VATCH (Vascular Anomaly Analysis for Therapy Choice): Phase II Study of Alpelisib Treatment in Subjects With TIE2/PIK3CA Pathway Driven Vascular Anomalies
Phase: PHASE2
Conditions: Vascular Anomalies, Vascular Anomaly, TIE2/PIK3CA Pathway Driven Vascular Anomalies
Sponsor: Children's Hospital of Philadelphia

 
 
 
 
Title: 
VATCH (Vascular Anomaly Analysis for 
Therapy Choice) 
Sub-protocol 2 – Phase II Study of Alpelisib Treatment in 
Subjects with TIE2/PIK3CA pathway Driven Vascular 
Anomalies 
Short Title 
Alpelisib in TIE2/PIK3CA pathway Vascular Anomalies 
Drug or Device 
Name(s): 
Alpelisib tablet/capsule 
FDA IND 
IND Exempt (as determined by the FDA) 
Regulatory Sponsor: 
 
eIRB Number 
Pending 
Protocol Date: 
30 May 2025 
Amendment 1 Date:  
Amendment 3 Date:  
Amendment 2 Date: 
Amendment 4 Date: 
Sponsor 
 Denise Adams, MD 
Children’s Hospital of Philadelphia 
3500 Civic Center Blvd, Suite 3514 
Philadelphia, PA 19104 
Email: adamsdm@chop.edu 
Phone #: (267) 426-9188 
Fax#: (267) 426-9940 

 
 
 
 
 
 
 
Study Principal Investigator  
Ionela Iacobas, MD 
Texas Children's Hospital – Baylor 
6701 Fannin St., Ste. 1510.0 
Houston, TX 77030 
Phone: (832) 824-4819 
ixiacoba@texaschildrens.org 
 
Study Co-Principal Investigator  
Joana M. Mack, MD 
Arkansas Children's Hospital 
1 Children’s Way Slot 512-10 
Little Rock, AR 72202 
Phone: (501) 406-0914 
JMMack@uams.edu 
 

 
 
 
 
CaNVAS Participating Institutions 
 
CaNVAS Consortium Coordinating Center 
Children's Hospital of Philadelphia 
 
 
 
 
PI: Denise Adams, MD 
3501 Civic Center Blvd, Suite 3514 
Philadelphia, PA 19104 
Phone: (267) 426-9188 
adamsdm@chop.edu 
 
 
 
Nationwide Children's Hospital 
PI: Bhuvana Setty, MD 
700 Children's Dr 
Columbus, OH 43205 
Phone: (614) 722-3561 
Bhuvana.Setty@nationwidechildrens.org 
 
 
Arkansas Children's Hospital 
PI: Shelley Crary, MD 
1 Children’s Way Slot 512-10 
Little Rock, AR 72202 
Phone: (501) 364-1494 
SECrary@uams.edu 
 
Nemours Children's Health, Jacksonville 
PI: Eric Sandler, MD 
807 Children’s Way 
Jacksonville, FL 32207 
Phone: (904) 697-3658 
Eric.Sandler@nemours.org 
 
Boston Children’s Hospital 
PI: Melisa Ruiz-Gutierrez 
300 Longwood Ave  
Boston, MA 02115 
Phone: (617) 919-7126 
Melisa.Ruiz-Gutierrez.harvard.edu 
 
NYU Grossman School of Medicine  
PI: Francine Blei, MD 
150 East 32nd Street, 2nd Fl.  
New York, NY 10016 
Phone: (212) 263-2610 
Francine.Blei@nyulangone.org 
 
Children’s Healthcare of Atlanta (CHOA) 
PI: Michael Briones, D.O 
1405 Clifton Road NE 
Atlanta, GA 30322 
Phone: (404) 785-1641 
Michael.Briones@choa.org 
 
Oregon Health & Science University 
PI: Melinda Wu, MD 
3181 SW Sam Jackson Park Rd, CDRC-P 
Portland, OR 97239 
Phone: (503) 494-3192 
wume@ohsu.edu 
 
Children’s Hospital of Colorado 
PI: Taizo Nakano, MD 
13123 East 16th Avenue, B-115  
Aurora, CO 80045 
Phone: (720) 777-6740 
taizo.nakano@childrenscolorado.org 
 
Riley Children’s Health 
PI: Rachael Schulte, MD 
575 Riley Hospital Dr, ROC 4340 
Indianapolis, IN, 46260 
Phone: (317) 948-5024 
rrschult@iu.edu 
 
Children’s Hospital of Los Angeles 
PI: Sara Kreimer, MD 
4650 Sunset Blvd., MS #54 
Los Angeles, CA 90027  
Phone: (323) 361-2529  
skreimer@chla.usc.edu 
 
Seattle Children’s  
PI: Whitney Eng, MD 
4800 Sand Point Way NE 
Seattle, WA 98105 
Phone: (206) 987-4606 
Whitney.eng@seattlechildrens.org  
Children's Hospital of Orange County 
PI: Diane Nugent, MD 
1201 West La Veta Avenue 
Orange, CA 92868 
Texas Children's Hospital – Baylor 
PI: Ionela Iacobas, MD 
6701 Fannin St., Ste. 1510.0 
Houston, TX 77030 

 
 
 
 
Phone: (714) 509-8459 
dnugent@choc.edu 
 
Phone: (832) 824-4819 
ixiacoba@texaschildrens.org 
Children's Wisconsin – Milwaukee 
PI: Nathan Schloemer, MD 
8701 Watertown Plank Road, MFRC 3018 
Milwaukee, WI 53226 
Phone: (414) 955-4170 
nschloem@mcw.edu 
 
University of North Carolina (UNC) 
PI: Alexandra Borst, M.D.  
Physician Office Building 
170 Manning Drive, CB #7236 
Chapel Hill, NC 2757236 
Phone: (919) 966-7629 
alexborst@unc.med.edu 
 
Cincinnati Children's Hospital  
PI: Adrienne Hammill, MD 
3333 Burnet Ave 
Cincinnati, OH 45229 
Phone: (513) 803-4862 
Adrienne.Hammill@cchmc.org 
 
University of California, San Francisco 
PI: Beth Winger, MD 
490 Illinois Street #305 
San Francisco, CA 94158 
Phone: 5103326296 
Beth.winger@ucsf.edu 
 
Columbia University Irving Medical Center 
PI: Margaret Lee, MD 
3959 Broadway 
New York, NY 10032 
Phone: (212) 305-9770 
ml653@cumc.columbia.edu 
 
UPMC Children's Hospital of Pittsburgh, 
University of Pittsburgh School of Medicine 
PI: Frederico Xavier, MD 
4401 Penn Avenue, Plaza Building 5th floor 
Pittsburgh, PA 15224 
Phone: (412) 692-6938 
frederico.xavier@chp.edu 
 
Dell Children’s Medical Center 
PI: Ginna Priola 
4910 Mueller, TX 78723 
Austin, TX 78723 
Phone: (207) 310-0833 
Ginna.priola@ascension.org 
 
Vanderbilt University Medical Center 
PI: Neeraja Swaminathan, MD 
2220 Pierce Avenue PRB 395 
Nashville, TN 37232 
Phone: (615) 322-9397 
neeraja.swaminathan@vumc.org 
Helen DeVos Children's  
PI: Kristy Pilbeam, MD 
100 Michigan Street NE 
Grand Rapids, MI 49503 
Phone: (616) 267-1925 
Kristy.Pilbeam@spectrumhealth.org 
 
 
Lucile Packard Children's Hospital – Stanford 
PI: Michael Jeng, MD 
700 Welch Road, Suite 200 
Palo Alto, CA 94304 
Phone: (650) 723-5535 
mjeng@stanford.edu 
 
Washington University in St. Louis 
PI: Bryan Sisk, MD 
MSC 8116-43-10 
Washington University School of Medicine 
660 South Euclid Avenue 
St. Louis MO  63110-1010 
Phone: (314) 273-9084 
siskb@wustl.edu 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
iii 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................................................... III 
LIST OF ABBREVIATIONS..................................................................................................................................... VII 
ABSTRACT................................................................................................................................................................ X 
PROTOCOL SYNOPSIS ......................................................................................................................................... XII 
EXPERIMENTAL DESIGN SCHEMA ................................................................................................................... XIX 
1 
BACKGROUND AND RATIONALE ................................................................................................................. 1 
1.1 
INTRODUCTION ............................................................................................................................................ 1 
1.2 
PATHWAY ................................................................................................................................................... 1 
1.3 
COMPLIANCE STATEMENT............................................................................................................................ 3 
2 
RATIONALE ...................................................................................................................................................... 3 
2.1 
INVESTIGATIONAL DRUG: ALPELISIB (VIJOICE®) ............................................................................................ 3 
2.1.1 
Rationale for Dose/Age ........................................................................................................................ 4 
2.2 
RATIONALE FOR INDIVIDUALIZED EVALUATIONS ............................................................................................. 4 
2.3 
RATIONALE FOR EXPLORATORY AIMS ........................................................................................................... 5 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................................................... 6 
3.1 
SPECIFIC HYPOTHESIS ................................................................................................................................ 6 
3.2 
PRIMARY OBJECTIVES ................................................................................................................................. 6 
3.3 
SECONDARY OBJECTIVES ............................................................................................................................ 6 
3.4 
EXPLORATORY OBJECTIVES ........................................................................................................................ 6 
4 
INVESTIGATIONAL PLAN ............................................................................................................................... 7 
4.1 
GENERAL SCHEMA OF STUDY DESIGN .......................................................................................................... 7 
4.2 
REGISTRATION, ENROLLMENT, AND SCREENING ........................................................................................... 7 
4.2.1 
Optional Biologic Studies ..................................................................................................................... 7 
4.3 
STUDY TREATMENT PHASE (START OF THE STUDY INTERVENTION) ................................................................ 8 
4.3.1 
Dosing .................................................................................................................................................. 8 
4.4 
FOLLOW-UP PHASE ..................................................................................................................................... 9 
4.5 
EXTENSION PHASE ...................................................................................................................................... 9 
4.6 
END OF TREATMENT .................................................................................................................................... 9 
4.7 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES .............................................................................. 9 
4.7.1 
Duration of Study Participation ............................................................................................................. 9 
4.7.2 
Total Number of Study Sites/Total Number of Subjects Projected ...................................................... 9 
4.8 
STUDY POPULATION .................................................................................................................................. 10 
5 
SUBJECT ELIGIBILITY .................................................................................................................................. 10 
5.1 
INCLUSION CRITERIA ................................................................................................................................. 10 
5.2 
EXCLUSION CRITERIA ................................................................................................................................ 12 
6 
STUDY PROCEDURES .................................................................................................................................. 13 
6.1 
SCREENING ASSESSMENTS ....................................................................................................................... 13 
Table 6-1: Protocol-required Safety Laboratory Assessments ....................................................................... 14 
6.2 
STUDY TREATMENT PHASE ........................................................................................................................ 17 
6.2.1 
Treatment Compliance and Adherence ............................................................................................. 17 
6.3 
EXTENSION PHASE OF THE STUDY ............................................................................................................. 17 
6.4 
FOLLOW-UP PHASE ................................................................................................................................... 18 
6.5 
UNSCHEDULED VISITS ............................................................................................................................... 18 
6.6 
SUBJECT COMPLETION/WITHDRAWAL ........................................................................................................ 18 

 
 
 
 
 
 
 
 
 
iv
7 
SUPPORTIVE CARE AND CONCOMITANT MEDICATION ......................................................................... 18 
7.1 
OTHER TREATMENT(S) .............................................................................................................................. 18 
7.2 
CONCOMITANT THERAPY ........................................................................................................................... 19 
7.2.1 
Permitted concomitant therapy requiring caution and/or action ......................................................... 20 
7.2.1.1 
Oral Anti diabetics ..................................................................................................................................... 20 
7.2.1.2 
Corticosteroids .......................................................................................................................................... 21 
7.2.1.3 
Gastric protection agents .......................................................................................................................... 21 
7.3 
PROHIBITED MEDICATION ........................................................................................................................... 21 
7.4 
RESCUE MEDICATION ADMINISTRATION ...................................................................................................... 22 
8 
STUDY EVALUATIONS AND MEASUREMENT ........................................................................................... 23 
8.1 
SCHEDULE OF ASSESSMENTS .................................................................................................................... 23 
Table 8-1 Schedule of Assesments ............................................................................................................................. 24 
8.1.1 
Medical Record Review ...................................................................................................................... 25 
8.1.2 
Physical Examination ......................................................................................................................... 25 
8.1.3 
Vital Signs ........................................................................................................................................... 25 
8.1.4 
Laboratory Evaluations ....................................................................................................................... 25 
8.1.5 
Pregnancy Testing ............................................................................................................................. 26 
8.1.6 
Other Evaluations, Measures ............................................................................................................. 26 
8.2 
EFFICACY EVALUATIONS ............................................................................................................................ 26 
8.2.1 
Radiographic Response ..................................................................................................................... 27 
8.2.1.1 
MRI/MRL:.................................................................................................................................................. 27 
8.2.1.2 
Other Radiographic Assessment .............................................................................................................. 27 
8.2.2 
Assessment of Patient Reported Outcome Measures (PROMs) ....................................................... 27 
Table 8-3 ...................................................................................................................................................................... 28 
8.2.3 
Assessment of Clinical Benefit ........................................................................................................... 29 
8.2.3.1 
Photography/Videos ................................................................................................................................. 30 
8.2.3.2 
Patient Narratives ..................................................................................................................................... 30 
8.3 
ASSESSMENT OF OVERALL RESPONSE ....................................................................................................... 30 
8.3.1 
Definitions ........................................................................................................................................... 30 
8.3.2 
Response Criteria for Overall Response ............................................................................................ 31 
8.3.3 
Duration of Response ......................................................................................................................... 32 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................... 32 
9.1 
SAMPLE SIZE AND POWER ......................................................................................................................... 32 
9.2 
SAFETY MONITORING ................................................................................................................................. 33 
9.3 
STATISTICAL ANALYSES PLAN .................................................................................................................... 33 
10 
DOSE MODIFICATION AND MANAGEMENT OF ADVERSE EVENTS ....................................................... 35 
10.1 
DOSE MODIFICATIONS ............................................................................................................................... 35 
10.1.1 
Dose Escalation ............................................................................................................................. 35 
10.1.2 
Dose Reduction .............................................................................................................................. 36 
TABLE 10-4  DOSE REDUCTION SEQUENTIAL STEPS FOR ALPELISIB IN AGES 18+ ........................................................ 36 
TABLE 10-5   DOSE REDUCTION SEQUENTIAL STEPS FOR ALPELISIB IN AGES 6-17 ...................................................... 37 
10.2 
MANAGEMENT OF ADVERSE EFFECTS ......................................................................................................... 37 
10.2.1 
Dose adjustments for QTcF prolongation ...................................................................................... 37 
Table 10-6 Criteria for interruption and re-initiation of alpelisib treatment due to QTcF prolongation .......................... 37 
10.2.2 
Guidelines for the treatment of alpelisib induced skin toxicity ....................................................... 38 
Table 10-7 Criteria for interruption and re-initiation of alpelisib treatment due to skin toxicity...................................... 38 
10.2.3 
Guidelines for the treatment of alpelisib induced hyperglycemia .................................................. 40 
Table 10-8 Criteria for interruption and re-initiation of alpelisib treatment due to hyperglycemia ................................. 41 
10.2.4 
Guidelines for treatment of alpelisib induced pneumonitis ............................................................ 44 
Table 10-9 Management of pneumonitis related to alpelisib with or without other agents in combination ................... 44 
10.2.5 
Guidelines for the treatment of alpelisib induced diarrhea............................................................. 44 
Table 10-10 Criteria for interruption and re-initiation of alpelisib treatment due to diarrhea ......................................... 45 
Table 10-11   NCI CTCAE version 5.0 grading of diarrhea for subjects without Colostomy ........................................ 49 
10.2.6 
Guidelines for the treatment of alpelisib induced stomatitis/oral mucositis ................................... 49 

