
resolved in > 7 days, drop 1 (one) dose level.  In 
subjects with pre-existent AST/ALT elevation 
(>3.0 – 5.0 x IULN) due to metastatic disease to 
liver, maintain dose level with LFTs monitored per 
protocol. 
Grade 3 (> 5.0 – 20.0 x 
IULN) without bilirubin 
elevation to > 2.0 x 
IULN 
Omit dose until resolved to < Grade 1 then drop 1 
(one) dose level. 
Hepatic - AST or ALT and 
concurrent Bilirubin                        
Note:   *LFTs include albumin, 
ALT, AST, total bilirubin 
(fractionated if total bilirubin > 
2.0 X ULN), alkaline 
phosphatase (fractionated if 
alkaline phosphatase is grade 2 
or higher) and GGT.                      
Hepatic toxicity monitoring (*for 
subjects with Gilbert Syndrome:  
total and direct bilirubin must be 
monitored, intensified 
monitoring applies to changes in 
direct bilirubin only; the 
monitoring includes the 
following LFTs:  albumin, ALT, 
AST, total bilirubin (fractionated 
if total bilirubin > 2.0 X ULN), 
alkaline phosphatase 
(fractionated if alkaline 
phosphatase is Grade 2 or 
higher) and GGT):                         
In case of any occurrence of 
ALT/AST/bilirubin* increase > 
Grade 2, the LFTs must be 
monitored weekly or more 
frequently if clinically indicated 
until resolved to < Grade 1.           
In case of any occurrence of 
ALT/AST/bilirubin* increase > 
Grade 3, the LFTs must be 
monitored weekly or more 
frequently if clinically indicated 
until resolved to < Grade 1; 
AST or ALT > 3.0 x 
IULN and total bilirubin 
> 2.0 x IULN 
Permanently discontinue BYL719/alpelisib 
 
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hereafter the monitoring should 
be continued every other week 
or more frequently if clinically 
indicated until the end of 
treatment with study medication.   
Subjects who discontinued 
study treatment should be 
monitored weekly, including 
LFTs* or more frequently if 
clinically indicated until resolved 
to < Grade 1 or stabilization (no 
CTCAE grade change over 4 
weeks). 
Hyperglycemia - Fasting Plasma 
Glucose (FPG)                              
NOTE:  A diabetologist 
consultation should always be 
considered.  Based on current 
experience, hyperglycemia 
usually resolves within a few 
days after BYL719/alpelisib 
omission.  Temporary omission 
of BYL719/alpelisib may be 
considered as clinically 
indicated to improve control of 
hyperglycemia. Special attention 
should be paid to the risk of 
hypoglycemia in subjects’ 
interruption BYL719/alpelisib 
treatment and receiving insulin 
or sulfonylurea. 
NOTE:  Fasting whole blood 
glucose testing is acceptable if 
fasting plasma glucose is not 
feasible. 
Grade 1 (> ULN - 160 
mg/dL) [> ULN - 8.9 
mmol/L] confirmed 
within 24 hours 
Continue BYL719/alpelisib dosing and maintain 
the current dose level.  As per Investigator's 
discretion, initiate or intensify medication with 
appropriate anti-diabetic treatment such as oral 
anti-hyperglycemic therapy (e.g. metformin).  
Check FPG as clinically indicated and at least 
weekly for 8 weeks, then continue checking at 
least every 2 weeks. 
Asymptomatic Grade 2     
(> 160 - 250 mg/dl)           
[> 8.9 - 13.9 mmol/L] 
Maintain dose level and recheck within 24 hours.     
If grade worsens or improves, follow specific 
recommendations.  If grading is confirmed, 
continue BYL719/alpelisib dosing.  Initiate or 
intensify medication with appropriate anti-diabetic 
treatment such as oral anti-hyperglycemic therapy 
(e.g. metformin).  As per Investigator's discretion, 
consider adding a second oral agent if no 
improvement after several days.  Monitor FPG as 
clinically indicated and at least weekly until FPG 
resolves to < Grade 1.  If FPG does not resolve to 
< Grade 1 within 14 days after institution of 
appropriate anti-diabetic treatment, reduce 
BYL719/alpelisib by 1 (one) dose level.  Continue 
with anti-diabetic treatment and check FPG 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/alpelisib and recheck within 24 
hours.  If grade worsens or improves, follow 
specific recommendation.  If grading is confirmed, 
omit BYL719/alpelisib dosing.  Consider 
administering intravenous hydration and 
intervention for 
electrolyte/ketoacidosis/hyperosmolar 
disturbances as clinically appropriate.  Initiate or 
intensify medication with appropriate anti-diabetic 
treatment (consider adding insulin) as per 
investigator's discretion.  Monitor FPG as clinically 
indicated and at least twice weekly until FPG 
resolves to < Grade 1.  If FPG resolves to Grade 
1 within 14 days, then restart BYL719/alpelisib 
and reduce 1 (one) dose level.  If FPG doesn't 
resolve to Grade 1 within 14 days, then 
discontinue subject from BYL719/alpelisib.  
Continue with anti-diabetic treatment and check 
FPG at least weekly for 8 wks; then continue 
checking at least every 2 wks. 
Grade 4 (> 500 mg/dL)  
[> 27.8 mmol/L] OR 
Grade 3 with signs or 
symptoms of 
Omit BYL719/alpelisib, initiate or intensify 
medication with appropriate anti-diabetic 
treatment (consider adding insulin), recheck within 
24 hours.                   If grade improves, then 
 
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hyperglycemia (i.e. 
mental status changes, 
excessive thirst, 
polyuria) 
follow specific grade recommendations.  If FPG is 
confirmed at Grade 4, discontinue subject from 
BYL719/alpelisib. 
Pancreatitis 
Grade > 3 
Discontinue subject from BYL 719 
Photosensitivity 
Grade 1 
Maintain dose level 
Grade 2 
Omit dose until resolved to < Grade 1.  If not 
resolved in < 7 days, reduce 1 (one) dose level.   
If resolved in > 7 days discontinue 
BYL719/alpelisib. 
Grade > 3 
Discontinue subject from BYL 719 
Serum Creatinine 
< 2 X IULN 
Maintain dose level 
2- 3 X IULN 
Omit dose until resolved to < Grade 1.   If 
treatment delay is < 7 days, restart at same dose.  
If not resolved in > 7 days, then reduce 1 (one) 
dose level. 
Grade 3 (>3.0 - 6.0) X 
IULN 
Permanently discontinue subject from 
BYL719/alpelisib 
Grade 4 (>6.0 X IULN) 
Permanently discontinue subject from 
BYL719/alpelisib 
Stomatitis/Oral Mucositis 
Grade 1/Tolerable 
Grade 2 
Maintain dose level. Non-alcoholic or salt water 
mouth wash 
Intolerable Grade 2 or 
Grade 3 
First occurrence hold until < Grade 1 and reduce 
1 (one) dose level. (If stomatitis is readily 
manageable with optimal management, re-
introduction at the same level might be considered 
at the discretion of the investigator). 
Grade 4 
Permanently discontinue subject from BYL 719 
All other adverse events (except 
pneumonitis, see pneumonitis 
management guidelines below) 
Grade 1 or 2 
Maintain dose level 
 
Grade 3 
Omit dose until resolved to < Grade 1; then 
reduce 1 (one) dose level. 
 
Grade 4 
Permanently discontinue subject from 
BYL719/alpelisib.                                              
Note:  Omit dose for > Grade 3 vomiting or Grade 
3 nausea only if the vomiting or nausea cannot be 
controlled. 
 
Management Guidelines for Macropapular Rash 
Grade              
(CTCAE v4.03) 
Actions and recommended concomitant medications 
Grade 1 
  
Maintain BYL719/alpelisib dosing. 
Initiate antihistamine dosing. Recommend non-sedating regimen (e.g. hydroxyzine 25 
mg bid) for at least 28 days 
Topical corticosteroid preparation**BID for affected areas for at least 28 days. 
Grade 2 
  
  
  
  
Maintain BYL719/alpelisib dosing. 
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. 
 
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Oral corticosteroid (recommend prednisone 0.5-0.75 mg per kg QD or equivalent 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 in 14 days, continue or re-administer oral corticosteroid 
(recommend prednisone 0.5-0.75mg/kg QD or equivalent for 10 days; longer periods 
of dosing require tapered dosing). 
If hyperglycemia has been noted previous to initiating corticosteroid dosing, continue 
daily finger stick and change FPG monitoring to twice weekly and adjust oral anti-
glycemic regimen according to hyperglycemia management guidance as needed with 
corticosteroid dosing (per study protocol). 
Grade 3 and 
intolerable Grade 2 
• 
Hold BYL719/alpelisib 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 0.5-0.75mg/kg QD or equivalent 
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 
(recommend prednisone 0.5-0.75mg/kg QD or equivalent) until resolved and 
BYL719/alpelisib is restarted. 
• 
If hyperglycemia has been noted previous to initiating corticosteroid dosing, 
continue daily fingerstick and change FPG monitoring to twice weekly and adjust oral 
antiglycemic regimen according to hyperglycemia management guidance as needed 
with corticosteroid dosing (per study protocol).   
• 
A dose reduction of one dose level is recommended if this is a second 
occurrence.  Dose reduction is not necessary following the first occurrence of Gr 3 or 
intolerable Gr 2 rash.  
• 
Upon rechallenge with BYL719/alpelisib (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 for a 
minimum of 28 days after rechallenge with BYL719/alpelisib.   
Grade 4  
Permanently discontinue BYL719/alpelisib 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/alpelisib should be permanently discontinued.) 
 
**Topical corticosteroid preparation recommended regimens 
 
• 
For face and/or intertriginous areas (including genitalia) recommend alclometasone 
0.05% of hydrocortisone 2.5% creams 
• 
For other body areas (i.e. trunk and extremities), recommend clobetasol or 
betamethasone 0.05% creams. Consider a spray preparation for ease of application on 
trunk. For scalp involvement, consider a foam preparation. 
 