 
 
 
 
 
 
 
 
 
v
Table 10-12   Criteria for interruption and re-initiation of alpelisib treatment due   to stomatitis ................................... 49 
10.2.7 
Guideline for treatment of alpelisib induced pancreatitis ............................................................... 50 
Table 10-13 Criteria for interruption and re-initiation of alpelisib treatment due to pancreatitis. ................................... 50 
10.2.8 
Investigations: alpelisib dose modifications ................................................................................... 50 
Table 10-14 
Criteria for interruption and re-initiation of alpelisib treatment: Investigations (hematologic)................ 51 
Table 10-15   Criteria for interruption and re-initiation of alpelisib treatment: Investigations (other) ............................ 51 
10.3 
FOLLOW-UP FOR TOXICITIES ...................................................................................................................... 54 
10.4 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA .......................................... 54 
10.4.1 
Criteria for Removal from Protocol Therapy .................................................................................. 54 
10.4.2 
Off Study Criteria ............................................................................................................................ 54 
10.5 
ADVERSE REPORTING REQUIREMENTS ...................................................................................................... 54 
10.5.1 
Clinical Adverse Events ................................................................................................................. 54 
10.5.2 
Definition of an Adverse Event ....................................................................................................... 55 
10.6 
ROUTINE REPORTING PROCEDURES FOR ALL AES ..................................................................................... 55 
10.7 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ..................................................................................... 56 
10.8 
LABORATORY AND OTHER SAFETY ASSESSMENT ABNORMALITIES REPORTED AS AES AND SAES ................ 56 
10.9 
RELATIONSHIP OF SAE TO STUDY DRUG OR OTHER INTERVENTION .............................................................. 57 
10.10 
TREATMENT DOSE MODIFICATIONS AND GUIDELINES FOR ADVERSE EVENT REPORTING SPECIFIC TO STUDY 
DRUG 
58 
10.11 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS.............................................. 58 
10.11.1 
Follow-up report ............................................................................................................................. 59 
10.12 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO COORDINATING CENTER. ........................ 59 
10.13 
MEDICAL EMERGENCIES ....................................................................................................................... 59 
10.14 
REPORTING OF STUDY TREATMENT ERRORS INCLUDING MISUSE/ABUSE ................................................. 60 
11 
STUDY ADMINISTRATION ............................................................................................................................ 61 
11.1 
IRB APPROVAL ......................................................................................................................................... 61 
11.2 
DATA COLLECTION AND MANAGEMENT ....................................................................................................... 61 
11.2.1 
Protection Against Risks ................................................................................................................ 62 
11.2.2 
Drug Accountability ........................................................................................................................ 62 
11.3 
CONFIDENTIALITY ...................................................................................................................................... 62 
11.4 
REGULATORY AND ETHICAL CONSIDERATIONS ............................................................................................ 63 
11.4.1 
Data and Safety Monitoring Plan ................................................................................................... 63 
11.4.2 
Audits ............................................................................................................................................. 63 
11.5 
RISK ASSESSMENT .................................................................................................................................... 64 
11.6 
POTENTIAL BENEFITS OF TRIAL PARTICIPATION .......................................................................................... 64 
11.6.1 
Risk-Benefit Assessment ............................................................................................................... 64 
11.7 
RECRUITMENT STRATEGY.......................................................................................................................... 65 
11.8 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ........................................................................ 65 
11.8.1 
Waiver of Consent.......................................................................................................................... 66 
11.9 
PAYMENT TO SUBJECTS/FAMILIES .............................................................................................................. 66 
12 
REPORTING OF PROTOCOL VIOLATIONS/DEVIATIONS AND UNANTICIPATED PROBLEMS ............ 66 
13 
COORDINATING CENTER RESPONSIBILITIES: ......................................................................................... 67 
13.1 
SAE/SAE REPORTING .............................................................................................................................. 67 
13.2 
SAE REPORTING IN THE FOLLOW UP PERIOD ............................................................................................. 67 
13.3 
SPONSOR RESPONSIBILITIES TO BE PERFORMED BY THE COORDINATING CENTER: ....................................... 67 
13.3.1 
Unexpected Fatal or Life-Threatening Suspected Adverse Reaction Reports .............................. 68 
13.3.2 
Unexpected, Serious Suspected Adverse Reactions .................................................................... 68 
13.3.3 
Serious Adverse Event Reporting Procedures to the CHOP IRB .................................................. 69 
14 
PUBLICATION ................................................................................................................................................ 69 
15 
REFERENCES ................................................................................................................................................ 70 
APPENDICES .......................................................................................................................................................... 75 

 
 
 
 
 
 
 
 
 
vi
APPENDIX I: PERFORMANCE SCORES .............................................................................................................. 75 
APPENDIX II: PROMIS ........................................................................................................................................... 76 
APPENDIX III: BLOOD SAMPLING ....................................................................................................................... 95 
APPENDIX IV: RADIOLOGY .................................................................................................................................. 96 
APPENDIX V: MEDICATIONS TO BE USED WITH CAUTION ........................................................................... 100 
APPENDIX VI: PROHIBITED MEDICATION ........................................................................................................ 101 
APPENDIX VII: MEDICATION DIARY .................................................................................................................. 102 
APPENDIX VIII: ROAD MAP................................................................................................................................. 103 
APPENDIX IX: CLINICAL BENEFIT OF ASSESSMENT ..................................................................................... 104 
                   

 
 
 
 
 
 
 
 
 
vii 
LIST OF ABBREVIATIONS 
 
ADL  
 
Activities of daily living 
AE(s)   
Adverse Event(s) 
AKT  
 
Serine/threonine kinase AKT (protein kinase B) 
ALK  
 
Anaplastic Lymphoma Kinase 
ALP  
 
Alkaline phosphatase 
ALT  
 
Alanine aminotransferase 
ANC  
 
Absolute neutrophil count 
ANG 1  
Angiopoietins 1  
ANG 2  
Angiopoietins 2  
AST  
 
Aspartate aminotransferase 
AVM 
 
Arteriovenous Malformation 
aPTT 
 
Activated partial thromboplastin time 
BID  
 
Twice daily 
BMI 
 
Body Mass Index 
BSA 
 
Body surface area 
BUN 
 
Blood Urea Nitrogen 
BRAT   
Bananas, rice, apples, toast (diet) 
BSA  
 
Body surface area 
C 
 
Centigrade 
CAG 
 
Center for Applied Genomics 
CaNVAS 
Consortium of iNvestigators of Vascular Anomalies 
CBA 
 
Clinical Benefit Assessment 
CBC  
 
Complete blood count 
cfDNA  
Cell-free  DNA 
CHOP  
Children’s Hospital of Philadelphia 
CI  
 
Confidence Interval 
CLA 
 
Complex lymphatic anomalies 
CLIA  
 
Clinical Laboratory Improvement Amendments 
CMP 
 
Complete Metabolic Panel 
CNS  
 
Central nervous system 
CO2  
 
Carbon dioxide  
 
COVID-19 
Coronavirus Disease 2019 
CPK  
 
Creatine phosphokinase 
CRF 
 
Case report/Record form 
CR  
 
Complete response 
CRO  
 
Contract Research Organization 
CSR 
 
Clinical study report 
CT  
 
Computerized Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DBP  
 
Diastolic Blood Pressure 
DDE  
 
Direct Data Entry 
ddPCR  
Droplet digital polymerase chain reaction  
DICOM  
Digital Imaging and Communications in Medicine 
DILI  
 
Drug-Induced Liver Injury 
DMEG  
Dysplastic Megalencephaly 
DNA 
 
Deoxyribonucleic acid 
DSMB   
Data Safety Monitoring Board 
DNA  
 
Deoxyribonucleic acid 
ECG  
 
Electrocardiogram 
ECHO  
Echocardiogram 
eCRF  
Electronic case report/record form 

 
 
 
 
 
 
 
 
 
viii 
EC 
 
Endothelial Cell 
ELISA  
Enzyme-linked immunosorbent assay 
EOT  
 
End of Treatment 
FAO 
 
Fibroadipose hyperplasia or Overgrowth 
FDA  
 
Food and Drug Administration 
G1 
 
Gap-1 
GCP  
 
Good Clinical Practice 
GI 
 
Gastrointestinal 
GT  
 
Gastric Tube 
HDL  
 
High density lipoprotein 
HHML  
Hemihyperplasia Multiple Lipomatosis 
Hgb 
 
Hemoglobin 
HIPAA  
The Health Insurance Portability and Accountability Act of 1996 
HR  
 
Hazard Ratio 
HRQoL  
Health-Related Quality of Life 
HTN 
 
Hypertension 
IB  
 
Investigator’s Brochure 
ICF  
 
Informed Consent Form 
ICH  
 
International Conference on Harmonization 
 
IEC  
 
Independent Ethics Committee 
Ig  
 
Immunoglobulin 
IND  
 
Investigational New Drug 
INR 
 
International normalized ratio 
IP  
 
Investigational Product 
IR  
 
Intermediate Response 
IRB  
 
Institutional Review Board 
IV  
 
Intravenous 
KLA 
 
Kaposiform lymphangiomatosis 
LAR 
 
Legally Authorized Representative 
LDH  
 
Lactate Dehydrogenase 
LDL 
 
Low Density Lipoprotein 
LFT 
 
Liver Function Test 
LIC 
 
Laboratory assessment of localized intravascular coagulation 
LLN 
 
Lower limit of normal 
LVEF 
 
Left Ventricular Ejection Fraction 
MAPK   
Mitogen-activated protein kinase 
MCAP  
Megalencephaly-Capillary Malformation 
MCH   
Mean corpuscular hemoglobin 
MCHC   
Mean corpuscular hemoglobin concentration 
M-CM  
Megalencephaly-Capillary Malformation 
MCV  
 
Mean corpuscular volume 
MedDRA  
Medical Dictionary for Regulatory Activities 
MEK  
 
MAPK/ERK kinase 
mg  
 
Milligram(s) 
ml 
 
Milliliter(s) 
MRI  
 
Magnetic resonance imaging 
MSDS   
Material Safety Data Sheet 
mTOR   
Mammalian target of rapamycin serine/threonine protein kinase 
NCI 
 
National Cancer Institute 
NGS 
 
Next-Generation Sequencing 
NGT 
 
Nasogastric tube 
NTI 
 
Narrow Therapeutic Index 
OS  
 
Overall Survival 

 
 
 
 
 
 
 
 
 
ix
OTC  
 
Over the counter 
PAS  
 
Pharmacokinetic analysis set 
PBPK  
Physiologically based pharmacokinetic  
PI  
 
Principal Investigator 
PI3K  
 
Phosphatidylinositide 3-kinase(s) 
PIK3CA 
Phosphatidylinositide 3-kinase p110 alpha 
PLT 
 
Platelet 
PFS  
 
Progression-free survival 
PRO 
 
Patient Reported Outcomes 
PROMIS 
Patient Reported Outcome Measurement Information System 
PO  
 
Orally administered 
PT  
 
Prothrombin time 
QD 
 
Once daily 
QOD 
 
Every other day 
QTcF 
 
QT interval corrected by Fridericia’s formula 
RAF  
 
Serine/threonine-specific protein kinase Raf (Rapidly accelerated fibrosarcoma) 
RAS/RAS Ras  (Rat sarcoma) proto-oncogene product/oncogene encoding RAS 
RBC  
 
Red blood cell(s) 
RECIST 
Response evaluation criteria in solid tumors 
RNA  
 
Ribonucleic acid 
RR  
 
Response Rate 
SAE(s)   
Serious adverse event(s) 
SAS 
 
Statistical adverse event(s) 
SC 
 
Subcutaneous 
SD  
 
Stable Disease 
SOP 
 
Standard operating procedure 
SR 
 
Substantial Response 
TIE2/TEK 
Thyrosine Kinase endothelial 
TTP 
 
Time to progression 
ULN 
 
Upper limit of normal 
UMI 
 
Unique molecular identifier 
UNK 
 
Unknown 
VA 
 
Vascular anomaly 
VATCH  
Vascular Anomaly Analysis for Therapy of Choice  
VEGF  
Vascular endothelial growth factor 
WBC 
 
White blood cell 
WD 
 
Worsening Disease 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
x
ABSTRACT 
Background 
PIK3CA and TIE-2/TEK pathway driven vascular anomalies represent an extremely heterogenous group 
of disorders (ranging from small, isolated overgrowth to life-threatening extensive vascular 
malformations) that in the past were treated aggressively with surgical and endovascular procedures.   
With recent phenotype genotype discovery, more directed therapy with PIK3CA inhibitors has shown 
promising results, although data is limited. Alpelisib is a PIK3CA inhibitor, orally bioavailable, 
developed initially for malignant disorders with PIK3CA variants. 
 
Objectives  
Primary Objectives are:  
1) To determine the proportion of subjects with objective beneficial response to alpelisib at the end 
of cycle 6 (24 weeks) of therapy, using an individualized response criterion based on radiologic 
assessment, Patient Reported Outcomes (PROs) Measures, and Clinical Benefit Assessment 
(CBA) 
2) To assess the safety of oral alpelisib in children and young adults with PIK3CA/TIE2/TEK 
driven VA.   
Secondary and exploratory objectives include biomarker analysis, duration of response, and 
tolerability of alpelisib over time in subjects with PIK3CA/TIE2/TEK pathway driven VA.  
 
Study Design  
This study is a Phase II multi-center non-randomized clinical trial. 
 
Setting/Subjects 
The Vascular Anomaly Analysis for Therapy CHoice (VATCH) study is the platform for matching 
targeted therapy agent sub-protocols to children and young adults with VA driven by corresponding 
genetic drivers. This study will be performed in the outpatient center of the 25 institutions that are 
members of the Consortium for the iNvestigation of Vascular AnomalieS (CaNVAS).  This is sub-
protocol 2 and will enroll 53 evaluable and eligible subjects with VA phenotypes and genotype 
alterations of the PIK3CA/TIE-2/TEK pathway.  Subjects will be included that are deemed to need 
systemic medical treatment. 
 
Study Interventions and Measures   
The PIK3CA inhibitor alpelisib will be administered in this protocol for subjects with 
PIK3CA/TIE2/TEK driven vascular anomalies (VA). The dose may be increased throughout the study 
depending on response at the discretion of the treating physician. PROs Measures and Clinical Benefit 
Assessment will be performed at screening and after every 6 cycles. Radiologic assessment will be 
performed at screening and after cycles 6 and 12 if deemed part of the individualized response criteria. If 
there are any signs of worsening prior to study evaluations, then the Principal Investigator (PI) should 
complete earlier assessment for evaluation of response. If there are any signs of worsening prior to study 
evaluations, then the Principal Investigator (PI) should complete earlier assessment for evaluation of 
response. 

 
 
 
 
 
 
 
 
 
xi
Study Outcomes 
Assessment of individualized response criteria after 6 cycles for primary endpoint and then every 
6 months. 
 
Substantial response: 
o Improvement in Radiologic assessment (if applicable) by 20% AND 
o Improvement in Global Health PROs by 3T-score points AND 
o Improvement in at least 1 CBA as reported by the clinician AND 
o No clinically meaningful worsening in any measure 
 
Intermediate response: 
o Improvement in Radiologic assessment (if applicable) by 20% OR 
o Improvement in Global Health PROs by 3 T-score points OR 
o Improvement in at least 1 CBA as reported by the clinicians AND 
o No clinically meaningful worsening in any measure 
 
Stable disease: 
o No clinically meaningful improvement or worsening from screening in   
• 
Radiologic assessment (if applicable), OR 
• 
Global Health PROs, OR 
• 
CBA as reported by the clinician  
 
Worsening disease: 
o Clinically meaningful worsening in   
• 
Radiologic assessment (if applicable) by 20%, OR 
• 
Global Health PROs by 3T-score points, OR 
• 
CBA as reported by the clinician  
• 
Regardless of any concomitant improvement in other measures. 

 
 
 
 
 
 
 
 
 
xii 
PROTOCOL SYNOPSIS 
Study Title 
VATCH (Vascular Anomaly Analysis for Therapy Choice) – Sub-
protocol 2 – Phase II Study of Alpelisib Treatment in Subjects with 
TIE2/PIK3CA pathway Driven Vascular Anomalies 
Funder 
CaNVAS, Novartis 
Clinical Phase 
PHASE II 
Study Rationale 
The purpose of this study is to assess the efficacy and safety of 
alpelisib in subjects with PIK3CA/TIE-2/TEK pathway driven 
vascular anomalies (VA).  These diseases are rare and there is much 
heterogeneity of phenotype thus an innovative assessment of 
response will be used based on: radiology assessment, Patient 
Reported Outcome (PRO) Measurements, and Clinical Benefit 
Assessments (CBAs). 
Study Objective(s) 
Primary  
• 
To determine the proportion of subjects with objective 
beneficial response to alpelisib at the end of cycle 6 using 
individualized response criteria based on radiologic assessment, 
Patient Reported Outcomes (PROs), and Clinical Benefit 
Assessment (CBA). 
• 
To determine the safety of oral alpelisib in children and young 
adults with PIK3CA/TIE-2/TEK pathway driven vascular 
anomalies. 
Secondary 
• To assess the duration of response in subjects receiving alpelisib 
at the end of 12 and 24 cycles.  
• To assess the proportions of subjects with a response at the 
scheduled protocol visits for disease evaluation at the end of 
cycles 12 and 24.  
• To assess the changes in symptoms and 
complications/comorbidities associated with PIK3CA and TIE-
2/TEK somatic activating variations in VA. 
• 
Determine the most common and most serious adverse events as 
defined by Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0) in this VA population 
Exploratory 
• 
To correlate serum biomarkers before and during pharmacologic 
suppression in subjects with PIK3CA/TIE-2/TEK pathway driven 
vascular anomalies. 
• 
To correlate cfDNA before and during pharmacologic 
suppression in subjects with PIK3CA/TIE-2/TEK pathway driven 
vascular anomalies. 

 
 
 
 
 
 
 
 
 
xiii 
• 
To describe the distribution of genetic variants and their 
associated responses to alpelisib treatment in subjects with 
vascular and complex lymphatic anomalies. 
Study Drug 
Alpelisib tablet 
Study Design 
 
This is a Phase II multi-center non-randomized study to assess the 
safety and efficacy of alpelisib in PIK3CA/TIE-2/TEK driven 
vascular anomalies. 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Signed informed consent and assent (when applicable) from 
the subject, parent/guardian or Legally Authorized 
Representative (LAR) must be obtained prior to any study 
related screening procedures. 
2. Males or females age > 2 years to < 30 years at the time of 
informed consent with critical disease needed systemic 
medical therapy.   
3. Documented laboratory validated pathogenic or likely 
pathogenic somatic activating variant in PIK3CA or somatic 
TIE2/TEK variant. Germline TIE2/TEK variants are 
acceptable. Variants of Unknown Significance (VUS) not 
predicted to be pathogenic will not be allowed.  
4. Subjects must have a symptomatic vascular anomaly in need 
of medical therapy. 
5. Measurable Disease: Subjects must have a disease-related 
lesion or lesions which can be measured objectively via: 
a. Radiographic/imaging study OR        
b. Quantitative Clinical Benefit Assessments 
measurement: If there is no quantifiable lesion by 
imaging, the quantitative CBA must be determined 
prior to enrollment and confirmed/approved by study 
PI and local PI.  
6. Performance Level:  Subjects must have a Lansky or 
Karnofsky performance status score of ≥ 50 (ECOG 
categories 0,1 or 2) within 14 days before study treatment 
start.  Lansky scale to be used for subjects < 16 years of age.  
Karnofsky to be used for subjects > 16 years of age. Subjects 
in a wheelchair, unable to walk due to condition but who are 
up in a wheelchair will be considered ambulatory.  
7. Organ Function: Have acceptable organ function as defined 
as: 
a. Renal function: 
i. Serum creatinine concentration ≤1.5 × 
institutional upper limit of normal (ULN) 
based on the age and sex, or creatinine 
clearance (CrCl) >50 mL/min (0.84 mL/s) (as 

 
 
 
 
 
 
 
 
 
xiv
measured preferably by a nuclear glomerular 
filtration rate scan, timed urine collection for 
CrCl, or calculated by the Schwartz formula 
[for subjects <18 years] or Cockcroft-Gault 
[for subjects ≥18 years] and normalized to a 
BSA of 1.73 m2).  
b. Hepatic Function: 
i. Total bilirubin < 1.5 x upper limit of normal 
(ULN) for age except for subjects with 
confirmed Gilbert’s syndrome who may only 
be included if the total bilirubin is ≤ 3.0 × 
ULN or direct bilirubin ≤ 1.5 × ULN 
ii. Alanine aminotransferase (ALT) or SPGT < 3 
x ULN  
iii. Aspartate aminotransferase (AST) or SGOT < 
5 ULN 
iv. Serum albumin may be lower in this subject 
population and will not be used to evaluate 
adequate liver function 
c. Adequate cardiac function as indicated by  
i. Left Ventricular Shortening fraction of > 27% 
by echocardiogram or ejection fraction of > 
50% by MUGA 
ii. No documented history of congestive heart 
failure (New York Heart Association 
functional classification III-IV) 
iii. No history of long QT syndrome, family 
history of idiopathic sudden death or 
congenital long QT syndrome 
d. Adequate Bone Marrow Function 
i. Hemoglobin > 8 g/dL (may receive RBC 
transfusions) 
ii. Absolute Neutrophil Count (ANC) > 750 x 
109/L  
iii. Platelets > 75 x 109/L (independent of 
transfusions) exception is made for 
Kaposiform lymphangiomatosis subjects who 
have a baseline coagulopathy and 
thrombocytopenia 
e. Additional Laboratory Assessments 
i. Calcium (corrected for serum albumin) and 
magnesium within normal limits or ≤ Grade 1 
according to NCI-CTCAE version 5.0 if 
judged clinically not significant by the 
investigator 

 
 
 
 
 
 
 
 
 
xv 
ii. Potassium within normal limits, or corrected 
with supplements 
iii. Fasting plasma glucose (FPG) ≤ 140 mg/dL 
(7.7 mmol/L) and glycosylated hemoglobin 
(HbA1c) ≤ 6.5% (both criteria have to be 
met) 
iv. Fasting Serum lipase ≤ ULN 
8. Persons who can get pregnant ³11 years of age or persons 
with early onset menarche must have a negative serum or 
urine pregnancy test within 7 days prior to the initiation of 
the study medication. 
9. Males and females of reproductive potential must agree to 
use an acceptable method of contraception, including 
abstinence, a barrier method (diaphragm or condom), IM 
progesterone depot, intrauterine contraceptive device, or an 
oral contraceptive, for the duration of time when they are 
receiving study drug and for 3 months following last dose. 
10. Subjects that have received alpelisib previously either via 
Managed Access Program from Novartis or commercial 
supply are eligible to enroll IF they have been off alpelisib 
for at least 7 days and there is clinical progression/worsening 
while off treatment.  
Exclusion Criteria 
1. Subject with only epidermal nevus/nevi in the absence of 
other PIK3CA vascular anomaly/overgrowth 
2. Debulking or other major surgery performed within 30 days, 
at time of informed consent. 
3. Clinically meaningful bleeding related to VA: Grade 2 
within 14 days or Grade 3 and more within 28 days 
before study treatment start as per CTCAE v. 5.0 
4. Sclerotherapy/embolization for vascular complications 
performed within 14 days before informed consent.  
5. Subjects, who previously received systemic treatment 
including alpelisib and targeted topical therapy including 
PIK3CA inhibitors for their vascular anomaly (e.g.,mTOR 
inhibitors, AKT inhibitors, anti-angiogenic agents), may 
enter the study if the following criteria are met: 
a. Not simultaneously on another clinical trial; 
b. Off systemic previous systemic treatment for at least 
30 days prior to consent; 
c. Off MTOR inhibitors for at least 14 days prior to 
initiation of alpelisib. 
6. Participation in any other prior investigational study 

 
 
 
 
 
 
 
 
 
xvi
within 4 weeks prior to study treatment start and within 5 
half-lives of the investigational product, whichever is 
longer 
7. Supportive care use of anticoagulants and compression 
garments is allowed. Subjects must have been using these 
interventions in an unchanged manner for 30 days before 
study enrollment. 
8. History of prior and or ongoing malignancy (within 5 years 
before informed consent except radically treated carcinoma 
in situ or radically treated basal-cell carcinoma of skin or 
thyroid gland, well-differentiated microcarcinoma or Stage 
1 Wilms’ tumor of a histology other than anaplastic), or 
ongoing investigations or treatment for malignancy at time 
of informed consent. 
9. Clinically significant heart disease not due to VA, 
including 
a. History of documented congestive heart failure (New 
York Heart Association functional classification III-
IV); 
b. Clinically significant uncontrolled cardiac 
arrhythmias; 
c. Long QT syndrome, family history of idiopathic 
sudden death or congenital long QT syndrome; 
d. Corrected QT (QTcF) at screening: >450 ms. 
10. Documented pneumonitis or interstitial lung disease not 
due to VA  
11. History of acute pancreatitis within 1 year before 
informed consent or past medical history of chronic 
pancreatitis 
12. Subjects with an established diagnosis of type I diabetes 
mellitus or uncontrolled type II diabetes mellitus 
13. Impaired gastrointestinal (GI) function that may 
significantly alter the absorption of the study drug (e.g., 
ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel 
resection) 
14. History of hypersensitivity to any drugs or metabolites of 
PI3K inhibitor or any of the excipients of alpelisib 
15. Known history of Steven Johnson’s syndrome, erythema 
multiform or toxic epidermal necrolysis 
16. History of seizures or epilepsy on enzyme inducing 
antiepileptic drug(s); uncontrolled seizures are only 
allowed if due to PIK3CA variation 
17. Concurrent severe and/or uncontrolled medical conditions 
not due to PIK3CA variation. Resolution of symptoms for 
at least 28 days must have occurred before consent 

 
 
 
 
 
 