 
 
 
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Management of pneumonitis  
1. Document review of baseline CT to confirm no relevant pulmonary complications are 
present 
2. 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). Specific questions should be asked regarding the occurrence of: cough, 
dyspnoea, shortness of breath, fatigue, and/or fever. 
3. Patients who are suspected to have developed pneumonitis [as evidenced by CXR 
findings or symptoms present] should undergo further appropriate imaging (high 
resolution CT scan) and consider a broncho-alveolar lavage for biopsy. Early 
consultation with a pulmonologist is mandatory. 
4. Patients with suspected pneumonitis should stop all study medications immediately. 
BLY719 must not be restarted in patients with a confirmed diagnosis of pneumonitis. 
5.  Infectious causes of interstitial lung disease should be ruled out. 
6. Investigators should follow institutional practice for management of pneumonitis which 
generally include treatment with high dose corticosteroids; antibiotic therapy should be 
administered concurrently if infectious causes have not been ruled out. 
7. The study drugs should be permanently discontinued and the risk of the occurrence of 
pneumonitis with other agents should be considered. 
 
Table 5: Dose Adjustment and Management Recommendations: Nab-Paclitaxel. The following 
guidelines should be considered for dose modifications for AEs that are suspected to be caused 
by Nab-Paclitaxel 
 
Toxicity 
Treatment Modification 
ANC < 1,000/μl on Day 
1,8,15 of a treatment cycle 
Hold Nab-Paclitaxel until ANC ≥ 1,000μl. Repeat counts at least weekly. 
Resume when counts have recovered, according to the following guidelines:      
IF ANC recovers to > 1,000/μl in ≤ 1 week, retreat at current dose.                      
IF ANC recovers to ≥ 1,000/μl after 1-3 weeks, the dose should be reduced by 
20% for subsequent cycles.                                                                                   
IF ANC < 1,000/μl after the 3-week delay, remove subject from Nab-Paclitaxel 
treatment.               
Platelets < 75,000/μl on Day 
1, 8, 15 of a treatment cycle 
Hold Nab-Paclitaxel until platelets are ≥ 75,000/μl.                                               
IF platelets recover to ≥ 75,000/μl in ≤ 1 week, retreat at the current dose.          
IF platelets recover to ≥ 75,000 /μl after 1-3 weeks, Nab-Paclitaxel should be 
given at 20% dose reduction for subsequent cycles.                                             
IF the platelet count fails to recover to ≥ 75,000/ μl within 3 weeks, remove the 
subject from Nab-Paclitaxel treatment but continue to follow the subject on 
study.                                                                
 (NOTE:  See below for dose modifications for Grade 3-4 thrombocytopenia). 
Febrile Neutropenia*  
Grade 3 
Day 1, 8, 15 of a treatment 
cycle 
At the discretion of the investigator, subsequent cycles may be given at either:   
1) full doses, but with prophylactic ciprofloxacin 500 mg PO BID or an 
alternative prophylactic antibiotic regimen of the investigator's choice, or            
2) a 20% dose reduction of Nab-Paclitaxel (either with or without prophylactic 
antibiotics).                                                                                         IF a 
second episode occurs, Nab-Paclitaxel will be reduced by 20% (based on the 
current dose) when chemotherapy is resumed in all subsequent cycles.              
IF a third episode occurs, remove the subject from Nab-Paclitaxel therapy and 
continue to follow the subject on study. 
Grade 3-4 
Thrombocytopenia 
Day 8, 15 of a treatment cycle 
Appropriate supportive care will be instituted.  The dose of Nab-Paclitaxel will 
be reduced by 20% (based on the current dose) for subsequent cycles. 
 
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*Febrile neutropenia is defined as: ANC < 1000/uL and a single temperature of > 38.3oC (101oF) or a 
sustained temperature of > 38oC (100.4o F) for more than one hour..                                                                      
1.  There will be no dose modifications for lymphopenia.                                
2.  There will be no dose modifications for Grade 2-4 anemia.  Transfusions will be given as clinically 
indicated. 
 Other Toxicities 
Treatment Modification 
In cases of Grade 2                  
non-hematologic AE (except 
alopecia) that are persistent 
despite medical management. 
Consider holding Nab-Paclitaxel until event resolves to Grade 1 or better, 
then re-introduce at a 20% reduced dose. 
Other toxicities Grade 3 
Hold therapy until recovery to < Grade 1.  At the discretion of the investigator, 
dose of Nab-Paclitaxel will either be resumed at full dose or reduced by 20%.  
If the Grade 3 toxicity occurred or recurred despite appropriate supportive 
measures, reduce the dose of Nab-Paclitaxel by 20% for subsequent cycles.  
If more than 3 weeks is required for recovery, remove the subject from the 
Nab-Paclitaxel portion of the protocol therapy, but continue to follow the 
subject on study. 
Other toxicities Grade 4 
Discontinue Nab-Paclitaxel treatment.  (If the investigator wishes to continue 
therapy, treatment may continue with a 20% dose reduction and institution of 
appropriate supportive measures with the consent of the KUCC Principal 
Investigator).  Subjects will continue to be followed on study. 
Patients with dose limiting cardiac events such as MI or unstable angina or dose-limiting neurological events 
such as stroke > Grade 3 should not be retreated. 
4.6 
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 those physician-prescribed medications, but also all over-the-
counter medications, herbal medications, and nutritional or vitamin supplements. Subjects will 
be instructed to notify the study site about any new medications he/she takes after starting study 
drug. Subjects taking medicine chronically should be maintained on the same dose and 
schedule throughout the sample period, as medically feasible. The days of full PK 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 PK 
sampling if medically feasible. 
 
Permitted Concomitant Therapy: In general, the use of any concomitant 
medication/therapies deemed necessary for the care of the subject is permitted, except 
as specifically prohibited in Section 4.6.2. 
Anti-emetics 
Use of anti-emetics is allowed. It is recommended that subjects use drugs that do not 
cause QT prolongation. Please note that some anti-emetics have a known risk for TdP 
and are prohibited (refer to Appendix B, Table 2) 
 
 
 
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Bisphosphonates and Denosumab 
The use of bisphosphonates and denosumab regardless of indication is allowed 
provided subjects have been on stable doses for at least two weeks prior to study entry. 
Stable dose should be maintained during the treatment period. Subjects 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 subjects’ source documentation. 
Oral anti-diabetics 
Subjects who develop diabetes mellitus during the study should be treated according to 
the ADA (American Diabetes Association) guidance. It is recommended to start 
treatment with glimepiride, glibenclamide, or metformin. Subjects receiving oral anti-
diabetics 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/alpelisib was found to be a moderate reversible 
inhibitor of these enzymes.  
4.6.1 Permitted Concomitant Therapy Requiring Caution and/or Action 
Hematopoietic Growth Factors 
Hematopoietic growth factors (e.g. erythropoietins, G-colony stimulating factor (G-CSF) 
and GM-CSF) are not to be used prophylactically in cycle one. Use of erythropoietins 
should be reserved to subjects with severe anemia as per the labeling of these agents or 
as dictated by local practice. Prophylactic use of G-CSF will be allowed after cycle one 
at the discretion of the treating physician. 
Anticoagulants 
Anticoagulants other than warfarin/coumarin derivates (for this, refer to Section 4.6.3) or 
anti-aggregation agents may be administered under the discretion of the investigator. 
However, caution is advised when BYL719/alpelisib is co-administered with anti-platelet 
pro-drugs such as clopidogrel, ticlopidine and prasugrel, which require metabolic 
activation by CYP3A4, CYP2C9 and CYP2C19. BYL719/alpelisib has the potential to 
inhibit these enzymes and may therefore decrease the metabolic activation and clinical 
efficacy of these pro-drugs. Subjects using anti-platelet/pro-drugs should be carefully 
monitored. 
Contraceptives 
Hormonal contraceptives may be affected by cytochrome P450 interactions and are 
therefore not considered effective for this study. For allowed contraceptive methods, 
refer to section 3.1.15. Highly effective contraception should be maintained throughout 
the study and for 90 days after study drug discontinuation. 
CYP450 Substrates 
In vitro studies demonstrate that BYL719/alpelisib may be a strong inhibitor of CYP3A4. 
BYL719/alpelisib may increase exposure to drugs metabolized by CYP3A4 by more than 
5-fold. BYL719/alpelisib may also inhibit the metabolic clearance of co-medications 
metabolized by CYP2C8, CYP2C9, and CYP2C19, if sufficiently high BYL719/alpelisib 
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 B, Table 1). Subjects receiving such medications must 
be carefully monitored for potential toxicity due to any individual concomitant 
medications. Particularly, caution is advised when BYL719/alpelisib is co-administered 
 
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with drugs that are sensitive substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 
and which have a narrow therapeutic index. Caution is advised when BYL719/alpelisib is 
coadministered 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. Subjects receiving BYL719/alpelisib and opioid analgesics should be 
carefully monitored. Synthetic opioids with clinically relevant interactions with CYP3A4 
inhibitors include, but are not limited to, propoxyphene, fentanyl, alfentanyl and 
sufentanil. Use of alfentanyl, a sensitive CYP3A4 substrate with narrow therapeutic 
window, should be fully avoided whenever possible. The use of methadone and 
levomethadyl is prohibited (refer to Appendix B, Table 2). 
Drugs With a Conditional or Possible Risk to Induce Torsade de Pointes/QT 
Prolongation 
If a subject enrolled in the study requires the concomitant use of any medication with a 
possible or conditional risk for TdP (see Appendix B, Table 3 for a list of such 
medications), then investigators, at their discretion, may co-administer such medications. 
Subjects receiving such medications must however be monitored. Note: please refer 
also to Appendix B, Table 3 for a list if prohibited QT prolonging medication. 
Gastric Protection Agents 
BYL719/alpelisib and buparlisib are characterized by a pH-dependent solubility. 
Medicinal products that alter the pH of the upper gastrointestinal tract may alter the 
solubility of BYL719/alpelisib and hence, its bioavailability. These agents include, but are 
not limited to, proton-pump inhibitors (PPI) (e.g. omeprazole, H2-antagonists (e.g. 
ranitidine) and antacids. Due to long PD effect of PPIs, i.e. long-lasting reduction of 
gastric acid production over 36 hours, H2-antagonists and antacids are recommended to 
be used over PPIs whenever possible. Note that some proton pump inhibitors may 
possibly also inhibit BCRP (refer to Appendix B, Table 4). BYL719/alpelisib 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. 
BCPR Inhibitors 
BYL719/alpelisib was identified as a substrate for human BCRP. Coadministration of 
BYL719/alpelisib with BCRP inhibitors may possibly increase systemic exposure and/or 
alter tissue uptake of oral BYL719/alpelisib. The treatment with BCRP inhibitors should 
be kept as short as possible or if possible, fully avoided. See Appendix B, Table 4 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 subjects 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 PD, subjects should discontinue treatment. No 
dose modification of study treatment is needed during radiotherapy. 
 