 
 
 
xvii 
18. Subject  may not be pregnant or breast feeding. 
19. Female subjects of childbearing age and male subjects 
who do not agree to abstinence or to a highly effective 
method of contraception (condoms and/or oral, injected or 
implanted hormonal methods of contraception, or 
placement of an intrauterine device or intrauterine system, 
or surgical sterilization for the duration of the study and 
for one week following discontinuation of alpelisib, or 
non-heterosexual partnerships) 
20. Human Immunodeficiency Virus (HIV) infection by 
history or by eligibility testing 
21. Concomitant treatment with Strong inducers of CYP3A4 
(Appendix VI) 
22. Subjects not able to understand and to comply with study 
instructions and requirements (in patients, legally 
authorized representatives, or guardians as applicable) at 
time of informed consent. 
Number of Subjects  
 
Enrollment is planned for 53 evaluable eligible subjects in total with 
participation of 25 sites across the United States. 
Study Duration 
Each subject’s participation will last 24 cycles (96 weeks) with an 
extension period up to 36 total cycles (3 total years including the 
first 24 cycles of therapy) if the subject has been found to have a 
beneficial response. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
Intervention study 
1. Screening: Screening for eligibility and obtaining consent 
2. Intervention: Study intervention/experimental treatment. 
3. Extension period: Continued therapy for subjects with 
response and acceptable toxicity. 
Efficacy Evaluations 
1. Radiologic assessment (if applicable): 
- For subjects with radiologically evaluable disease. 
Subjects without radiologically evaluable disease 
may have a CBA substituted for radiologic 
evaluation. 
-MRI evaluation will be at screening, and at the end 
of cycles 6,12, and 24 (if applicable) on treatment. If 
there are signs of worsening, earlier assessment 
should be done.  
2. Patient reported outcome (PRO) measurements: 
- Screening to end of study- Every 6 cycles  
3. Clinical Benefit Assessment (CBA): 
- Screening to the end of study- every 6 cycles  

 
 
 
 
 
 
 
 
 
xviii 
Safety Evaluations 
Safety assessments will be conducted through the study 
(according to the assessment schedule) 
• Monitoring of adverse events (AEs) and serious adverse 
events (SAEs) 
• Physical examination 
• Body weight and vital signs  
• Height and body mass index (BMI)  
• Karnofsky/Lansky performance status 
• Laboratory assessment including hematology, biochemistry, 
urinalysis, and coagulation. 
• Serum or urine pregnancy test for subjects of child-bearing 
potential 
• Echocardiography 
Statistical and 
Analytic Plan 
For all the analyses, subjects who received any dose of alpelisib will 
be included in the analyses. For the primary efficacy analysis of 
objective response at the end of cycle 6, we will test a null 
hypothesis of response of 60% against an alternative hypothesis of 
response rate of 80%. We will follow the Simon’s optimal two-stage 
design: an interim analysis will be conducted after 19 subjects have 
been observed for response, and if 11 or fewer intermediate, 
substantial, or stable responses are observed, the trial will be 
stopped for futility; otherwise, the trial will continue to enroll a total 
of 53 evaluable subjects and at the end of the trial if 37 or more 
intermediate or substantial responses are observed, the treatment 
will be declared promising. This design provides >=90% power 
when the true response rate is 80% and yields a one-sided type I 
error of <=0.05 when the true response rate is 60%.  
For evaluating toxicity, a sample size of 53 provides 93% 
probability to observe at least one toxicity event when the 
underlying true toxicity rate is 5%, so that we have good confidence 
to observe a rare toxicity type. In addition, this sample size provides 
a reasonable precision on the estimate of the toxicity rate. For 
example, with 10 observed toxicity events out of 53 subjects, the 
estimated toxicity rate is 19%, with the 95% exact confidence 
interval (CI) as 9% - 32%. 
Data and Safety 
Monitoring Plan 
This study will be monitored in accordance with a Data Safety 
Monitoring Plan for Phase II Studies. In brief, the role of the Data 
and Safety Monitoring Board (DSMB) is to protect the interests of 
subjects and the scientific integrity for clinical trials. The DSMB 
will monitor this trial at a frequency determined by the DSMB 
Chair, but at least twice annually. Approximately 2 weeks before 
each meeting of the DSMB, the study chair will be responsible for 
working with the study statistician to prepare study reports for 

 
 
 
 
 
 
 
 
 
xix
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EXPERIMENTAL DESIGN SCHEMA 
Treatment Schema: 
 
 
Day 1: 
 
 
 
 
 
 
   Day 28: 
 
Begin Cycle  
 
 
 
 
   End of Cycle 
 
review by the DSMB. The DSMB will provide recommendations to 
change the study or to continue the study unchanged. 
Monitoring and auditing procedures will be followed to ensure that 
the study is conducted, documented, and reported in accordance 
with the IRB approved protocol, the International Conference on 
Harmonization (ICH), Good Clinical Practice (GCP) Guidelines, 
and applicable regulatory requirements of federal regulations.  
Verification of eligibility and appropriate documentation of 
informed consent will be performed for all subjects enrolled into the 
study. Monitoring of timeliness of AE and SAE reporting will be 
done as events are reported. CRFs for each subject enrolled will be 
monitored for completeness and quality by comparing data in the 
CRFs to data in the source documents.  
 

 
 
 
 
 
 
 
 
 
xx 
 
A cycle of therapy is 28 days.  
Subjects will receive study therapy daily for 28-day cycles. 
Radiologic assessment will occur at screening and the end of cycles 6, 12, and 24 (if applicable). 
Radiologic assessment at other time points will be at the discretion of the treatment team.  PROs 
Measurements and CBA will begin at screening and will occur at the end of every 6 cycles 
throughout the duration of the study and extension period. If there are any signs of worsening 
prior to study evaluations, then the Principal Investigator (PI) should complete earlier assessment 
for evaluation of response.            
 
Therapy will be discontinued if there is evidence of worsening disease or drug related dose-
modifying toxicity that requires removal from therapy. Treatment may otherwise continue to the 
end of the study intervention phase and subsequent extension period provided the subject meets 
the criteria for starting subsequent cycles and does not meet criteria for removal. 
 
 
 
 
 

 
  
 
 
1
1 
BACKGROUND AND RATIONALE 
1.1 Introduction 
Vascular anomalies (VA) and Complex lymphatic anomalies (CLA) are a group of 
malformations with highly variable presentations. Patients with vascular and lymphatic 
anomalies suffer from significant morbidity, disfigurement, and mortality with limited 
available systemic treatment options. The current systemic therapies utilized have limited 
evidence to support their efficacy and safety in part because of the highly diverse and 
variable diseases. This clinical heterogeneity reflects the complex genetic underpinnings of 
each subject’s disease making the delivery of therapy targeted to individual subjects 
challenging.  
 
Vascular Anomaly analysis for Therapy CHoice (VATCH) is a collaborative nationwide 
clinical trial run through the Consortium for the iNvestigation of Vascular Anomalies 
(CaNVAS) as a multi-agent/multi-arm clinical trial designed to provide a therapy which is 
targeted to the specific genetic drivers of a subject’s specific CLA or VA.  
1.2  Pathway  
The PI3K/AKT/mTOR mammalian target of rapamycin (mTOR) signaling pathway plays a 
major role in the physiological processes regulating cellular growth, proliferation, 
angiogenesis, survival, and metabolism.1-3  The hyper-activation of the PI3K/AKT/mTOR 
pathway results in dysregulation of cellular functions, leading to a competitive growth 
advantage. Somatic mutations and gains or losses in these genes are linked to different solid 
and hematological tumors as well as overgrowth syndromes.4  PIK3CA encodes the p110α 
catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which transduces activation of 
tyrosine kinase growth factor and hormone receptors into activation of Protein Kinase B 
(AKT) and Mammalian Target of Rapamycin (mTOR) signaling to promote tissue growth. 
Patients who develop mosaic activating variants (typically somatic) in the PIK3CA gene can 
develop overgrowth of a particular section of the body, referred to as “PIK3CA-related 
overgrowth spectrum” (PROS).  
 
PROS (FIG 1)5,6 can encompass a range of clinical findings in which the core features are 
congenital or early-childhood onset of segmental/focal overgrowth with or without cellular 
dysplasia. The predominant areas of overgrowth include the brain, limbs, abdomen, chest, 
and face, and occur in an asymmetric distribution. A clinical spectrum is observed even 
though all the conditions are related to the PROS umbrella, where PIK3CA is the causative 
gene. PROS includes Fibroadipose hyperplasia or Overgrowth (FAO), Hemihyperplasia 
Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular 
Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, 
macrodactyly, Fibroadipose Infiltrating Lipomatosis, and the related megalencephaly 
syndromes, Megalencephaly-Capillary Malformation (MCAP or M-CM) and Dysplastic 
Megalencephaly(DMEG). Vascular malformations may include capillary, venous, and less 
frequently, arterial or mixed (capillary-lymphatic-venous or capillary-venous-lymphatic) 
malformations. These may be in various locations (internal and/or external) and can cause 
various clinical issues, including swelling, pain, and occasionally localized bleeding 

 
  
 
 
2
secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a 
vascular malformation. Intellectual disability may be a feature and appears to be mostly 
related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and 
hydrocephalus.  
 
Endocrine issues affect a small number of individuals and most commonly include 
hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and 
growth hormone deficiency. First clinical evidence of PROS usually occurs at birth or early 
in life (first 6-18 months of life). Affected areas generally keep growing throughout life, but 
at a slower pace after the subject reaches their third decade of life. Previously, there was no 
drug therapy for PROS, the treatment consisted of symptom management, mainly surgical 
interventions of overgrowth lesions that ultimately led to severe physical disabilities with 
unsatisfactory quality of life (QOL). The potential to modify and control disease progression 
is greatest during the rapid disease progression stage which occurs in early childhood. In 
more recent years, allosteric mTOR inhibitors such as sirolimus have been shown to slow 
the growth of cancers bearing PIK3CA variants.7  Sirolimus also potently attenuates 
pathological AKT signaling and reduces cell proliferation in dermal fibroblasts derived from 
people with PROS and is currently being used in the treatment of PROS. Published reports 
of sirolimus therapy in PROS have suggested efficacy.8-10 The use of Sirolimus and 
subsequent studies in participants with vascular anomalies and PROS support the hypothesis 
that agents targeting PI3K/AKT/mTOR pathway genes may be better candidates should be 
further explored in patients with specific PIK3CA mutations. 
 
 
FIGURE 1: PI3K/AKT Pathway and Related Disorders 

 
  
 
 
3
Venous Malformations (VM) can be caused by PIK3CA (20%) and TIE-2/TEK 80% of the 
time. They can be focal, multi-focal or extensive and can cause issues with pain, organ 
dysfunction, functionality and can lead to significant life-threatening complications such as 
bleeding and pulmonary emboli.    The mTOR inhibitor sirolimus has been used in 
prospective studies revealing good efficacy and tolerability and this has been validated in 
animal models.  (Sirolimus is efficacious in treatment for extensive and/or complex slow-
flow vascular malformations: a monocentric prospective phase II study.11,12 
 Many patients do not respond to sirolimus or lack durable responses, and this medication is 
known to be an immunosuppressant.  Recently, alpelisib has been shown to be efficacious 
and safe in patients with complicated venous malformations.  
 
1.3 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, and 312. All episodes of 
noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with The Children’s Hospital of Philadelphia IRB Policies and 
Procedures and all federal requirements. Collection, recording, and reporting of data will be 
accurate and will ensure the privacy, health, and welfare of research subjects during and 
after the study.  
 
2 
RATIONALE 
2.1  Investigational drug: Alpelisib (Vijoice®) 
Alpelisib (BYL719) is an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) 
inhibitor belonging to the 2-aminothiazole class of compounds. Alpelisib has demonstrated 
antitumor activity in a variety of cancer cell lines, specifically those with PIK3CA variants 
and in xenograft models with mutated or amplified PIK3CA.13 Human clinical studies also 
demonstrated the antitumor activity of alpelisib, especially in tumors with PIK3CA 
alterations, with a well charaterized safety profile.14,15 Alpelisib is a first-in-class α-specific 
phosphatidylinositol 3-kinase inhibitor approved for the treatment of patients with estrogen 
receptor–positive metastatic breast cancer. Alpelisib demonstrated efficacy in a mouse 
model of PROS/CLOVES, which was followed by the use of alpelisib in patients with 
PROS under a compassionate use program consisting of 19 patients with PROS disorders 
led to substantial clinical improvement and a radiological response in all patients.16 Children 
(<18 years) received alpelisib at 50 mg per day orally; adult participants received 250 mg 
per day orally. Disease evaluation was performed at baseline, then after 3 and 6 months of 
treatment. There was clinical improvement with partial or complete recovery from PROS-
related complications (for instance, chronic gastrointestinal bleeding, disseminated 
intravascular coagulation, scoliosis, cognitive function and changed behavior) and with 

 
  
 
 
4
changes in concomitant medication (for instance, cessation of strong analgesics, heparin, 
steroid treatment in participants who received these medications because of PROS-related 
complications). There have been subsequent case reports describing the successful use of 
alpelisib in patients with CLOVES and other PROS.17,18 In summary, the PI3K/AKT 
pathway, which is dysregulated in PIK3CA-related overgrowth spectrum, is frequently 
activated through mutations in PIK3CA, thus, inhibition of PIK3CA by alpelisib is a rational 
approach for the therapeutic intervention in such diseases.   
2.1.1  Rationale for Dose/Age 
Drug dosing is based on two studies, EPIK-P1, NCT 04285723, and EPIK- P2, 
NCT04589650. The EPIK-P140 study was a non-interventional, site-based, medical chart 
review of patients > or = 2 years with PROS with severe/life-threatening conditions who 
received at least dose of alpelisib at least 24 weeks before the study cut-off date.  On April 
05, 2022, alpelisib received accelerated approval from the US FDA for the treatment of 
adult and pediatric patients aged ≥2 years with severe manifestations of PROS who require 
systemic therapy41.   From this study, dosing for the present EPIK-P242: a Phase II double-
blind study with an upfront, 16-week randomized, placebo-controlled period to assess the 
efficacy, safety, and pharmacokinetics of alpelisib (BYL719) in pediatric and adult patients 
with PIK3CA-related overgrowth spectrum (PROS) was used. The same dosing per age will 
be used for this study. 
2.2  Rationale for Individualized Evaluations 
Enrolled patients must have a documented laboratory validated pathogenic or likely 
pathogenic germline or somatic vascular anomaly driven by by PIK3CA/TIE-2/TEK -
pathway alteration. The phenotype and clinical characteristics will be heterogenous between 
subjects. The optimal measure of disease response in subjects with complex vascular 
anomalies has not been established. Current practice includes decreases in size of the VA, 
according to the subject perception, a physical exam, or radiographic (most commonly MRI) 
evaluations, laboratory assessments and other clinical testing and/or quality of life measures. 
These methods individually are challenging to assess because of heterogeneity in growth 
patterns, diversity of associated clinical and laboratory abnormalities and a fluctuating 
clinical course dependent upon factors other than treatment, such as intercurrent infection, 
puberty, and trauma. Further, lesion size, determined radiographically and clinical changes 
or quality of life (QOL) measures is not clearly correlated. For these reasons the efficacy of 
alpelisib treatment will be based on an Individualized Response Criteria protocol with three 
distinct components: Radiologic evaluation, PROMIS Patient reported Outcome (PRO) 
Measurements, and Clinical Benefit Assessments (CBA). CBA can be substituted for 
radiologic evaluation in subjects without radiologically evaluable disease after approval 
from study PI or co-PI. These three components will be performed at discrete time points to 
quantitatively determine the individualized response to alpelisib therapy for subjects with 
vascular anomalies driven by PIK3CA/TIE-2/TEK alterations.  Similar response criteria 
have been used in other studies. 28 Primary response outcome based solely on imaging 
criteria has not proven effective.  
 

 
  
 
 
5
2.3  Rationale for Exploratory Aims 
To correlate serum biomarkers with single cell findings before and during 
pharmacologic TIE2/TEK suppression 
 
The angiopoietin-TIE2/TEK signaling pathway is critical for blood and lymphatic 
development and maintenance.43-46Angiopoietins 1 (Ang1) and 2 (Ang2) are endothelial-
specific growth factors. Ang-1 activates the TIE2 receptor, leading to vessel remodeling, 
stabilization, and quiescence. Mutations involving TIE2 have been associated with venous 
and arteriovenous malformations. Ang-2 can promote vascular leakage, inflammation, and 
metastasis in blood ECs, and in lymphatic ECs may activate lymphangiogenesis. 47,48 
Elevated levels of Ang-2 and low Ang-1 levels have been found in KLA as well as other 
CLAs.45 Measurement of Ang-2 is now a clinical test for diagnosis and monitoring of 
treatment response. However, the cell populations expressing Ang-1 and Ang-2 in different 
VA are not well defined. Cell populations expressing Ang-2 will be identified using 
scRNA-seq analysis, and levels of Ang-2, and other biomarkers will be correlated with 
transcriptomic findings. Ang-2 will be measured using our clinically validated ELISA in 
serum samples from enrolled subjects with VA before treatment, and at the end of cycles 6 
and 12 into treatment.  Ang-2 biomarker levels will be correlated with diagnosis, genotype, 
disease progression and severity, blood cell counts and treatment response. Additional 
biomarkers, including VEGFR3 (soluble VEGFR3), Tenascin C, VEGF-A, -C, -D, 
CXCl12, will also be identified by scRNA-seq analysis and correlated with clinical 
features. 
To evaluate cell free DNA (cfDNA) for acquired variants as disease causing 
biomarker in plasma samples from vascular anomalies subjects and follow 
variant load in plasma every six cycles x2 as response to therapy 
The center for applied genomics (CAG) at CHOP, has optimized methods for isolation and 
purification of cell-free DNA (cfDNA) from low concentrations of cell-free DNA, 
addressing instability and the small fragment sizes. This highly valuable material is of 
critical importance for variant detection in subjects with vascular malformations, using NGS 
technologies for data generation and ddPCR or NGSure for variant validation. CAG uses the 
Streck Cell-Free DNA BCT, collecting samples from different bodily fluids, including 
blood, chylous fluid and lymph fluid.  CAG has successfully uncovered disease causing 
variants in over 30 patients using cfDNA (impossible to make diagnosis any other way), 
leading to better informed decisions regarding treatment plans, therapeutic effectiveness.  
We use our UMI panel with 49 of the most relevant disease causing (lymphatic/vascular 
malformation) genes.  We have successfully identified and validated variants across the 
PIK3CA/mTOR and Ras/MAPK pathway genes using cfDNA in the allele frequency range 
of 0.05% and higher, using our customized UMI panel with sequence fold coverage of 
30,000-60,000x.  We propose to analyze all subjects entering this study using our 
customized UMI gene panel in the CLIA-certified laboratory at the CAG, including deep 
coverage of 49 candidate lymphatic/vascular malformation genes. For those who are 
positive (estimate over 40% of subjects today with growing success rate as the technology 
matures), we will then obtain new sample for cfDNA isolation at week 24 and 48 to follow 

 
  
 
 
6
variant load in response to therapy with Alpelisib and other drugs as informed by the 
variants identified.  We anticipate the variant load will go down and possibly resolve 
completely as we continue long-term treatment of these subjects. 
3 
OBJECTIVES AND ENDPOINTS 
3.1 Specific Hypothesis 
Alpelisib is effective and safe for subjects with the diagnosis of vascular anomalies and 
overgrowth syndromes caused by somatic activating variants in PIK3CA and TIE-2/TEK 
genes. 
3.2 Primary Objectives 
• To determine the proportion of subjects with an objective beneficial response to alpelisib 
at the end of cycle 6 using an individualized response criterion based on Radiologic 
Assessment, Patient Reported Outcomes (PROs) and Clinical Benefit Assessment 
(CBA). 
• To determine the safety of oral alpelisib in children and young adults with 
PIK3CA/TIE2/TEK pathway driven vascular anomalies at the end of 6 cycles. 
 
3.3 Secondary Objectives 
• To assess the duration of response in subjects receiving alpelisib at the end of cycles 12 
and 24. 
• To assess the proportions of subjects with a response at the scheduled protocol visits for 
disease evaluation at the end of cycles 12 and 24. 
• To assess the changes in symptoms and complications/comorbidities associated with 
PIK3CA and TIE-2/TEK somatic activating variants in VA. 
• Determine the most common and most serious adverse events as defined by Common 
Terminology Criteria for Adverse Events (CTCAE, version 5.0) in this vascular 
anomalies population 
3.4 Exploratory Objectives  
• 
To correlate serum biomarkers with before and during pharmacologic suppression in 
subjects with PIK3CA/TIE-2/TEK pathway driven vascular anomalies. 
• To correlate cfDNA before and during pharmacologic suppression in subjects with 
PIK3CA/TIE-2/TEK pathway driven vascular anomalies. 
• To describe the distribution of genetic anomalies and their associated responses to 
alpelisib treatment in subjects with PIK3CA and TIE-2/TEK activating variants 
 

 
  
 
 
7
4 
INVESTIGATIONAL PLAN 
4.1 General Schema of Study Design 
This study is a single-arm, open-label investigational Phase II study of alpelisib 
administered orally on a continuous 28-days, for up to 24 total cycles in subjects ages 2 
years to 30 years. Subjects in the absence of toxicity and with clinical benefit may continue 
into the extension period for 36 cycles total.   
4.2 Registration, Enrollment, and Screening 
Potential subjects will be identified by VA provider-referral or self-referral and screened 
using protocol inclusion and exclusion criteria.   
 
The investigational nature and objectives of the study, the procedures and treatments 
involved, benefits and potential adverse effects, and potential alternative therapies will be 
carefully explained to the subject or to the subject’s parents or guardian/LAR. A signed 
informed consent and assent will be obtained according to institutional guidelines. 
 
Documentation of the informed consent for screening will be maintained in the subject’s 
research chart. Studies or procedures that were performed for clinical indications (not 
exclusively to determine eligibility) may be used for screening values even if the studies 
were done before informed consent was obtained. 
 
All clinical and laboratory studies to determine eligibility must be performed within 14 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
must be no older than 14 days at the start of therapy. Laboratory tests need not be repeated if 
therapy starts within 14 days of obtaining labs to assess eligibility.   
 
Subjects will be given a study specific identified assigned by CASTOR when they are 
registered in CASTOR, the study’s data management system.  
 
4.2.1 Optional Biologic Studies 
Correlative molecular biology studies will be conducted as part of the current trial. All 
subjects should be approached for consent to all of these biology studies. Subjects may 
participate in the treatment portion of this trial without consenting to the biology studies.  
 
Biomarker samples (frozen serum or plasma samples) will be analyzed in Dr. Tim Le Cras’s 
lab at Cincinnati Children’s Hospital Medical Center Biomarker analysis can include 
measurement of levels of VEGF-A, C, D, Endothelin-1 and Angiopoietin-1, 2. Frozen serum 
samples are preferred but, in some instances, frozen plasma samples can be used. Serum and 
plasma samples should be frozen at -70-80C and transported frozen on dry ice.  
 
 
Cell-free DNA will be analyzed in Dr. Hakon Hakonarson’s lab at Children’s Hospital of 
Philadelphia (Appendix III).  

 
  
 
 
8
 
These biomarkers will be collected at screening, at the end of Cycle 6, and at the end of  
Cycle 12. 
 
Samples that are not immediately analyzed will be stored in Dr. Hakon Hakonarson’s lab at 
Children’s Hospital of Philadelphia. Leftover and or unused samples will be deidentified and 
used in future research.  
4.3 Study Treatment Phase (start of the study intervention) 
Alpelisib should be taken once daily with food, at approximately the same time each day. If 
a dose of alpelisib is missed, it can be taken immediately after food and within 9 hours after 
the time it is usually administered. After more than 9 hours, the dose should be skipped for 
that day.  On the next day, alpelisib should be taken at the usual time.  If the subject vomits 
after taking the alpelisib dose, the subject should not take an additional dose on that day and 
should resume the usual dosing schedule the next day at the usual time. 
 
Alpelisib is available as 50, 125, and 200mg tablets and will be dosed mg/day and not 
adjusted for body weight or body surface area. 
4.3.1 Dosing 
For subjects 18 years and older, alpelisib will be administered at 125mg daily (with the 
potential to increase up to a maximum dose of 250 mg orally once daily) on a continuous 
dosing schedule and can be adjusted for toxicity per the recommendations in this treatment 
plan. Alpelisib cannot be combined with other investigational agents as there are no safety 
data available.  
 
For subjects 6-17 years of age, alpelisib will be administered at 50mg daily (with the 
potential to increase up to a maximum dose of 200 mg orally once daily) on a continuous 
dosing schedule and can be interrupted for toxicity per the recommendations in this 
treatment plan. Alpelisib cannot be combined with other investigational agents as there are 
no safety data available. 
 
For subjects 2-5 years of age, alpelisib will be administered at 50 mg orally once daily on a 
continuous dosing schedule and can be interrupted for toxicity per the recommendations in 
this treatment plan. Alpelisib cannot be combined with other investigational agents as there 
is no safety data available. Alpelisib should be swallowed whole (tablets should not be 
chewed, crushed [with the exception of crushing under water to create an oral suspension], 
or split prior to swallowing. Tablets that are broken, cracked, or otherwise not entact should 
not be ingested and are to be returned to site staff. For participants who are unable to 
swallow, alpelisib can be administried as a drinkable suspension by crushing tablets under 
water with a spoon.  
 
Refer to Section 10 for dose modifications for toxicity. 

 
  
 
 
9
 
4.4  Follow-up Phase 
Subjects who have stopped alpelisib therapy due to completion of therapy or toxicities will 
be followed for 30 days after treatment cessation or resolution of toxicities, whichever is 
longer.   
4.5  Extension Phase 
Subjects showing clinical benefit may continue into the extension period for up to 12 
additional cycles (36 total cycles, including the treatment phase). This will be at the 
discretion of the treating physician and the subject’s family.  
 
4.6 End of Treatment 
Treatment will be discontinued if one of the below conditions are met: 
• after completing up to 24 cycles of therapy (for subjects who do not participate in the 
extension phase); or  
• after completing up to 36 cycles of therapy (for subjects who participate in the 
extension phase); or 
• by subject (or legal guardian/LAR) decision; or 
• by physician’s decision if the subject has progressive disease, severe side effects or 
does not comply with the study requirements; or 
• by decision of CaNVAS based on Safety Monitoring Board  
 
4.7 Study Duration, Enrollment and Number of Sites 
4.7.1 Duration of Study Participation 
The study duration per subject may be up to 30 days of the Screening Phase, up to 24  
complete cycles of Study Treatment Phase, and up to 30 days follow-up once medication has 
been discontinued. Subjects deriving benefit from study drug may be eligible for the 12 
cycles of the Extension Phase following the initial 24 cycles of treatment.  
Active recruitments will take 2 years and there will be follow up after discontinuation of 
study treatment for a period of 30 days.  
4.7.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be a multi-site trial through the CaNVAS Consortium which currently 
comprises 25 sites throughout the United States.  
 
Recruitment will stop when 53 evaluable subjects are enrolled.  It is expected that 
approximately 61 subjects will be enrolled to produce 53 evaluable subjects.  

 
  
 
 
10 
4.8  Study Population 
Study entry is open to subjects regardless of gender or ethnic background. While there will 
be every effort to seek out and include females and minority subjects, the subject population 
is expected to be no different than that of subject backgrounds at the CaNVAS consortium 
membership sites. 
 
5 
SUBJECT ELIGIBILITY 
The study plans to enroll approximately 53 evaluable subjects in total. The study will 
enroll both adult and pediatric subjects ≥2 years old. 
 