 
 
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4.6.2 Prohibited Concomitant Therapy 
Other Investigational and Antineoplastic Therapies 
Other investigational therapies must not be used while the subject is on the study. 
Anticancer therapy (chemotherapy, biologic or radiation therapy and surgery) other than 
the study treatments must not be given to subjects while the subject is on the study 
medication. If such agents are required for a subject, then the subject must be 
discontinued from the study. 
Drugs With a Known Risk for Torsades de Pointes/QT Prolongation 
If a subject enrolled in the study requires the concomitant use of any medication 
included in Appendix B, Table 2, 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/alpelisib administration must be 
interrupted as long as the subject requires therapy with the QT prolonging agent. Note 
that Appendix B, Table 2 also prohibits drugs that are substrates for CYP3A and CYP2C 
with a possible or conditional risk for TdP. If the subject requires long-term therapy with 
such a QT prolonging agent, leading to study treatment interruption of > 21 days, the 
subject must be permanently discontinued from BYL719/alpelisib. 
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. 
Subjects should stop using these herbal medications 7 days prior to first dose of study 
drug. 
Warfarin and Coumarin Derivatives 
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin derivative 
anticoagulants are not permitted. Warfarin has a narrow therapeutic range and 
BYL719/alpelisib is a possible inhibitor or CYP2C8 and 2C9, the major metabolizing 
enzyme of warfarin. Therapeutic anticoagulation may be accomplished using low 
molecular weight heparin.  
4.7 
Duration of Therapy 
Subjects will be treated for 6 cycles, a complete treatment cycle being defined as 28 days 
during which BYL719/alpelisib is taken daily on days 1-28 and Nab-Paclitaxel is administered on 
days 1, 8, and 15 +/- 1 day. In subjects with stable disease/PR/CR after 6 cycles of treatment, 
subjects can either continue both study drugs until disease progression/unacceptable toxicity or, 
Nab-Paclitaxel can be stopped (at the discretion of the treating physician) but subjects will 
continue BYL719/alpelisib until disease progression/unacceptable toxicity. 
 
Treatment may be stopped at any time during the schedule if any of the following occur: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Death 
• 
Subject decision to withdraw from the study, OR 
• 
General or specific changes in the subject’s condition which render the subject 
unacceptable for further treatment in the judgment of the investigator 
 
 
 
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4.8 
Duration of Follow-Up 
Subjects will be followed for 30 days after removal from treatment or until death, whichever 
occurs first. A follow-up visit will be scheduled 30 (+/-) days post-end of treatment. Subjects 
removed from treatment for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
4.9 
Removal of Subjects From Protocol Therapy  
Subjects will be removed from therapy when any of the criteria listed in Section 5.4 apply. 
Notification will be sent to the Principal Investigator and documentation of the reason for study 
removal and the date the subject was removed will be reported in the Case Report Form within 
5 days of removal. The subject should be followed per protocol. Subjects who are removed from 
protocol therapy due to disease progression or toxicity will be counted as a treatment failure in 
the efficacy analysis. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline and All Study Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining Informed Consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
Informed Consent was obtained. 
 
All lab screening procedures must be performed within 14 days prior to registration unless 
otherwise stated. All other screening procedures must take place within 30 days. The screening 
procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical, surgical and oncology history as well as history of infections 
are obtained at screening. Any changes from screening (e.g. worsening severity 
or abnormal findings) are considered to be adverse events (AEs). 
5.1.3 Demographics 
Demographic profile will include date of birth, gender, race, ethnicity and zip 
code. 
5.1.4 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3.0 to ensure subject 
qualification for study entry. 
5.1.5 Review previous and concomitant medications 
All prior medication taken by the subject within 30 days before starting the study 
is to be recorded. At minimum, the start year of the medication should also be 
recorded. Concomitant medications taken by the subject during the study are to 
be recorded up until 30 days after last study dose. If a reportable adverse event 
(see Section 6.0) occurs within 30 days after last study dose, recording of 
concomitant medications should continue until resolution of the adverse event. 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight, and 
assessment of all major body systems 
 
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5.1.7 Performance status 
Subject performance status based on ECOG criteria (Zubrod scale) will be 
evaluated prior to study entry and possibly during study. Specific criteria for 
assessing performance status can be found in Appendix A. 
5.1.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See 
Section 6.0 for Adverse Event monitoring and reporting. 
5.1.9 Hematology 
Hematology to include hemoglobin (Hgb), platelets, red blood cells, white blood 
cells and differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils) 
5.1.10 Serum chemistries 
Serum chemistry to include: albumin, alkaline phosphatase, ALT, AST, GGT, 
bicarbonate, calcium, chloride, creatinine,  potassium, sodium, calcium, 
magnesium, total bilirubin (direct must be collected only in case total bilirubin is 
elevated > IULN, total protein, BUN or urea. 
5.1.11 Fasting Plasma Glucose (FPG) 
FPG will be assessed at screening and on days 8, 15, 22 for cycle 1 and 2, then 
day 1 for each subsequent cycle and at EOT. Subjects must be fasting overnight 
for at least 8 hours prior to the blood draw. The study personnel will ask the 
subject whether he or she has been fasting, which will be recorded in the eCRF. 
NOTE:  Fasting whole blood glucose testing is acceptable if fasting plasma 
glucose is not feasible. 
5.1.12 Hemoglobin A1C 
Hemoglobin A1C will be measured at screening, then on day 1 of every three 
cycles starting on Day 1 Cycle 3 and then again at the end of treatment 
5.1.13 Coagulation 
International normalized INR will be measured at screening and then as clinically 
indicated 
5.1.14 C-Peptide  
C-Peptide will be measured on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, and 
then again at the end of treatment 
5.1.15 Insulin (IRI) 
Insulin (IRI) will be measured on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1,  
and then again at the end of treatment 
5.1.16 Blood draw for correlative studies 
See Section 8.1.1 for details. 
5.1.17 Pregnancy test (for women of child bearing potential) 
See Section 3.1.15 for definition.  
 
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5.1.18 ECG 
Must be performed D-30 to D-1, D1 for cycles 2 – 6 and at end of treatment only. 
5.1.19 MUGA/ECHO 
Subjects must have a Left Ventricular Ejection Fraction (LVEF) of > 50% as 
determined by MUGA scan or ECHO. 
5.1.20 Ophthalmologic Evaluation  
A slit lamp exam must be performed at screening for all subjects and then as 
clinically indicated. 
5.2 
Procedures During Treatment 
5.2.1 Screening/Enrollment 
No more than 30 days prior to treatment start date: 
• Signing of Informed Consent Form 
• Medical History/Current Medical Conditions 
• Demographics 
• Inclusion/Exclusion Criteria Screening 
• Concomitant Medications 
• Physical Exam 
• Performance Status 
• Pregnancy Test 
• ECHO 
• ECG 
• Tumor assessment by RECIST v1.1 criteria 
• Ophthalmologic examination including a slit lamp examination 
 
No more than 14 days prior to treatment start date: 
• 
Hematology and Chemistry Labs 
• 
Fasting Plasma Glucose  
• 
Hemoglobin A1C 
• 
Coagulation Status (INR) 
• 
Pregnancy Test 
 
Note: For Cycle 1, all labs, procedures and exams from screening (as long as done 
within the specific time frame) are sufficient, with the exception of the physical exam, 
hematology/chemistry labs which must be done with 7 days of Day 1 Cycle 1. When 
subject starts subsequent cycles, labs, procedures and exams must be done at the start 
of the cycle +/- 3 days. A window of + / - 3 days for protocol requirements on Days 8, 15, 
and 22 (if applicable, is allowed if needed). 
5.2.2 Day 1, Cycle 1 
• BYL719/alpelisib Dispensing 
• BYL719/alpelisib Dosing 
• Nab-Paclitaxel Administration 
• PK Sampling (only for Phase I subjects) 
• Study Labs (C-peptide and insulin) 
NOTE:  ECG done during screening will be used for Cycle 1. 
 
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5.2.3 Days 2-7, Cycle 1 
• BYL Dosing 
5.2.4 Day 8, Cycle 1 
• Hematology and Chemistry Labs 
• Fasting Plasma Glucose (Fasting whole blood glucose testing is 
acceptable if fasting plasma glucose is not feasible.) 
• BYL719/alpelisib Dosing 
• Nab-Paclitaxel Administration 
• Study Drug Compliance 
NOTE:  Laboratory assessments scheduled AFTER Cycle 1 Day 1 may be performed up 
to 24 hours BEFORE each visit, in order to facilitate subject fasting + eating breakfast at 
home before BYL dosing. 
5.2.5 Days 9-14, Cycle 1 
• BYL719/alpelisib Dosing 
5.2.6 Day 15, Cycle 1 
• Hematology and Chemistry Labs 
• Fasting Plasma Glucose (Fasting whole blood glucose testing is 
acceptable if fasting plasma glucose is not feasible.) 
• BYL719/alpelisib Dosing 
• Nab-Paclitaxel Administration 
• Study Drug Compliance 
5.2.7 Days 16-21, Cycle 1 
• BYL719/alpelisib Dosing 
5.2.8 Day 22, Cycle 1 
• Hematology and Chemistry Labs 
• Fasting Plasma Glucose (Fasting whole blood glucose testing is 
acceptable if fasting plasma glucose is not feasible.) 
• BYL719/alpelisib Dosing 
• Study Drug Compliance 
5.2.9 Days 23-28, Cycle 1 
• BYL719/alpelisib Dosing 
5.2.10 Repeat Cycle 1 for a total of 6 cycles, after which Nab-Paclitaxel may be 
stopped, but BYL719/alpelisib will continue until disease 
progression/unacceptable toxicity. (NOTE:  Please refer to Schedule of 
Events/footnotes for exceptions.) 
5.2.11 Safety follow-up phone call 30 days after treatment termination 
5.2.12 Survival follow-up by phone, e-mail, etc. every 3 months for 36 months.  
 