5.1 Inclusion Criteria 
The eligibility criteria listed below are interpreted literally and cannot be waived. Subjects 
eligible for inclusion in this study must meet all of the following criteria:  
 
1. Signed informed consent and assent (when applicable) from the subject, 
parent/guardian/LAR must be obtained prior to any study related screening 
procedures. 
2. Males or females age > 2 years to < 30 years at the time of informed consent with 
critical disease needed systemic medical therapy.   
3. Documented laboratory validated pathogenic or likely pathogenic somatic 
activating variant in PIK3CA or somatic TIE2/TEK mutation. Germline TIE2/TEK 
variants are acceptable. Variants of Unknown Significance (VUS) not predicted to be 
pathogenic will not be allowed. 
4. Subjects must have a symptomatic vascular anomaly in need of medical therapy. 
5. Measurable Disease: Subjects must have at least one disease-related lesion which can 
be measured objectively via: 
a. Radiographic/imaging study OR        
b. Quantitative Clinical Benefit Assessments measurement (Appendix IX) If 
there is no quantifiable lesion by imaging, the quantitative CBA must be 
determined prior to enrollment and confirmed/approved by study PI and local 
PI.  
6. Performance Level:  Subjects must have a Lansky or Karnofsky performance status 
score of ≥ 50 (ECOG categories 0,1 or 2) within 14 days before study treatment start.  
Lansky scale to be used for subjects < 16 years of age.  Karnofsky to be used for 
subjects > 16 years of age. Subjects in a wheelchair, unable to walk due to condition 
but who are up in a wheelchair will be considered ambulatory.  
7. Organ Function: Have acceptable organ function as defined as: 
a. Renal function: 
i. Serum creatinine concentration ≤1.5 × institutional upper limit of 
normal (ULN) based on the age and sex, or creatinine clearance 
(CrCl) >50 mL/min (0.84 mL/s) (as measured preferably by a nuclear 
glomerular filtration rate scan, timed urine collection for CrCl, or 

 
  
 
 
11 
calculated by the Schwartz formula [for subjects <18 years] or 
Cockcroft-Gault [for subjects ≥18 years] and normalized to a BSA of 
1.73 m2).  
b. Hepatic Function: 
i. Total bilirubin < 1.5 x upper limit of normal (ULN) for age except for 
subjects with confirmed Gilbert’s syndrome who may only be 
included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 
× ULN 
ii. Alanine aminotransferase (ALT) or SPGT < 3 x ULN  
iii. Aspartate aminotransferase (AST) or SGOT < 5 ULN 
iv. Serum albumin may be lower in this subject population and will not 
be used to evaluate adequate liver function 
c. Adequate cardiac function as indicated by  
i. Left Ventricular Shortening fraction of > 27% by echocardiogram or 
ejection fraction of > 50% by MUGA 
ii. No documented history of congestive heart failure (New York Heart 
Association functional classification III-IV) 
iii. No history of long QT syndrome, family history of idiopathic sudden 
death or congenital long QT syndrome 
d. Adequate Bone Marrow Function 
i. Hemoglobin > 8 g/dL (may receive RBC transfusions) 
ii. Absolute Neutrophil Count (ANC) > 750 x 109/L  
iii. Platelets > 75 x 109/L (independent of transfusions) exception is made 
for Kaposiform lymphangiomatosis subjects who have a baseline 
coagulopathy and thrombocytopenia 
e. Additional Laboratory Assessments 
i. Calcium (corrected for serum albumin) and magnesium within normal 
limits or ≤ Grade 1 according to NCI-CTCAE version 5.0 if judged 
clinically not significant by the investigator 
ii. Potassium within normal limits, or corrected with supplements 
iii. Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and 
glycosylated hemoglobin (HbA1c) ≤ 6.5% (both criteria have to be 
met) 
iv. Fasting Serum lipase ≤ ULN 
8. Persons who can get pregnant 11 years of age or persons with early onset menarche 
must have a negative serum or urine pregnancy test within 7 days prior to the 
initiation of the study medication. 
9. Males and females of reproductive potential must agree to use an acceptable method 
of contraception, including abstinence, a barrier method (diaphragm or condom), IM 
progesterone depot, intrauterine contraceptive device, or an oral contraceptive, for 
the duration of time when they are receiving study drug and for 3 months following 
last dose. 
10. Subjects that have received alpelisib previously either via Managed Access Program 
from Novartis or commercial supply are eligible to enroll IF they have been off 
alpelisib for at least 7 days and there is clinical progression/worsening while off 
treatment.  

 
  
 
 
12 
5.2 Exclusion Criteria 
A potential subject must meet all of the inclusion criteria above. A potential subject who meets 
any of the following exclusion criteria is ineligible to participate in the study. 
1. Subject with only epidermal nevus/nevi in the absence of other PIK3CA vascular 
anomaly/overgrowth 
2. Debulking or other major surgery performed within 30 days, at time of informed 
consent. 
3. Clinically meaningful bleeding related to VA: Grade 2 within 14 days or 
Grade 3 and more within 28 days before study treatment start as per CTCAE 
v. 5.0 
4. Sclerotherapy/embolization for vascular complications performed within 14 
days before informed consent.  
5. Subjects, who previously received systemic treatment including alpelisib and 
targeted topical therapy including PIK3CA inhibitors for their vascular anomaly 
(e.g.,mTOR inhibitors, AKT inhibitors, anti-angiogenic agents), may enter the 
study if the following criteria are met: 
i. Not simultaneously on another clinical trial; 
ii. Off systemic previous systemic treatment for at least 30 days prior 
to consent; 
iii. Off MTOR inhibitors for at least 14 days prior to initiation of 
alpelisib. 
6. Participation in any other prior investigational study within 4 weeks prior to 
study treatment start and within 5 half-lives of the investigational product, 
whichever is longer 
7. Supportive care use of anticoagulants and compression garments is allowed. 
Subjects must have been using these interventions in an unchanged manner for 
30 days before study enrollment. 
8. History of prior and or ongoing malignancy (within 5 years before informed 
consent except radically treated carcinoma in situ or radically treated basal-cell 
carcinoma of skin or thyroid gland, well-differentiated microcarcinoma or Stage 
1 Wilms’ tumor of a histology other than anaplastic), or ongoing investigations 
or treatment for malignancy at time of informed consent. 
9. Clinically significant heart disease not due to VA, including 
a. History of documented congestive heart failure (New York Heart 
Association functional classification III-IV); 
b. Clinically significant uncontrolled cardiac arrhythmias; 
c. Long QT syndrome, family history of idiopathic sudden death or 
congenital long QT syndrome; 
d. Corrected QT (QTcF) at screening: >450 ms. 
10. Documented pneumonitis or interstitial lung disease not due to VA  
11. History of acute pancreatitis within 1 year before informed consent or past 
medical history of chronic pancreatitis 
12. Subjects with an established diagnosis of type I diabetes mellitus or 

 
  
 
 
13 
uncontrolled type II diabetes mellitus 
13. Impaired gastrointestinal (GI) function that may significantly alter the 
absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 
14. History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any 
of the excipients of alpelisib 
15. Known history of Steven Johnson’s syndrome, erythema multiform or toxic 
epidermal necrolysis 
16. History of seizures or epilepsy on enzyme inducing antiepileptic drug(s); 
uncontrolled seizures are only allowed if due to PIK3CA variant 
17. Concurrent severe and/or uncontrolled medical conditions not due to PIK3CA 
variant. Resolution of symptoms for at least 28 days must have occurred before 
consent 
18. Subject  may not be pregnant or breast feeding. 
19. Female subjects of childbearing age and male subjects who do not agree to 
abstinence or to a highly effective method of contraception (condoms and/or 
oral, injected or implanted hormonal methods of contraception, or placement of 
an intrauterine device or intrauterine system, or surgical sterilization for the 
duration of the study and for one week following discontinuation of alpelisib, 
or non-heterosexual partnerships) 
20. Human Immunodeficiency Virus (HIV) infection by history or by eligibility 
testing 
21. Concomitant treatment with Strong inducers of CYP3A4 (Appendix VI) 
22. Subjects not able to understand and to comply with study instructions and 
requirements (in patients, legally authorized representatives, or guardians as 
applicable) at time of informed consent.  
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  
6 
STUDY PROCEDURES 
Subjects will be evaluated for study eligibility at a screening visit up to 30 days prior to 
enrollment on study. All laboratory tests done to confirm eligibility must be performed 
within 14 days unless otherwise noted prior to enrollment. Radiologic disease evaluations 
must be done within 30 days of enrollment. Subjects will be seen by medical providers for 
prior history, physical exam, and required assessments as noted below to monitor for 
toxicities and assess disease status. Any results falling outside of the reference ranges may 
be repeated at the investigator’s discretion. All on-study visit procedures are allowed a 
window of ± 7 days unless otherwise noted. Treatment or visit delays for public holidays or 
weather conditions do not constitute a protocol violation but should be noted in the source 
documents. 
6.1 Screening Assessments 
Eligibility/screening studies and procedures to be performed at the screening visit (up to 30 
days prior to enrollment with the exception of those noted # below).   

 
  
 
 
14 
• Informed Consent: A written, signed informed consent form (ICF)/a Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be 
obtained before any study-specific assessments are initiated. A signed copy will be 
given to the subject and a copy will be filed in the medical record. The original will 
be kept on file with the study records. 
• Documentation of validated laboratory result demonstrating a somatic PIK3CA or 
somatic TIE2/TEK pathway alteration.   
• Medical history, physical examination (PE) including skin examination (Screening 
photograph(s) of cutaneous lesions, lymphedema, or other), medications, and 
medical records review including history of prior treatments and any residual toxicity 
relating to prior treatment.  
• Height and Weight 
• Vital Signs: temperature, pulse, blood pressure, respiratory rate, oxygen saturation 
by pulse oximeter 
• Performance Status: Karnofsky/Lansky Performance Score.  
• Laboratory Studies: as outlined in Table 6-1: Protocol-required Safety Laboratory 
Assessments  
 
Table 6-1: Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments  
Parameters 
Comprehensive 
Metabolic Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Carbon Dioxide 
• 
Urea Nitrogen 
• 
Creatine 
• 
Fasting Glucose 
• 
Calcium  
• 
Total Bilirubin 
• 
Total Protein 
• 
Albumin 
• 
Alkaline Phosphatase 
• 
Alanine Aminotransferase 
• 
Aspartate Aminotransferase 
CBC with 
Differential  
• 
Absolute Neutrophils 
• 
Absolute Lymphocytes 
• 
Absolute Monocytes 
• 
Absolute Eosinophils 
• 
Absolute Basophils 
• 
Absolute Immature Granulocyte 
• 
Nucleated RBC Automated 
• 
Platelet count 
• 
MPV 
• 
Neutrophils % 
• 
Lymphocytes % 
• 
Monocytes % 

 
  
 
 
15 
• 
Eosinophils % 
• 
Basophils % 
• 
Immature Granulocyte % 
• 
Absolute Neutrophils 
• 
Absolute Lymphocytes 
• 
Absolute Monocytes 
• 
Absolute Eosinophils 
• 
Absolute Basophils 
• 
Absolute Immature Granulocyte 
• 
Nucleated RBC Automated  
Coagulation  
• 
Fibrinogen 
• 
D Dimer 
• 
PT/INR 
• 
PTT Profile 
Additional Lab 
Studies 
• 
CK 
• 
Lipase 
• 
Phosphorous 
• 
Magnesium 
• 
Hemoglobin A1C 
Pregnancy testing1 
Serum or urine pregnancy testing (within 7 days of starting study medication) 
WBC= white blood cell; RBC= red blood cell; HGB= hemoglobin; HCT= hematocrit; MCV= mean 
corpuscular volume; MCH= mean corpuscular hemoglobin; MCHC= mean corpuscular hemoglobin 
concentration; RDW= red cell distribution; MPV= mean platelet volume; PT/INR = prothrombin 
time/international normalized ratio; PTT= partial thromboplastin time; CK=creatine kinase 
1 Standard pregnancy testing for all people who can get pregnant of childbearing age 
o Optional Biologic Studies 
 Biomarker 
 cfDNA 
• Cardiac Assessment:  
o Echocardiogram 
 An age-appropriate transthoracic echocardiogram is recommended 
with interpretation by a pediatric or adult cardiologist. Documentation 
of left ventricular shortening fraction and left ventricular ejection 
fraction is required. Multigated acquisition scan (MUGA) may be 
substituted for echocardiogram at the discretion of the investigator 
with a documentation of the left ventricular ejection fraction. To be 
completed at screening and to be repeated at investigator discretion 
only if clinically indicated.  
o  ECG 
 An age-appropriate ECG is recommended with interpretation by a 
pediatric or adult cardiologist. Documentation of the corrected QTC 
interval is required. To be performed as part of screening, at the end 
of cycles 6, 12, 18, 24, 30, 36, and end of study (not triplicate). To be 
repeated at investigator discretion only if abnormal at screening.  
• Individualized Response Criteria  
o Radiologic assessment (within 4 weeks of enrollment) 

 
  
 
 
16 
 Imaging modality of choice based on underlying vascular anomaly 
(MRI, MRL, US, X-rays, CT scan)  
o Patient Reported Outcome (PRO) Measurement 
 
Construct 
Adult Subject 
18+ y/o 
Parent Proxy 
1-5 y/o 
Parent Proxy 5-
17 y/o 
Pediatric 
Subject 8-17 
y/o 
Primary Outcome for Individualized Response 
Global Health 
– Physical 
Health 
Subscale  
(4 items) 
PROMIS 
Scale v1.2 - 
Global Health 
PROMIS Early 
Childhood 
Parent-Report 
Scale v1.0 - 
Global Health 
8a 
PROMIS Parent 
Proxy Scale v1.0 
- Global Health 
7+2 
PROMIS 
Pediatric Scale 
v1.0 - Global 
Health 7+2 
Secondary Outcome for Individualized Response 
Pain 
Interference 
PROMIS 
Short Form 
v1.1 - Pain 
Interference 4a 
N/A 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Pain 
Interference 8a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Pain Interference 
8a 
 
Exploratory Outcomes 
Fatigue 
PROMIS 
Short Form 
v1.0 - Fatigue 
4a 
N/A 
 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Fatigue 10a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Fatigue 10a 
 
Anxiety 
PROMIS 
Short Form 
v1.0 - Anxiety 
4a 
PROMIS Early 
Childhood 
Parent-Report 
Short Form v1.0 
- Anxiety 4a 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Anxiety 8a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Anxiety 8a 
 
Depression 
PROMIS 
Short Form 
v1.0 - 
Depression 4a 
PROMIS Early 
Childhood 
Parent-Report 
Short Form v1.0 
- Depressive 
Symptoms 4a 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Depressive 
Symptoms 6a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Depressive 
Symptoms 8a 
 
 
o Clinical Benefit Assessments (CBA) 

 
  
 
 
17 
 
At the screening visit, the site PI and treatment team with parental/patient input will 
determine the CBA or CBAs to be followed for that subject and will document 
during that study visit. If the site PI has any questions, they will be discussed with 
the Chair and Co-chair of the protocol.  
 