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5.3 
Schedule of Events 
 
Screening/Enrollment 
Cycle 1 and 2 (28 days each) 
 
D-30 to D1 
D-14 to D1 
D1 
D2-D7 
D8 
D9-D14 
D15 
D16-D21 
D22 
D23-
D28 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History/Current Medical 
Conditions 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
 
Ongoing 
Physical Exam 
X 
 
X 
 
 
 
 
 
 
 
Performance Status 
X 
 
X 
 
 
 
 
 
 
 
Hematologym 
  
X 
Xg 
  
X 
  
X 
 
X 
 
Chemistrym  
  
X 
Xg 
 
X 
  
X 
 
X 
 
Fasting Plasma Glucosem 
 
X 
X 
 
X 
 
X 
 
X 
 
Hemoglobin A1Cm 
 
Xc 
 
 
 
 
 
 
 
 
Coagulation (INR) m 
  
Xf 
  
  
  
  
  
 
 
 
C-Peptiden,m 
 
 
Xn 
 
 
 
 
 
 
 
Insulin (IRI)n,m 
 
 
Xn 
 
 
 
 
 
 
 
Pregnancy Test 
  
Xh 
  
  
  
  
  
 
 
 
Correlative Blood Draw  
  
X 
Xj  
  
  
  
  
 
 
 
Archived Tissue Collection  
Xi 
  
 Xi 
  
  
  
  
 
 
 
PK Samples 
  
  
Xk 
  
  
  
  
 
 
 
MUGA/ECHO 
X 
  
  
  
  
  
  
 
 
 
ECG 
Xl 
 
Xl 
 
 
 
 
 
 
 
Ophthalmologic Evolution  
X 
  
  
  
  
  
  
 
 
 
BYL719/alpelisib Dispensing 
  
  
Xd 
 
 
  
  
 
 
 
BYL719/alpelisib Dosing 
  
  
X 
 X 
X  
X 
X  
X 
X 
X 
Abraxane Administration 
  
  
X  
  
X  
 
X  
 
 
 
Subject Drug Compliance 
 
 
X 
 
X 
 
X 
 
X 
 
Tumor Assessment 
X 
  
Xe 
  
  
  
  
 
 
 
Adverse Events 
  
  
Ongoing 
 
 
 
 
 
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Cycle 3 – 6a (28 days each) 
Cycle 
7+ 
EOT 
Safety 
FU 
Surviv
al FU 
 
D1 
D2 to D7 
D8 
D9-D14 
D15 
D16-D21 
D22 
D23-D28 
D1 
 
30 
days 
post-
EOT 
Every 
3 mos 
for 36 
month
s 
Concomitant Medications 
 Ongoing 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology m 
 X 
  
 X 
  
  X 
  
 
 
X 
X 
 
 
Chemistrym   
 X 
 
 
 
 
  
 
 
X 
X 
 
 
Fasting Plasma Glucosem 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Hemoglobin A1Cm 
Xc 
 
 
 
 
 
 
 
 
X 
 
 
C-Peptide 
 Xn 
 
 
 
 
 
 
 
 
Xn 
 
 
Insulin (IRI) 
Xn 
 
 
 
 
 
 
 
 
Xn 
 
 
Pregnancy Test 
 X  
 
  
  
  
  
  
 
 
 
 
 
ECG 
Xl 
 
 
 
 
 
 
 
 
Xl 
 
 
Correlative Blood Draw m 
 Xj 
 
  
  
  
  
  
 
X 
Xj 
 
 
BYL719/alpelisib 
Dispensing 
 Xd 
  
 
 
 
  
  
 
X 
 
 
 
BYL719/alpelisib Dosing 
 X 
X  
 X 
 X 
  X  
X 
X  
X 
X 
 
 
 
Abraxane Administration 
X 
  
 X  
  
  X  
 
  
 
Xb 
 
 
 
Subject Drug Compliance 
X 
 
 X 
 
  X 
 
X 
 
X 
 
 
 
Tumor Assessment 
Xe 
  
 
  
  
  
  
 
Xe 
X 
 
 
Adverse Events 
Ongoing 
 
 
 
Safety Follow-Up via 
Phone Call 
 
 
X 
 
Survival Follow-Up via 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Calendar Legend 
 
a) Study treatment will continue for a minimum of 6 cycles in subjects with stable 
disease/PR/CR. 
b) After 6 cycles, Nab-Paclitaxel treatment can end, but BYL719/alpelisib will be continued 
until disease progression/unacceptable toxicity. If subject continues on both Nab-
Paclitaxel and BYL719/alpelisib, the hematology, chemistry and FPG monitoring for 7+ 
cycles will be similar to Cycles 3-6. 
c) After measurement at screening, Hemoglobin A1C will be measured every third cycle, 
starting Day 1 Cycle 3 and then again at end of treatment. 
d) BYL719/alpelisib will be dispersed for each cycle on Day 1. 
e) Tumor assessment per RECIST v1.1 after every even # cycle. See section 9 for details. 
NOTE:  For subjects who are on metformin and have been asked to hold metformin for 
full body scans, the treating physician may withhold the study drug (BYL719/alpelisib) on 
the days that metformin is withheld. 
f) International normalized INR will be measured at screening and then on Day 1 of each 
treatment cycle as clinically indicated. 
 
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g) These assessments are done in screening for Cycle 1, but should be performed on Day 
1 Cycle 2. 
h) All female subjects of child bearing potential must undergo a serum pregnancy test at 
screening. Women of child-bearing potential must additionally undergo a urine or serum 
pregnancy test on Day 1 of each cycle. 
i) Archived tumor block/20 unstained slides either from the primary or metastatic site will 
be collected. Subject can start study treatment even if the tumor tissue has not been 
collected. 
j) Blood samples will be collected at time of enrollment, prior to each treatment cycle 
starting from Cycle 2 and at the time of disease progression; see section 8.1.1 for further 
details. 
k) Only for Cycle 1 Day 1 for subjects in phase I portion of the study.  See section 8.2. 
l) Occurs during Day -30 to 1 and then on Day 1 of cycles 2, 3, 4, 5, 6, and at end of 
treatment only. 
NOTE:  ECG done during screening will be used for Cycle 1. 
m) All laboratory assessments scheduled AFTER Cycle 1 Day 1 may be performed up to 24 
hours BEFORE each visit, in order to facilitate subject fasting + eating breakfast at home 
before BYL dosing.  NOTE:  Fasting whole blood glucose testing is acceptable if fasting 
plasma glucose is not feasible. 
n) C-Peptide and Insulin (IRI) will be measured on Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 
Day 1, and then again at the end of treatment. 
5.4 
Removal of Subjects from Study Treatment and Study 
Subjects can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
5.4.1 Subject voluntarily withdraws from treatment (follow-up permitted); 
5.4.2 Subject withdraws consent (termination of treatment and follow-up); 
5.4.3 Subject is unable to comply with protocol requirements; 
5.4.4 Subject demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
5.4.5 Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.4.6 Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.4.7 Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event; see Section 6.0); 
5.4.8 Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.4.9 Lost to follow-up.  
If a research subject cannot be located to document survival after 3 attempts by 
mail and/or telephone, the subject may be considered “lost to follow-up” All 
attempts to contact the subject must be documented. 
 
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6.0 
ADVERSE EVENTS 
Text below in italics is verbatim from “Guidance for Industry and Investigators. Safety 
Reporting Requirements for INDs and BA/BE Studies”, issued December 2012 by U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research, and Center for Biologics Evaluation and Research.  The 
guidance may be retrieved from:  
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM227351.pdf?source=govdelivery. 
6.1 
Definitions 
6.1.1 Adverse Event [21 CFR 312.32(a)]  
An adverse event means any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, use 
in combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 
 
This study will use the descriptions and grading scales from Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.03) for hematologic and non-
hematologic toxicities.  Detailed information may be found on the Cancer Therapy 
Evaluation Program (CTEP) website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Information for adverse events, whether reported by the subject, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported in the CRF as described in the following sections.  
 
Adverse events experienced by subjects will be collected and reported from 
administration of the first dose of protocol therapy, throughout the study, and within 30 
days of the last dose of protocol therapy.  Subjects who experience an ongoing 
adverse event related to a study procedure and/or study medication beyond 30 days 
will continue to be contacted by a member of the study team until the event is 
resolved, stabilized, or determined to be irreversible by the principal investigator. Study 
subjects should also be instructed to report any new serious post-study event(s) that 
might reasonably be related to participation in this study. 
 
Medical conditions/diseases, or cancer related symptoms present before starting study 
treatment are considered adverse events only if they worsen after initial screening. 
Adverse clinical events occurring before starting study drug but after signing the 
Informed Consent form are to be recorded on the Medical History/Current Medical 
Conditions CRF. All cancer-related symptoms that have occurred in the last 30 days 
prior to start of study drug must also be recorded on this CRF. 
  
 
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Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, or require therapy.  In this case they will be recorded on 
the Adverse Events CRF, along with the associated signs, symptoms or diagnosis. 
As far as possible, each adverse event will also be described by: 
• 
its duration (start and end dates), 
• 
grading of severity, 
• 
its relationship to the study drug, 
• 
the action(s) taken,  
• 
outcome. 
6.1.2 Suspected Adverse Reaction [21 CFR 312.32(a)] 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug.  
 
Suspected adverse reactions are the subset of all adverse events for which there is a 
reasonable possibility that the drug caused the event. Inherent in this definition, and in 
the requirement to report suspected adverse reactions, is the need for the sponsor to 
evaluate the available evidence and make a judgment about the likelihood that the 
drug actually caused the adverse event.  
 
Factors to be considered in assessing the relationship of the adverse event to study 
drug include: 
• 
The temporal sequence from study drug administration: The event should occur 
after the study drug is given.  The length of time from study drug exposure to 
event should be evaluated in the clinical context of the event. 
• 
Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-
challenge): Subject’s response after drug discontinuation (de-challenge) or 
subject’s response after study drug re-introduction (re-challenge) should be 
considered in the view of the usual clinical course of the event in question. 
• 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated 
in the context of the natural history and course of the disease being treated and 
any other disease the subject may have. 
• 
Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of 
them may be suspected to cause the event in question. 
• 
The pharmacology and pharmacokinetics of the study drug: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the test drug(s), 
coupled with the individual subject’s pharmacodynamics should be considered. 
 
Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned as follows: 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Possible - The AE may be related to the study treatment.  
• 
Probable - The AE is likely related to the study treatment. 
• 
Definite - The AE is clearly related to the study treatment. 
 
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6.1.3 Unexpected [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application… "Unexpected," as used in this definition, also 
refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the Particular drug under investigation. 
 
This definition relies entirely on a listing of the adverse events or suspected adverse 
reactions in the investigator brochure…as the basis for determining whether newly 
acquired information generated from clinical trials or reported from other sources is 
unexpected. This means that events not listed for the Particular drug under 
investigation in the investigator brochure are considered “unexpected” and those listed 
are considered “expected.”  When new adverse event information is received, it is the 
sponsor’s responsibility to determine whether the event is “unexpected” for safety 
reporting purposes. 
6.1.4 Serious [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes: Death, 
a life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
6.1.5 Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the patient or 
patient at immediate risk of death. It does not include an adverse event or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
6.2 
Reporting Requirements for Adverse Events 
6.2.1 Submitting Serious Adverse Events Reports to IRB 
For serious adverse events, the clinical research site will follow local IRB policies and 
procedures.  
6.2.2 Study Investigator Notification of Adverse Events 
All expected and unexpected serious adverse events occurring after the subject has 
signed the Informed Consent and has started protocol treatment must be reported to the 
study principal investigator within 24 hours of becoming aware of the event: 
Priyanka Sharma, M.D. 
 
 
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6.2.3 DSMC Notification of SAEs 
All expected and unexpected serious adverse events occurring after the subject has 
signed the Informed Consent and has started protocol treatment must be reported by 
phone or email to the KUCC DSMC within 24 hours of becoming aware of the event to: 
KUCC DSMC 
 
 
 
 
A follow-up written report in the form of a MEDWATCH Form FDA 3500A is required 
within 5 days.  
6.2.4 Reporting to Novartis:  
 
 
 
 
 
 
 
 
: 
    
 
 
 
 
 
 
 
 
 
6.2.5 Pregnancies 
 
 
 
 
 
 
 
 
 
 
. 
 
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6.2.6 Submitting IND Safety Reports to FDA 
The investigator-sponsor must report in an IND safety report any suspected adverse 
reaction that is both serious and unexpected. Before submitting this report, the sponsor 
needs to ensure that the event meets all three of the definitions contained in the 
requirement:  
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected  
If the adverse event does not meet all three of the definitions, it should not be submitted 
as an expedited IND safety report. 
 
The following reports require expedited reporting.  
• 
unexpected fatal or life-threatening adverse experiences associated with the use 
of the drug are to be reported by telephone or fax no later than 7 calendar days 
after initial receipt of the information [21 CFR 312.32(c)(2)] 
• 
any adverse experience associated with the use of the drug that is both serious 
and unexpected is to be reported in writing no later than 15 calendar days after 
initial receipt of the information [21 CFR 312.32(c)(1)] 
6.2.7 Recording Adverse Events and Documentation in VELOS 
All expected and unexpected adverse events and serious adverse events occurring 
after the patient has signed the Informed Consent and has started protocol treatment 
must be fully recorded in the subject’s case record form. 
 
All AEs and SAEs regardless of causality must be entered in the KU implementation of 
eVELOS, called the Comprehensive Research Information System (CRIS).  All SAEs 
regardless of causality must be entered into CRIS within 24 hours.  Unexpected and 
expected adverse events must be entered within 5 days and include:  new unexpected 
adverse events; worsening baseline conditions; clinically significant laboratory findings; 
disease-related signs and symptoms that were not present at baseline, and any event of 
findings that the Investigator feels is clinically significant. 
 
Documentation must be supported by an entry in the subject’s file.  A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged relevant 
by the investigator, should be reported as an adverse event.  Each event should be 
described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome. 
6.2.8 Reporting of Unexpected, Related SAEs for Concomitant Medications 
For concomitant medications, all unexpected, related serious adverse experiences will 
be forwarded to the product manufacturer by the investigator using the Voluntary 
MEDWATCH Form FDA 3500. 
 
 
 
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6.2.9 Summary of Expedited Serious Adverse Event Reporting 
 
Relationship 
to Study Drug 
KUCC DSMC 
& Novartis 
 
IRB 
PI 
VELOS 
Unexpected 
SAE 
Related 
24 hrs 
Follow local 
IRB reporting 
requirements 
24 hrs 
24 hrs 
Unexpected 
SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 
Expected 
SAE 
Related 
24 hrs 
24 hrs 
24 hrs 
Expected 
SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 
 
7.0 
DRUG INFORMATION 
7.1 
BYL719/Alpelisib 
Please refer to the current Investigator’s Brochure for more comprehensive information. 
 
• 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
  
7.2 
Nab-Paclitaxel 
7.2.1 Description 
Nab-Paclitaxel is a novel biologically interactive albumin-bound paclitaxel combining a 
protein with a chemotherapeutic agent in the particle form. This composition provides a 
novel approach of increasing intratumoral concentration of the drug by a receptor-
 
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mediated transport process allowing transcytosis across the endothelial cell wall, thereby 
breaching the blood/tumor interface. This albumin-specific receptor-mediated process 
involves the binding of a specific receptor (gp60) on the endothelial cell wall, resulting in 
activation of a protein caveolin-1, which initiates an opening in the endothelial wall with 
formation of little caves or caveolae, with transport of the albumin-bound 
chemotherapeutic complex via these caveolae to the underlying tumor interstitium. A 
protein specifically secreted by the tumor (SPARC) binds and entraps the albumin, 
allowing release of the hydrophobic drug to the tumor cell membrane. Nab-Paclitaxel is 
the first biologically interactive nanoparticle leveraging this gp-60/caveolin-1/SPARC 
pathway to increase intratumoral concentration of the drug and reducing toxic drug in 
normal tissue. Nab-Paclitaxel is an antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for interphase and mitotic 
cellular function. 
7.2.2 Drug Interactions 
The metabolism of Nab-Paclitaxel is catalyzed by CYP2C8 and CYP3A4. Thus, Nab-
Paclitaxel metabolism may be modified by drugs that induce, inhibit or are metabolized 
by cytochromes P2C8 and P3A4 
7.2.3 Toxicity/Side Effects 
• 
Neutropenia is the dose-limiting hematologic toxicity 
• 
During organogenesis, Nab-Paclitaxel is embryotoxic and fetotoxic 
• 
Hypersensitivity reactions are rare, but can occur 
• 
Neurotoxicity (parasthesias, dysthesias, pain) 
• 
Thrombocytopenia and anemia 
• 
Infections and febrile neutropenia 
• 
Bradycardia and hypotension 
• 
Abnormal ECG changes 
• 
Nausea/Vomiting/Diarrhea 
• 
Mucositis 
• 
Alopecia 
• 
Transaminase or bilirubin elevation 
• 
Arthralgias/myalgias  
7.3 
Drug Accountability/Subject Compliance 
Records of study medications used, dosages administered, and intervals between visits 
will be kept during the study. Subjects will be asked to fill out a pill diary and bring with 
them for review after each cycle of study treatment. Drug accountability will be noted at 
the completion of the trial. Subjects will be asked to return all unused medication at the 
end of the study. Drug compliance will be calculated based on documentation of study 
drug dispensed vs. study drug returned. 
7.4 
Return and Retention of Study Drug 
 
 
 
 
 
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8.0 
CORRELATIVES/SPECIAL STUDIES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 
Pharmacokinetic Sampling and Analysis 
Samples for PK will be obtained through an intravenous line (IV line/port used for 
delivery of chemotherapy can be used for PK samples after adequate flushing) on Day 1 
Cycle 1 only for subjects participating in the Phase I portion of the study. Blood samples 
will be collected in K3EDTA heparin tubes. A baseline blood sample will be obtained 
prior to BYL719/alpelisib and Nab-Paclitaxel administration. Oral dosing with 
BYL719/alpelisib will occur one hour prior to the start of Nab-Paclitaxel administration. 
Subjects will receive 100 mg/m2 Nab-Paclitaxel as a 30 minute infusion. Blood samples 
 
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for bioanalysis for both Nab-Paclitaxel and BYL719/alpelisib will be obtained at the end 
of infusion, at 30 minutes and at 1, 1.5, 2, 4, and 6 hours after the end of infusion.  
 
Window for PK draw times will be as follows: 
• 
+/- 5 min windows for the 0.5 and 1 hour draws 
• 
+/- 10 min for 1.5 – 4 hour draws 
• 
+/- 20 for the 6 hour draws 
 
Plasma preparation of Samples will be processed according to the KU Cancer Center 
Correlative Laboratory Standard Operating Procedures (See Appendix C). 
 
 
 
 
 
 
 
 
 
 
 
  
 
9.0 
MEASUREMENT OF EFFECT 
9.1 
Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) committee[34]. 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST v1.1 criteria. 
9.1.1 Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of their first 
treatment with study drug. 
 
Evaluable for objective response. Only those subjects who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response. These subjects will 
have their response classified according to the definitions stated below. (Note: Subjects 
who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
9.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques (CT, MRI, x-ray, PET scan) or as >10 mm with spiral CT scan. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
 
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Note: Previously irradiated lesions are non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm with conventional techniques or <10 mm using spiral CT 
scan), are considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-
measurable. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ and 6 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on 
the basis of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). A sum of the 
longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 6 target lesions should be identified as non-target lesions 
and should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up.  
9.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 30 days before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
 
The following radiologic and clinical assessments will be performed 
• 
Chest, abdomen and pelvic CT at screening and at each subsequent tumor 
assessment. The preferred radiologic technique is CT with intravenous (IV). If a 
subject is known to have a contraindication to CT contrast media or develops a 
contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed. 
• 
A full body scan at screening for bone lesions according to institutional guidelines 
(e.g. Tc-99 bone scan, whole body bone MRI or positron emission tomography 
(PET)). If such a scan was already done during the regular work up of the subject 
within 6 weeks prior to the start of treatment, this scan can be considered as the 
screening scan for this study. After screening, scans need not be repeated, unless 
clinically indicated. If indicated, the same methodology as at screening should be 
used. 
 