Some suggestions for CBA: See Appendix IX.  
 
Examples of testing or assessments that can be followed to complete this grading scale 
include: 
 
• Pulmonary function testing 
• Lymphedema staging  
• Laboratory parameters 
• Bleeding assessment 
• PLE grading 
• Effusion assessment 
• Infection rates 
• Seizure grading 
• Photography 
• Videos 
• Patient narratives 
 
6.2 Study Treatment Phase 
Subjects must meet all eligibility criteria by Day 1 to continue into the study treatment 
phase. The study treatment phase begins with Cycle 1, day 1 and continues through 28-day 
cycles. Please refer to Table 8-1 Schedule of Assessments for required assessments.  
6.2.1 Treatment Compliance and Adherence 
Subjects will document medication adherence in a medication diary, Appendix VII. The 
diary will be provided to the Investigator or designee at each visit, and the subject will then 
receive a new diary. Remaining medication volume or tablets will be reviewed at each study 
visit to assess adherence. At the dispensing visit, subjects will be asked to bring all 
remaining study drug supplies to their onsite visit to assess adherence to treatment. 
6.3 Extension Phase of the Study 
Subjects in the absence of toxicity and with clinical benefit may continue into the extension 
period for up to 12 additional cycles (36 total cycles, including the treatment phase). This 
will be at the discretion of the treating physician and subject/subject’s family. A subject may 
receive extension therapy for a total duration of 36 cycles (including the first 24 cycles of 
study treatment). 

 
  
 
 
18 
6.4 Follow-up Phase  
All subjects, including those who discontinue protocol therapy early, will be followed at 
least 30 days following cessation of study drug unless withdrawal of consent occurs. 
There will be one scheduled visit 30 days following completion of the trial (after cycle 24 if 
not continuing on to the extension phase) or cessation of study drug.  The following 
procedures will be performed at the follow-up visit: 
• 
Medical history and Assessment for adverse events 
• 
Concomitant medications 
• 
PE with dermatologic examination (Photograph(s) of new or changing cutaneous 
lesions, lymphedema, or other) 
• 
Height, weight, and vital signs: temperature, pulse, blood pressure, respiratory rate, 
oxygen saturation by pulse oximeter  
• 
Performance Status: Karnofsky/Lansky Performance Score.  
• 
Laboratory studies as outlined in section 6.1 Screening Assessments  
• Pregnancy testing for all persons who can get pregnant of childbearing age 
subjects of childbearing potential: serum or urine pregnancy testing 
• Collect unused study drug and diary 
6.5 Unscheduled Visits 
Unscheduled visits will occur for any symptoms or concerns for toxicity, drug tolerance, 
acute changes in physical well-being, or other concerns.  Study subjects will call study team 
representative and be seen in the clinic or by their local medical provider, or emergency 
department with communication with study team.   
6.6  Subject Completion/Withdrawal 
Criteria for withdrawal of subjects and plans for provision of care after withdrawal.  
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also discontinue study participation at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, AEs, due investigator discretion, or 
family/subject preference. The Investigator or the Sponsor (if applicable) may also withdraw 
subjects who violate the study plan, or to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the 
clinical study. If the Investigator becomes aware of any serious, related adverse events after 
the subject completes or withdraws from the study, they will be recorded in the source 
documents and on the CRF. 
7 
SUPPORTIVE CARE AND CONCOMITANT MEDICATION 
7.1 Other Treatment(s) 
All subjects will be allowed to receive concomitant medication and/or other non-medication 
treatment (e.g., rescue surgery) when clinically indicated to control comorbidities and/or 
complications of VA except for agents known to have significant interactions with Alpelisib as 

 
  
 
 
19 
noted in Section 7.3. Rescue surgery is defined as a salvage intervention, and includes e.g. 
debulking surgery, orthopedic surgery, invasive vascular surgeries/procedures. As much as 
possible, surgery targeting PROS-related lesion volume reduction should be avoided. Systemic 
therapy targeting PI3K/AKT/mTOR pathway other than alpelisib and/or any investigational/not 
approved medication for PROS are not allowed during the conduct of the study. 
During the course of the study, the subject must also not receive anti-angiogenic agents for 
the purpose to treat PROS. 
The subject must discontinue from specific treatment with small molecules (such as mTOR 
inhibitors, AKT inhibitors, MEK inhibitors) for PROS before any of study related assessments 
and at least 4 weeks before study treatment start. An exception is made for MTOR inhibitors 
that should be discontinued at least 2 weeks before study treatment start because of drug half-
life. 
Subjects are not allowed to receive any other investigational drugs. 
7.2 Concomitant Therapy 
Subjects will be instructed to inform the investigator prior to starting any new medications 
from the time of first dose of study treatment until the end of the study. 
At each study visit subjects should be asked: “Have you taken any new medicines, other 
than those provided in this study, since your last visit/contact?” or, ”Has your child needed 
to take any medicines, other than those provided in this study, since his/her last 
visit/contact?”.   
All medications (other than alpelisib) including non-prescription medication(s), vitamins 
and herbal product(s), taken during the study will be recorded in the CRF.  Any significant 
non-drug therapies should also be noted in the subject’s CRF. 
      Subjects should receive all necessary supportive care during the study. 
 
 
Examples of permissible concomitant therapies: 
• Transfusions of blood and blood components 
• Pain relief medication 
• Anti-infective medications (see prohibited and cautioned medications in the 
Section 7.2.1and Section 7.3 below).  
• Treatment for concomitant medical conditions, adverse events (see 
prohibited and cautioned medications in the Section 7.2.1and Section 
7.3 below) 
• Supplemental nutrition (enteral, parenteral) 
• Routine vaccinations 
• Supportive care use of anticoagulants and compression garments is allowed. 
Subjects must have been using these interventions in an unchanged manner for 3 
months before study enrollment 

 
  
 
 
20 
7.2.1 Permitted concomitant therapy requiring caution and/or action 
Medications to be used with caution are described below and listed in Appendix V. This list 
is not comprehensive and is only meant to be used as a guide. 
These medications should be excluded from subject use if possible. If they must be given 
based on the investigator’s judgment, then use with caution and consider an alpelisib 
interruption, as appropriate, if the concomitant medication is only needed for a short time. 
 
Medications to be used with caution (Appendix V): 
• 
CYP2C9 substrates with narrow therapeutic index (NTI) (e.g., anticoagulants): 
In vitro evaluations indicated that pharmacological activity may be reduced by the 
CYP2C9 induction effects of alpelisib. In the absence of clinical data, caution is 
recommended with therapeutic doses of warfarin sodium (Coumadin®) or any other 
coumarin-derivative anticoagulants as alpelisib may reduce the clinical activity of 
such drugs. Alternatively, therapeutic anticoagulation may be accomplished using 
low- molecular weight heparin or Direct Thrombin inhibitors (DTIs) and Factor Xa 
inhibitors. 
• 
CYP2B6 sensitive substrates or CYP2B6 substrates with NTI: Based on a static 
mechanistic assessment with sensitive CYP2B6 substrates such as bupropion, a 
reduction of exposure by up to 3-fold can be expected when co-administered with 
alpelisib. In the absence of clinical data, sensitive CYP2B6 substrates (e.g., 
bupropion, evafirenz) or CYP2B6 substrates with a narrow therapeutic window 
should be used with caution in combination with alpelisib, as alpelisib may reduce 
the clinical activity of such drugs. 
• 
Selected CYP3A4 substrates: Alpelisib can be co-administered with sensitive 
CYP3A4 substrates (e.g., midazolam) and CYP3A4 substrates with narrow 
therapeutic window (e.g., fentanyl). Caution is recommended when alpelisib is 
used in combination with CYP3A4 substrates that also possess an additional time 
dependent inhibition and induction potential on CYP3A4 that affects their own 
metabolism Systemic exposures of such CYP3A4 auto-inhibitors and auto-
inducers may be either decreased or increased depending on the drug and nature of 
auto-perpetrator potential, respectively, when alpelisib is co-administered, based 
on PBPK simulations. 
• 
Please refer to the latest version of alpelisib Investigator's Brochure for 
additional information pertaining to alpelisib. 
7.2.1.1 Oral Anti diabetics 
Subjects who develop hyperglycemia during the study should be treated according to the ADA 
(American Diabetes Association)/EASD (European Association for the Study of Diabetes) 
guidance. It is recommended to start treatment with metformin. Metformin is not 
recommended in subjects below the age of 10 years, metformin extended release (XR) is not 
recommended in pediatric subjects below the age of 18 years. Consultation with a 
diabetologist is needed to find the optimal individualized treatment for hyperglycemia, 
especially in pediatric subjects under 10 years old (where international or local guidelines may 
apply). Subjects receiving oral anti-diabetics which are predominantly metabolized by 

 
  
 
 
21 
CYP2C9 and CYP2C8, including but not limited to, repaglinide, rosiglitazone, glipizide and 
tolbutamide, should be monitored with respect to their effectiveness as alpelisib was found to 
be an inducer of CYP2C9 in vitro. 
7.2.1.2 Corticosteroids 
Chronic dosing of high levels of corticosteroids such as dexamethasone and prednisone may 
prolong or aggravate hyperglycemia (steroid-induced diabetes). Hyperglycemia is a common 
adverse event for PI3K inhibitors like alpelisib; corticosteroids should therefore be used with 
caution and subjects should be closely monitored. 
7.2.1.3 Gastric protection agents 
Alpelisib is characterized by a pH-dependent solubility. Therefore, acid reducing agents 
(ARAs, e.g., proton-pump inhibitors, H2-antagonists and antacids) may alter the solubility of 
alpelisib and hence its bioavailability. A drug-drug interaction study in human healthy 
volunteers confirmed that co-administration of alpelisib with the H2-antagonist ranitidine 
after a meal lead to a decrease in exposure by only ~20%, considered not to be clinically 
relevant. Alpelisib can be co-administered with any ARAs. 
 
7.3 Prohibited medication 
The following medications are prohibited during treatment with alpelisib (Appendix VI): 
This list is not comprehensive and is only meant to be used as a guide. 
• Strong inducers of CYP3A4: 
Co-administration of alpelisib with a strong CYP3A4 inducer may decrease 
alpelisib concentration, which may decrease alpelisib activity. Avoid 
coadministration of alpelisib with strong CYP3A4 inducers. 
• Inhibitors of BCRP: 
Co-administration of alpelisib with a BCRP inhibitor may increase alpelisib 
concentration, which may increase the risk of toxicities. Avoid the use of BCRP 
inhibitors in subjects treated with alpelisib. 
• 
Bisphosphonates: 
 
Zoledronic acid or other bisphosphonates administration will not be allowed during 
the alpelisib treatment period due to increased risk of osteonecrosis. 
• 
Herbal Medications: 
The use of herbal preparations/medications and dietary supplements (except for 
vitamins) are prohibited throughout the study, as a potential drug-drug interaction is 
possible. Herbal medication include but are not limited to St. John’s Wort (Hypericum 
perforatum), and Avasimibe or BCRP inhibitors such as Curcumin.Medications such 
as Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw 
palmetto, black cohosh and ginseng should be avoided if possible due to their potential 

 
  
 
 
22 
for complex interactions. Subjects must stop using all herbal medications and dietary 
supplements at least 7 days prior to first dose of study treatment. 
• Other investigational and antineoplastic therapies 
In addition, the subject should discontinue from specific treatment with small 
molecules (such as mTOR inhibitors, AKT inhibitors) and/or anti angiogenic agents 
for PROS before any of study related assessments or at least 4 weeks before study 
treatment starts whichever comes first. 
7.4 Rescue Medication Administration 
Supportive care measures including but not limited to antimicrobials, topical steroids, 
antiemetics, blood products, fluids, electrolytes, albumin infusions, immunoglobulin infusions 
will be permitted while on study as rescue medications for adverse events or other causes 
(acute hypotension, acute or chronic anemia, acute or chronic hypoalbuminemia, acute 
infection, etc).  Decision for supportive care will per administered per the provider’s discretion 
at the time subject presents with symptoms or signs requiring escalation of care (emergency 
department, urgent care, inpatient setting, primary provider). 

 
  
 
 
23 
8 
STUDY EVALUATIONS AND MEASUREMENT 
8.1 Schedule of Assessments 
The schedule of assessments Table 8-1 lists all the assessments to be performed as part of the 
study, an "X" in the table indicates the visit(s) when they are to be performed. 
All data obtained from these assessments must be supported in the subject’s source 
documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Subjects who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of 
the assessments listed for the end of treatment visit will be performed. At this visit, all 
dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the eCRF.  
During the course of the study, test procedures should occur on schedule whenever possible 
as per allowable visit. For Cycles 1-3, the window is +/- 3 days; for all other cycles, the 
window is +/- 7 days.  
If the COVID-19 or other pandemic limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented. Phone calls or virtual contacts 
(e.g. teleconsultation), can replace on-site study visits, for the duration of the pandemic until 
it is safe for the subject to visit the site again. 
 