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• 
If brain metastases are suspected, brain CT or MRI scan at screening. Brain CT or 
MRI will be continued at subsequent tumor assessments if brain lesions are 
identified at screening. 
Clinical assessment of any existing superficial lesions (skin nodules and palpable lymph 
nodes) at screening and at each subsequent tumor assessment. CT or MRI of any other 
lesion not captured by any of the above listed images (e.g. neck) at screening and at 
each subsequent tumor assessment as clinically indicated.  
9.2 
Response Criteria 
9.2.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by 
two separate observations conducted not less than 4 weeks apart. There can be 
no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD. There 
can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment 
started, or the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
9.2.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-
target lesion(s) and/or maintenance of tumor marker level above the normal 
limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
9.2.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
 
 
 
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Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
Note: If subjects respond to treatment and are able to have their disease 
resected, the subject’s response will be assessed prior to the surgery. 
9.3 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.  
 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started.  
9.3.1 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment until objective tumor progression or death. Subjects who do not 
experience objective tumor progression or death during the evaluation period, or 
are lost to follow-up, will be censored on the date they were last known to be 
alive and without objective tumor progression. 
9.3.2 Time to Progression 
Time to progression is defined as the duration of time from start of treatment until 
objective tumor progression. Subjects who do not experience objective tumor 
 
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progression during the evaluation period will be censored on the date of death, 
lost to follow-up, or were last known to be without objective tumor progression.   
9.3.3 Overall Survival 
Overall survival is defined as the duration of time from start of treatment to death. 
Subjects who do not experience death during the evaluation period, or are lost to 
follow-up, will be censored on the date they were last known to be alive. 
9.3.4 Safety/tolerability 
Analyses will be performed for all subjects having received at least one dose of 
study drug. The study will use the CTCAE version 4.03 
(http://ctep.cancer.gov/reporting/ctc.html) for reporting of non-hematologic 
adverse events and modified criteria for hematologic adverse events. Interim 
assessments for safety and associated early stopping criteria are detailed below.   
10.0 
DATA AND SAFETY MONITORING 
10.1 
Oversight and Monitoring Plan 
The DSMC of the KUCC is responsible for monitoring subject safety for this trial. The 
DSMC is responsible for: 
• Review of all clinical trials conducted by the KUCC for progress and safety  
• Review of all adverse events requiring expedited reporting as defined in the protocol  
• Submission of recommendations for corrective action to the PI and the Deputy Director 
of the KUCC or designee 
• Notification of external sites participating in multi-institution clinical trials coordinated by 
the KUCC of adverse events requiring expedited reporting and subsequent committee 
recommendations for study modifications.  
10.2 
Review and Oversight Requirements 
a) Serious Adverse Event  
Serious adverse events that require expedited reporting will be reviewed by the DSMC 
Chair or designee who will determine if immediate action is required. If determined to 
be necessary by the DSMC, all participating sites will be notified of the event and of 
any resulting action within one working day of this determination.  
 
b) Review of Adverse Event Rates  
Once per month, adverse event rates will be monitored by the DSMC Coordinator. If 
any study has had 2 or more of the same SAE reported within one month, or more 
than 6 of the same SAE in 6 months, the DSMC will review summaries of SAEs, and 
discuss events in detail with the PI. The DSMC chair or designee determines whether 
further action is required.  The DSMC Coordinator ensures that collaborating 
investigators and IRBs for all participating sites are notified of any resulting action. 
c) Study Safety and Progress – Semi-Annual Review 
An overall assessment of toxicities as described in the protocol is reviewed at quarterly 
DSMC meetings, but due to the expected slow accrual rate of this study, it is 
appropriate to review it on a semi-annual basis. This review enables DSMC members 
to assess whether significant risks are occurring that would warrant study 
suspension/closure or protocol amendment. 
 
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11.0 
REGULATORY CONSIDERATIONS 
11.1 
Protocol Review and Amendments 
This protocol, the proposed Informed Consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The Principal Investigator will disseminate protocol amendment 
information to all participating investigators. All decisions of the IRB concerning the 
conduct of the study must be made in writing. 
11.2 
Informed Consent 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file. 
11.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
 
1. 
ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm  
 
2. 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
- 
Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
- 
Title 21 Part 50 – Protection of Human Patients 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
 
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- 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
- 
Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
- 
Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
3. 
State laws 
4. 
Institutional research policies and procedures 
 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  
12.0 
REGISTRATION PROCEDURES 
12.1 
General Guidelines for KUCC AND Other Participating Organizations 
 
 
 
 
 
 
 
 
 
 
 
 
12.2 
Registration Process for KUCC and Other Participating Centers 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13.0 
STUDY MANAGEMENT 
13.1 
Investigator Files and Retention of Documents 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. Original source documents supporting entries in the case report forms include but are 
not limited to hospital records and clinic charts, laboratory and pharmacy records, ECG, signed 
ICFs, subject diaries and pathology reports. All study-related documents must be retained for 
the maximum period required by applicable federal regulations and guidelines or institutional 
policies.  
13.2 
Case Report Forms 
Case report forms (CRFs) will be completed for each subject enrolled in a timely fashion to 
ensure accurate interim analyses. All CRFs will be complete and accurate. The medical chart 
and any other clinical worksheets, procedural reports, etc. are the source of verification of the 
data captured into the study database.   
13.3 
Study Monitoring 
The study will be monitored at appropriate intervals to assure compliance to GCP and to assess 
the data quality and study integrity. The frequency of monitoring may vary depending on 
enrollment rate and the quality of data collected. The Study Monitoring plan will describe 
monitoring activities to be conducted. 
 
The investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit on request for review. The study monitor will have 
direct access to source data for data verification. Data verification will be conducted by 
comparing the data entered into the CRFs with source data. 
 
We will employ the following Bayesian sequential monitoring rule for toxicity in the Phase II: We 
will stop the study if P(toxicity > 33% I data from the trial) > 0.95. That is, given the outcomes 
from the subjects who have already been evaluated, if we determine that there is more than a 
95% chance that the toxicity/DLT rate is more than 33%, we will stop enrollment. 
 
This decision rule gives the following stopping rule. We assume a uniform prior distribution for 
the toxicity rate. Stop the study if: [# of subjects with toxicity / # subjects evaluated] 
≥4/6, 5/7, 6/9, 7/11, 8/13, 9/16, 10/18, 11/20, 12/23, 13/25, 14/28, 15/30. 
 
The operating characteristics of this study design are shown in the following table: 
 
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Operating Characteristics of Safety Monitoring Rule – Maximum 33 Subjects 
Rate of Toxicity 
Probability of 
Stopping 
Sample Size 
0.10 
0.002 
33 
33 
33 
0.20 
0.025 
33 
33 
33 
0.30 
0.143 
33 
33 
33 
0.40 
0.456 
10 
33 
33 
0.50 
0.810 
6 
12 
27 
0.60 
0.972 
6 
6 
12 
 
Once we have completed the study, we will estimate the toxicity rate with a 90% credible 
interval (Thall, et al, 1995). 
14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Study Design/Sample Size and Accrual 
We will employ the 3+3 design to find the MTD of BYL719/alpelisib when given in 
combination with Nab-Paclitaxel. We will enroll a maximum of 18 subjects in cohorts of 
size 3 in each subject group. We will start by enrolling 3 subjects at the dose level 1 from 
the table below.  After 3 subjects have been accrued to a dose level, that dose level will 
be closed to accrual until safety assessment of all the 3 patients is performed at the end 
of Cycle 1.  If the dose level is well tolerated during these 4 weeks, then dose escalation 
will be performed at the next cohort. 
 
Dose Level 
BYL719/alpelisib 
Nab-Paclitaxel 
-1 
200 mg 
100 mg/m2 
1 
250 mg 
100 mg/m2 
2 
300 mg 
100 mg/m2 
3 
350 mg 
100 mg/m2 
 
We will then follow the algorithm described below: 
• 
Enroll 3 subjects at the next highest dose until at least 1 subject experiences a 
DLT 
 
• 
If 1 of 3 subjects experiences a DLT, then enroll a second cohort of 3 subjects at 
the current dose 
 
• 
If only 1 of 6 subjects experience a DLT, then enroll 3 subjects at the next 
highest dose 
 
• 
If 2 or more of 6 subjects experience a DLT at the current dose level, then the 
MTD has been determined and escalation will stop. 
 
• 
Once the MTD has been determined, treat another 3 subjects at the previous 
dose level if there were only 3 subjects treated at that dose level 
 
• 
The MTD is the highest dose level at which 6 subjects were treated and at most 
2 subjects experienced a DLT.  Recommended phase 2 dose (RPTD) will be the 
previous dose at which < 1/6 subjects experienced a DLT. 
 
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• 
We do not plan to go beyond the 350 mg dose even if it is not the MTD 
 
• 
The -1 dose level of 200 mg is to be used in the event that the 250 mg dose is 
not tolerated. Based on the availability of further data from ongoing studies with 
BYL719/alpelisib the dosing schedule at each dose level may be modified in the 
future (five days on, two days off every 7 days) 
 
Since there are only three doses to be considered, and since we will have only a 
maximum of 6 subjects at each MTD, the maximum number of subjects enrolled in the 
phase I portion of the trial will be 18. 
 
Once the MTD has been determined, we will evaluate the PK/PD data and the AE data 
at each of the three dose levels and determine the recommended phase II dose (RPTD).  
The RP2D is defined as the next lower dose level below MTD (dose at which < 1/6 
subjects experienced a DLT). The Phase II portion of the study follows a Simon’s two 
stage Minimax design to detect an improvement in ORR from 20% to 40% (alpha 0.05 
and power of 0.8). In the first stage, 18 subjects treated at the RPTD will be assessed 
with the study proceeding to the second stage if there are at least 5 responses. 
Enrollment into the second stage will not start until at least 5 responses in the first stage 
have been observed. In the second stage, an additional 15 subjects will be enrolled. If 
11 or more subjects have an objective response among all 33 eligible subjects, the 
regimen would be considered promising. Assuming 10% of subjects are non-
evaluable/ineligible, up to 36 subjects may be accrued at the RPTD.  
14.2 
Data Analyses Plans 
Subject demographics and clinical characteristics will be summarized and reported for each 
dose level in the Phase I. Adverse events will be summarized and presented for each dose level 
in the Phase I. All analyses used to determine the RPTD will be reported. 
 
Subject demographics and clinical characteristics will be summarized and reported for subjects 
enrolled in the Phase II portion of the study. ORR will be reported for both stages of the Simon’s 
two-stage design. 
 
At the conclusion of the study, the objective response, complete response, partial response, and 
stable disease rates will be estimated and 95% confidence intervals will be calculated. 
Progression free survival (PFS) and overall survival (OS) time in days will be assessed using 
Kaplan-Meier. Median PFS and OS times will be estimated. 
 
 
 
 
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15.0 
REFERENCES 
1. 
2013, C.F.a.F. 
2. 
Early Breast Cancer Trialists' Collaborative, G., Effects of chemotherapy and hormonal 
therapy for early breast cancer on recurrence and 15-year survival: an overview of the 
randomised trials. Lancet, 2005. 365(9472): p. 1687-717. 
3. 
Miller, K., et al., Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic 
breast cancer. N Engl J Med, 2007. 357(26): p. 2666-76. 
4. 
Cortes, J., et al., Eribulin monotherapy versus treatment of physician's choice in patients 
with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. 
Lancet, 2011. 377(9769): p. 914-23. 
5. 
West, K.A., S.S. Castillo, and P.A. Dennis, Activation of the PI3K/Akt pathway and 
chemotherapeutic resistance. Drug Resist Updat, 2002. 5(6): p. 234-48. 
6. 
Katso, R., et al., Cellular function of phosphoinositide 3-kinases: implications for 
development, homeostasis, and cancer. Annu Rev Cell Dev Biol, 2001. 17: p. 615-75. 
7. 
Liu, P., et al., Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug 
Discov, 2009. 8(8): p. 627-44. 
8. 
McCubrey, J.A., et al., Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in 
malignant transformation and drug resistance. Adv Enzyme Regul, 2006. 46: p. 249-79. 
9. 
Samuels, Y. and V.E. Velculescu, Oncogenic mutations of PIK3CA in human cancers. 
Cell Cycle, 2004. 3(10): p. 1221-4. 
10. 
Hennessy, B.T., et al., Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat 
Rev Drug Discov, 2005. 4(12): p. 988-1004. 
11. 
Markman, B., et al., Status of PI3K inhibition and biomarker development in cancer 
therapeutics. Ann Oncol, 2010. 21(4): p. 683-91. 
12. 
Wong, K.K., J.A. Engelman, and L.C. Cantley, Targeting the PI3K signaling pathway in 
cancer. Curr Opin Genet Dev, 2010. 20(1): p. 87-90. 
13. 
Yuan, T.L. and L.C. Cantley, PI3K pathway alterations in cancer: variations on a theme. 
Oncogene, 2008. 27(41): p. 5497-510. 
14. 
Sansal, I. and W.R. Sellers, The biology and clinical relevance of the PTEN tumor 
suppressor pathway. J Clin Oncol, 2004. 22(14): p. 2954-63. 
15. 
Shayesteh, L., et al., PIK3CA is implicated as an oncogene in ovarian cancer. Nat 
Genet, 1999. 21(1): p. 99-102. 
16. 
Kalinsky, K., et al., PIK3CA mutation associates with improved outcome in breast 
cancer. Clin Cancer Res, 2009. 15(16): p. 5049-59. 
17. 
Stemke-Hale, K., et al., An integrative genomic and proteomic analysis of PIK3CA, 
PTEN, and AKT mutations in breast cancer. Cancer Res, 2008. 68(15): p. 6084-91. 
18. 
Depowski, P.L., S.I. Rosenthal, and J.S. Ross, Loss of expression of the PTEN gene 
protein product is associated with poor outcome in breast cancer. Mod Pathol, 2001. 
14(7): p. 672-6. 
19. 
Perez-Tenorio, G., et al., PIK3CA mutations and PTEN loss correlate with similar 
prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res, 
2007. 13(12): p. 3577-84. 
20. 
Umemura, S., et al., Increased phosphorylation of Akt in triple-negative breast cancers. 
Cancer Sci, 2007. 98(12): p. 1889-92. 
21. 
Marty, B., et al., Frequent PTEN genomic alterations and activated phosphatidylinositol 
3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res, 2008. 10(6): p. 
R101. 
22. 
Moulder, S.L., Does the PI3K pathway play a role in basal breast cancer? Clin Breast 
Cancer, 2010. 10 Suppl 3: p. S66-71. 
 
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23. 
Balko, J.M., et al., Profiling of residual breast cancers after neoadjuvant chemotherapy 
identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med, 2012. 18(7): 
p. 1052-9. 
24. 
O'Brien, N.A., et al., Activated phosphoinositide 3-kinase/AKT signaling confers 
resistance to trastuzumab but not lapatinib. Mol Cancer Ther, 2010. 9(6): p. 1489-502. 
25. 
Ibrahim, Y.H., et al., PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-
proficient triple-negative breast cancer to PARP inhibition. Cancer Discov, 2012. 2(11): 
p. 1036-47. 
26. 
Hahne, J.C., et al., Anti-tumour activity of phosphoinositide-3-kinase antagonist AEZS 
126 in models of triple-negative breast cancer. J Cancer Res Clin Oncol, 2013. 139(6): 
p. 905-14. 
27. 
O'Brien, C., et al., Predictive biomarkers of sensitivity to the phosphatidylinositol 3' 
kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res, 2010. 
16(14): p. 3670-83. 
28. 
Moestue, S.A., et al., Metabolic biomarkers for response to PI3K inhibition in basal-like 
breast cancer. Breast Cancer Res, 2013. 15(1): p. R16. 
29. 
Gradishar, W.J., et al., Phase III trial of nanoparticle albumin-bound paclitaxel compared 
with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol, 
2005. 23(31): p. 7794-803. 
30. 
Gradishar, W.J., et al., Significantly longer progression-free survival with nab-paclitaxel 
compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol, 
2009. 27(22): p. 3611-9. 
31. 
Gradishar, W.J., Albumin-bound paclitaxel: a next-generation taxane. Expert Opin 
Pharmacother, 2006. 7(8): p. 1041-53. 
32. 
Hu, L., et al., Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in 
in vitro and in vivo ovarian cancer models. Cancer Res, 2002. 62(4): p. 1087-92. 
33. 
Clark, A.S., et al., Constitutive and inducible Akt activity promotes resistance to 
chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther, 2002. 
1(9): p. 707-17. 
34. 
Therasse, P., et al., New guidelines to evaluate the response to treatment in solid 
tumors. European Organization for Research and Treatment of Cancer, National Cancer 
Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 
2000. 92(3): p. 205-16. 
 
 
 
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16.0 
APPENDICES 
APPENDIX A. Performance Status 
 
Zubrod (ECOG) Performance Scale 
 
POINT 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair. 
 
 
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APPENDIX B: List of Concomitant Medications 
 
Table 1: List of CYP450 substrates to be used with caution 
 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
  
Amodiaquine 
Celecoxib 
Clopidogrel 
Alfentanil1,2 
Ergotamine2 
Cerivastatin 
Diclofenac 
Diazepam 
Alphy-
dihydroergocryptine1 
Everolimus1 
Repaglinide 
Glipizide 
Esoprazole 
Alprazolam 
Felodipine1 
Rosiglitazone 
Isbesartan 
Lansoprazole 
Amlopidine 
Fentanyl2 
Torasemide  
Irbesartan  
Moclobemide  
Aplaviroc  
Fluticasone 1 
  
Losartan  
Omeprazole  
Aprepitant 1 
Indinavir 1 
  
Phenytoin 2 
Pantoprazole  
Aripiprazole  
Lopinavir 1 
  
Piroxicam  
Phenobarbitone  
Atorvastatin  
Lovastatin 1 
  
S-ibuprofen  
Phenytoin 2 
Boceprevir  
Maraviroc 1 
  
Sulfamethoxazole  
Proguanil  
Brecanavir  
Midazolam 1 
  
Tolbutamide  
Rabeprazole  
Brotizolam 1 
Nifedipine  
  
Torasemide  
S-mephenytoin  
Budesonide 1 
Nisoldipine  
  
  
  
Buspirone 1 
Nitrendipine  
  
  
  
capravirine 
Perospirone 1 
  
  
  
casopitant 
Quinine  
  
  
  
Conivaptan 1 
Saquinavir 1 
  
  
  
Cyclosporine 2 
Sildenafil 1 
  
  
  
Darifenacin 1 
Simvastatin 1 
  
  
  
Darunavir 1 
Sirolimus 1,2 
  
  
  
Diazepam  
Telaprevir  
  
  
  
Diergotamine 2 
Tipranavir 1 
  
  
  
Diltiazem  
Tolvaptan  
  
  
  
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 
supplemented by GDA’s “Guidance for Industry, Drug Interaction Studies” and the University of Washington’s Drug 
Interaction Database. 
1Sensitive substrates: Drugs whose plasma UAC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor of the respective enzyme. 
2Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g. TdP). 
 
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All QT-prolonging drugs listed in Table 2 are prohibited for all subjects from screening through 
permanent discontinuation of study treatment 
 
Table 2: List of prohibited QT prolonging drugs 
Drug 
QT risk* 
Comment 
Amiodarone 
known risk 
Female>Males, TdP risk regarded as low 
Amitriptyline 
conditional risk 
Risk of TdP with overdose.  Substrate of CYP2C19 
Arsenic trioxide 
known risk 
  
 Astemizole 
known risk 
No longer available in U.S. Substrate for 3A4 
Bepridil 
known risk 
Females > Males 
Chloroquine 
known risk 
  
Chlorpromazine 
known risk 
  
Cisapride 
known risk 
No longer available in 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. 
Dronedatone 
possible risk 
Substrate for 3A4 
Droperidol 
known risk 
  
Erythromycin 
known risk 
Females > Males.  Substrate 3A4 
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 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 QT durgs.org Advisory Board of the Arizona CERT 
 
 
 
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Table 3: List of QT prolonging drugs to be used with caution 
 
Drug 
QT risk* 
Comment 
Alfuzosin 
possible risk 
  
Amantadine 
possible risk 
  
Atazanavir 
possible risk 
  
Azithromycin 
possible risk 
Rare reports 
Chloral hydrate 
possible risk 
  
Ciprofloxacin 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Clozapine 
possible risk 
  
Desipramine 
conditional risk 
Risk of TdP with overdose 
Diphenhydramine 
conditional risk 
Risk of QT increase/TdP in overdoses 
Dolasetron 
possible risk 
  
Doxepin 
conditional risk 
  
Eribulin 
possible risk 
  
Escitalopram 
possible risk 
  
Famotidine 
possible risk 
  
Felbamate 
possible risk 
  
Fingolimod 
possible risk 
  
Fluconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Fluoxetine 
conditional risk 
  
Foscarnet 
possible risk 
  
Fosphenytoin 
possible risk 
  
Galantamine 
conditional risk 
  
Gatifloxacin 
possible risk 
  
Gemifloxacin 
possible risk 
  
Granisetron 
possible risk 
  
Imipramine 
conditional risk 
Risk of TdP in overdose 
Indapamide 
possible risk 
  
Isradipine 
possible risk 
  
Itraconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Ketoconazole 
conditional risk 
Drug metabolism inhibitor 
Levofloxacin 
possible risk 
  
Lithium 
possible risk 
  
Moexipril/HCTZ 
possible risk 
  
Nicardipine 
possible risk 
  
Nortriptyline 
conditional risk 
  
Octreotide 
possible risk 
  
Ofloxacin 
possible risk 
  
Ondansetron 
possible risk 
  
Oxytocin 
possible risk 
  
Paliperidone 
possible risk 
  
Paroxetine 
conditional risk 
  
 
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Perflutren lipid 
microspheres 
possible risk 
  
Protriptyline 
conditional risk 
  
Ranolazine 
possible risk 
  
Risperidone 
possible risk 
  
Roxithromycin* 
possible risk 
*not available in the United States 
Sertindole 
possible risk 
  
Sertraline 
conditional risk 
  
Solifenacin 
conditional risk 
  
Tizanidine 
possible risk 
  
Trimethoprim-Sulfa 
conditional risk 
  
Trimipramine 
conditional risk 
  
Venlafaxine 
possible risk 
  
Voriconazole 
possible risk 
  
Ziprasidone 
possible risk 
  
* Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
 
 
 
 
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Table 4: BCRP inhibitors to be used with caution 
 
Drug 
Comments 
Diketopiperazines 
P-glycoprotein inhibitors 
Fumitremorgin C 
Elacridar (GF-120918) 
Tryprostatin A 
Tariquidar (XR-9576) 
Indolyldiketopiperazines 
Biricodar 
Steroid(-like) compounds 
Flavonoids 
Corticosterone 
Chrysin 
Digoxin 
Biochanin A 
Beclometasone 
Benzoflavone 
6 α-Methylprednisolone 
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 
 
 
 
 
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APPENDIX C: Specimen Collection for Correlative Studies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX D: Guidelines for Management of Diarrhea 
• 
Avoid milk, caffeinated beverages, alcohol, high-fat foods and high osmolar supplements 
• 
Drink 8-10 glasses of clear liquids every day (water, Gatorade, broth) 
• 
Eat frequent small meals and BRAT diet (Banana, Rice, Applesauce, Toast, Pasta) 
• 
Start Loperamide (Imodium) after you have the first loose stool/diarrhea 
• 
Dosing of Imodium: Take 4 mg (2 tablets) after the first loose stool, followed by 2 mg 
every 4 hours or after every loose stool until free of diarrhea for 12 hours 
• 
If diarrhea doesn’t resolve in the next 12-24 hours, call your doctor 
• 
You may need IV fluids or antibiotics 
• 
If diarrhea resolves, you can gradually add solid foods to diet 
 
Management of diarrhea 
 
General Recommendations: 
• 
Stop all lactose-containing products, alcohol 
• 
Stop laxatives, bulk fiber (e.g. Metamucil®) and stool softeners (e.g. docusate sodium, 
Colace®) 
• 
Stop high-osmolar food supplements such as Ensure Plus® and Jevity Plus® (with fiber) 
• 
Drink 8-10 large glasses of clear fluids per day (e.g. water, Pedialyte®, Gatorade®, 
broth) 
• 
Eat frequent small meals (e.g. bananas, rice, applesauce, toast) 
• 
It is recommended that subjects are provided with loperamide tablets at the start of each 
cycle. Subjects should be instructed on the use of loperamide at Cycle 1 in order to 
manage signs and symptoms of diarrhea at home. Subjects should be instructed to start 
oral loperamide (initial administration of 4 mg, then 2 mg every 4 hours (maximum of 16 
mg/day)) at the first sign of loose stool or symptoms of abdominal pain. These 
instructions should be provided at each cycle and the site should ensure that the subject 
understands the instruction. A the beginning of each cycle, each subject should be 
specifically questioned regarding any experience of diarrhea or diarrhea related 
symptoms, If symptoms were experienced, then the site should question the subject 
regarding the actions taken for these symptoms 
• 
Intensive management of diarrhea must be instituted at the first sign of abdominal 
cramping, loose stool or overt diarrhea. Note that all concomitant therapies used for 
treatment of diarrhea must be recorded on the Concomitant Medications eCRF. 
• 
Loperamide is the first-line treatment of diarrhea (any grade) in this recommended 
algorithm 
• 
Persistent symptoms may require the administration of high dose loperamide followed by 
treatment with second-line agents such as opium tincture and octreotide acetate, based 
on severity and duration of diarrhea and related signs/symptoms. Another first-line 
treatment for diarrhea is diphenoxylate hydrochloride/atropine sulfate. This medication 
may be used in place of loperamide, however it is important to note that loperamide and 
diphenyloxylate hydrochloride/atropine sulfate must not be used in conjunction with one 
another due to the risk of developing paralytic ileus. Upon treatment with any 
antidiarrheal agents, the subject’s response to treatment should be observed and 
appropriately documented in the source document and eCRF. 
 
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Treatment of diarrhea CTCAE Grade 1 or 2: 
Diarrhea CTCAE Grade 1 or 2 will be treated with standard loperamide (initial at first 
administration 4mg, the 2 mg every 4 hrs (maximum of 16 mg/day) or after each 
unformed stool). 
 
12-24 hrs later: 
 
Diarrhea resolved 
• 
Continue instructions for dietary modification 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide after 12 hrs diarrhea-free interval 
 
Diarrhea unresolved 
• 
Persisting diarrhea CTCAE Grade 1 or 2 will be treated with addition of opium 
tincture or dihydrocodeine tartrate tablets/injections with monitoring of subjects 
condition to rule out dehydration, sepsis, ileus) medical check and selected 
workup if the subject does not need hospitalization (see section “Diarrhea 
Workup” and additional test in the particular trial protocol). Observe subject for 
response to antidiarrheal treatment. 
• 
Persisting diarrhea CTCAE Grade 3 or 4 may be treated with hospitalization, high 
dose loperamide (initial 4 mg, the 2 mg every 2 hours) and addition of opium 
tincture (DTO) or dihydrocodeine tartrate tablets/injections, start of IV fluids and 
antibiotics as needed with monitoring of subjects condition (to rule out 
dehydration, sepsis, ileus) medical check and workup (perform appropriate 
additional testing. Observe subject for response. 
 
After 12-24 hrs: 
 
Diarrhea resolved 
• 
Continue instructions for dietary modifications 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide and/or other treatment after 12 hrs diarrhea-free interval 
 
Diarrhea unresolved 
• 
If diarrhea still persisting (CTCAE Grades 1 and 2) after 2x24 hrs with high dose 
loperamide and opiates then admit to hospital and employ measures as for 
CTCAE Grade 3 and 4 until diarrhea resolved 
• 
If diarrhea still persisting and progressed to CTCAE Grades 3 and 4, employ 
measures described below 
 
Treatment of diarrhea CTCAE Grade 3 or 4 
Severe diarrhea CTCAE Grade 3 or 4 may be treated with hospitalization, high dose 
loperamide,(initial 4 mg, then 2 mg every 2 hrs and addition of opium tincture or 
dihydrocodeine tartrate tablets/injections, start of IV fluids and antibiotics as needed with 
monitoring of subject’s condition (to rule out dehydration, sepsis, ileus) medical check 
and workup (see section “Diarrhea Workup” and additional test in the particular trial 
protocol). Observe subject for response. 
 
 
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 Principal Investigator:  Priyanka Sharma, MD 
 
 
 
 
 
After 12-24 hours: 
• 
If diarrhea persisting, administer s.c. sandostatin/octreotide (100-500 µg TID) 
• 
Continue IV fluids and antibiotics as needed 
• 
If diarrhea CTCAE Grade 3 or 4 still persists, subjects should receive opium 
tincture or dihydrocodeine tartrate injections s.c. or i.m. 
• 
If diarrhea CTCAE Grade 3 or 4 is still persisting, s.c. sandostatin/octreotide 
(500-1000 µg TID) should be administered 
• 
To controls and/or resolve diarrhea, next cycle of treatment should be delayed 
by 1 or 2 weeks. Treatment should be continued only when diarrhea resolved. 
 
Diarrhea Workup 
• 
Perform appropriate tests (Fine et al, 1999) 
 
 
 
 
 
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 Principal Investigator:  Priyanka Sharma, MD 
 
 
 
 
 
APPENDIX E: Summaries of Changes 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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