 
 

 
 
 
 
 
24 
Table 8-1 Schedule of Assesments  
 

 
 
 
 
 
25 
Footnotes: 
Day1: Cycles 1-3: +/- 3 days; Cycles 6-24: +/- 7 days  
Laboratory studies2: as outlined in section 6.1 Screening Assessments 
Urine or serum pregnancy3: as outlined in section6.1 Screening Assessments 
ECG4: repeat during study if abnormal at screening or as clinically indicated per treating team (not 
triplicate)  
X4: can repeat during study if abnormal at screening or by decision of the treating team (not triplicate) 
Radiologic assessment5: At screening and at the end of every 6 cycles on treatment are mandatory. 
Following radiologic assessments as per decision of local treating team  
X6: Within 4 weeks (28 days) of screening 
Optional Biologic Studies7: As outlined in section 6.1 Screening Assessments 
X8: All labs, physical exams, and vital signs, must be done within 14 days of starting Alpelisib 
X9: If applicable, dependent on treating team 
 
8.1.1 Medical Record Review 
The following will be abstracted from the medical chart (paper or electronic): 
• 
Demographic characteristics (age, gender, race, ethnicity) 
• 
Location/locations of vascular anomaly 
• 
Histologic Diagnosis  
• 
Diagnostic vascular anomaly data 
• 
Vascular Anomaly Past Medical History including: 
o Surgical procedures 
o Interventional Radiology procedures 
o Prior vascular anomaly directed medical therapy (medication, dates, response) 
• 
General Past Medical History: 
o Diagnoses and relevant dates 
o Surgeries and relevant dates 
o Medications 
• 
Current laboratory testing (within 14 days of screening) 
• 
Current radiologic assessment  
8.1.2 Physical Examination 
General physical examination will include assessments of the following systems: General, 
Head/Ears/Eyes/Nose/Throat (HEENT), Respiratory, Circulatory, Abdominal, Neurologic, 
Musculoskeletal, Dermatologic, Lymphatic, Psychiatric, and Dental exam.  
8.1.3 Vital Signs 
Vital signs to be collected per institutional age-appropriate standards: Height, Weight, 
Temperature, Pulse, Respiratory Rate, Blood pressure, and Pulse Oximetry. 
8.1.4  Laboratory Evaluations 
• 
Blood sampling will be performed per institutional standards.  
• 
Laboratory studies as outlined in section 6.1 Screening Assessments. 

 
 
 
 
 
26 
 
8.1.5 Pregnancy Testing 
Pregnancy testing as outlined in section 6.1 Screening Assessments. 
8.1.6 Other Evaluations, Measures 
• Echocardiogram: As outlined in 6.1 Screening Assessments. 
• Electrocardiogram (ECG): As outlined in 6.1 Screening Assessments. 
8.2 Efficacy Evaluations 
The optimal measure of disease response in subjects with complex vascular anomalies has 
not been established. Current practice includes changes in physical exam, radiographic 
(MRI) evaluations, laboratory assessments and/or quality of life measures. These lesions are 
difficult to assess with any one method because of heterogeneity in growth patterns, diversity 
of associated clinical and laboratory abnormalities and a fluctuating clinical course 
dependent upon factors other than treatment, such as intercurrent infections, puberty, and 
trauma. It is currently unclear if there is a good correlation between lesion size, determined 
radiographically and clinical changes or quality of life measures. For these reasons we have 
elected to assess disease response using three distinct criteria generating a single composite 
or  
Individualized Response Criteria: 
 
Radiologic Response 
PROMIS 
Assessment of Clinical Benefit 
(examples) 
-MRI (recommended) 
-MRL (see notation below) 
-CT Scan 
-US 
-Xray 
-Dexascan 
See below (8.2.2) 
Parameters for grading the 
Clinical Benefit Assessment 
(Appendix IX) 
 
Examples of testing or 
assessments that can be 
followed to complete this 
grading scale include: 
o Pulmonary function 
testing 
o Lymphedema staging  
o Laboratory parameters 
o Bleeding assessment 
o PLE grading 
o Effusion assessment 
o Infection rates 
o Seizure grading 
o Photography 
o Videos 
o Patient narratives 
 
 
 

 
 
 
 
 
27 
 
 
8.2.1 Radiographic Response 
8.2.1.1 MRI/MRL: 
MRI or MRL imaging will be recommended as primary imaging modality for all subjects 
enrolled in VATCH sub-protocols. For subjects with disease manifestation better characterized 
by alternative quantitative imaging modality (i.e. X-ray or ultrasound) this may be substituted 
and used as alternative imaging. MRI or MRL is the preferred method of imaging. MRI/MRL 
imaging will be done at screening and at the end of cycles 6, 12, and 24(if applicable) on 
treatment. Additional assessments can be performed in accordance with the local institutional 
practice.  For each imaging assessment timepoint initial radiographic response will be reviewed 
by each site’s radiologist.  
When possible and appropriate, volumetric imaging will be used in combination with standard 
vascular MRI protocols to assess vascular anomaly response. MRI will be performed using a 1.5 
Tesla system (HDX 15.0 series MRI, GE and Espree B-15 series MRI, Siemens). Coronal and 
axial fast spin-echo T2-weighted sequences will be performed with and without fat suppression. 
Up to 3 lesions should be identified as target lesions and recorded and measured at screening. 
Target lesions should be selected on the basis of their size and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). The same method of 
assessment and the same technique should be used to characterize each target lesion at screening 
and during follow up (APPENDIX IV).  
8.2.1.2  Other Radiographic Assessment 
Other imaging modalities including, but not limited to Computed tomography (CT) Scan, 
Ultrasound (US) or X-ray may be utilized for radiographic assessment criteria either in 
supplement to or in replacement of MR imaging as noted above. Target lesions should be 
selected on the basis of their size and their suitability for accurate repeated measurements (either 
by imaging techniques or clinically). The modality and imaging methods will be determined for 
enrollment screening and the same method of assessment, and the same technique, should be 
used to characterize each target lesion at screening and during each imaging follow up. Examples 
of imaging would be X-Ray for bone disease, ultrasound for pleural effusions, dexascan for 
lymphatic anomalies with bone lesions, and US (contrast or non-contrast for superficial lesions 
to assess size and other characteristics such as flow. 
8.2.2 Assessment of Patient Reported Outcome Measures (PROMs) 
Quality of life is an essential component of high-quality clinical care. 32 The Patient Reported 
Outcomes Measurement Information System (PROMIS) is a validated parent/patient-reported 
scoring system that was developed with the National Institutes of Health (NIH) that can compare 
values across a variety of medical conditions.33,34 PROMIS is validated in individuals aged 8 years 
and older. 35-37 A caregiver proxy report for the PROMIS measure is also available for use in 
children; for individuals younger than 8 years old, assessments must be completed by a caregiver 
proxy. PROMIS is considered to be the gold standard for HRQOL measurement in clinical trials. 
The recall timeframe for each question includes the past week. Each question has five response 
categories. A raw score can be calculated for each PROMIS subscale. Raw scores are then 

 
 
 
 
 
28 
translated into a T-score metric with mean of 50 (standard deviation of 10). A higher PROMIS T-
score represents more of the concept being measured. Additional details for scoring and measure 
interpretation are available at https://www.healthmeasures.net/score-and-interpret/interpret-
scores/promis. Higher scores represent better functioning. A difference or change in score of three 
points on the PROMIS Pediatric scale is considered a minimally important difference (MID).  
In consultation with subjects, patient advocates, clinicians, and psychometricians, we will use 
global health measures as the primary outcome and pain interference as the secondary outcome. 
For exploratory outcomes, we will administer PROMIS measures for fatigue, anxiety, and 
depression. This survey battery will be administered every 6 cycles, starting at enrollment and 
continuing during participation in the study.  
For subjects 18+ years old at enrollment, please refer to “Adult subject 18+ y/o” column in 
Table 8-3. In total, this battery of measures will include 26 items. We will also include 2 open-
ended questions for exploratory analysis: 1) What positive or negative changes have you noticed 
since you started taking the medication? 2) What else would you like us to know? For adults 
with cognitive impairment, guardian/LAR may provide proxy answers for the surveys at the 
discretion of the study chair and co-chair on a case-by-case basis.   
 
For subjects 8-17 years old at enrollment, please refer to “Pediatric Subject 8-17 y/o” column 
in Table 8-3. In total, this battery of surveys will include 43 items. We will also include 2 open-
ended questions for exploratory analysis: 1) What good or bad changes have you noticed since 
you started taking the medication? 2) What else do you want us to know? For subjects aged 8-
17 years old at enrollment, we will simultaneously administer subject-report and proxy-report 
surveys. (see next paragraph for proxy measures) 
 
For subjects 5-17 years old at enrollment, please refer to “Parent Proxy 5-17 y/o” column in 
Table 8-3. In total, this battery of surveys will include 41 items. We will also include 2 open-
ended questions for exploratory analysis:  1) What positive or negative changes have you noticed 
since your child started taking the medication? 2) What else would you like us to know? 
 
For subjects 1-5 years old at enrollment, please refer to “Parent Proxy 1-4y/o” column Table 
8-3. In total, this battery of surveys will include 16 items. 
 
If subjects change age category after enrollment, they will continue using the same 
measures from their time of enrollment, rather than switching measures. 
Table 8-3 
Construct 
Adult Subject 
18+ y/o 
Parent Proxy 
1-5 y/o 
Parent Proxy 5-
17 y/o 
Pediatric 
Subject 8-17 
y/o 
Primary Outcome for Individualized Response 
Global Health 
– Physical 
PROMIS 
Scale v1.2 - 
PROMIS Early 
Childhood 
PROMIS Parent 
Proxy Scale v1.0 
PROMIS 
Pediatric Scale 

 
 
 
 
 
29 
Health 
Subscale  
 
Global Health 
Parent-Report 
Scale v1.0 - 
Global Health 
8a 
- Global Health 
7+2 
v1.0 - Global 
Health 7+2 
Secondary Outcome for Individualized Response 
Pain 
Interference 
PROMIS 
Short Form 
v1.1 - Pain 
Interference 4a 
N/A 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Pain 
Interference 8a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Pain Interference 
8a 
 
Exploratory Outcomes 
Fatigue 
PROMIS 
Short Form 
v1.0 - Fatigue 
4a 
N/A 
 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Fatigue 10a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Fatigue 10a 
 
Anxiety 
PROMIS 
Short Form 
v1.0 - Anxiety 
4a 
PROMIS Early 
Childhood 
Parent-Report 
Short Form v1.0 
- Anxiety 4a 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Anxiety 8a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Anxiety 8a 
 
Depression 
PROMIS 
Short Form 
v1.0 - 
Depression 4a 
PROMIS Early 
Childhood 
Parent-Report 
Short Form v1.0 
- Depressive 
Symptoms 4a 
PROMIS Parent 
Proxy SF GenPop 
v3.0 - Depressive 
Symptoms 6a 
 
PROMIS 
Pediatric SF 
GenPop v3.0 - 
Depressive 
Symptoms 8a 
 
 
*For adults with cognitive impairment, guardian/LAR may provide proxy answers for the 
surveys at the discretion of the study chair and co-chair on a case-by-case basis.   
8.2.3 Assessment of Clinical Benefit  
A set of clinical benefit assessments will supplement the radiographic and the PROMIS measures. 
The clinical benefit assessment tools will be determined at initial screening evaluation for the 
subject. The same clinical benefit assessment tools will be completed at enrollment and then every 
6 cycles for the duration of the study. The investigator will determine the clinical benefit 
assessment and have this reviewed by the study PI if no radiologic assessment is noted. See 
Appendix IX.  

 
 
 
 
 
30 
8.2.3.1 Photography/Videos 
Assessment with photography and video evaluation can be performed if clinically relevant. If 
selected as a clinical benefit assessment at initial screening evaluation for the subject this will be 
documented and obtained as part of enrollment screening. Photography will be obtained at each 
assessment. Images will be obtained per institutional standard for inclusion into the medical record. 
Photography under the same conditions and positioning to allow for accurate quantification and 
qualification on lesional changes is recommended. 
8.2.3.2 Patient Narratives  
To capture patient narratives, we will administer 5 open-ended questions along with the patient-reported 
outcome measures at the 6-month time point. Participant responses will be reported in the electronic data 
capturing system. The questions are listed below. 
The study team would like to learn how this medication has affected you. We are interested in any 
changes caused by the medication. Below, the questions will be about how the medication has 
affected your vascular anomaly and your overall health. You can skip questions that do not apply 
to you, or you can respond “none”. 
1. How has your vascular anomaly gotten better since starting on medication? It is okay to 
write “none” if nothing has gotten better. 
a. How has the rest of your health gotten better since starting on medication in this 
study? It is okay to write “none” if nothing has gotten better. 
2. How has your vascular anomaly gotten worse since starting on medication? It is okay to 
write “none” if nothing has gotten worse. 
a. How has the rest of your health gotten worse since starting on medication in this 
study? It is okay to write “none” if nothing has gotten better. 
3. What else would you like us to know about your experience taking this medication 
 
8.3 Assessment of Overall Response 
8.3.1 Definitions 
Evaluable for Toxicity: All subjects will be evaluable for toxicity from the time of their first study 
drug treatment. 
Evaluable for Objective Response: Only those subjects have received at least one therapy cycle 
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 for response.) 
Target Lesions: All measurable lesions up to a maximum of three lesions total (and a maximum 
of two lesions per organ) representative of all involved organs should be identified as target 
lesions and recorded and measured at screening radiographic assessment or clinical photograph. 

 
 
 
 
 
31 
Target lesions will 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 lesion response.  
Nontarget Lesions: All other lesions (or disease sites), including any measurable lesions over and 
above the three target lesions should be identified as nontarget lesions and should also be 
recorded at screening. It is possible to record multiple nontarget lesions involving the same organ 
as a single item on the case record form (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver lesions”). Bone lesions may be measurable if ≥ 1 cm on MRI. Measurements of 
these lesions are not required, but the presence or absence of each will be noted throughout 
follow-up. 
 
8.3.2 Response Criteria for Overall Response 
The primary endpoint of this VATCH sub-protocol is to determine whether the PIK3CA 
inhibitor alpelisib administered once a day on a continuous dosing schedule to subjects with 
PIK3CA pathway driven Vascular Anomalies provides an objective response at the end of cycle 
6. Assessment of response is an individualized response criterion based on radiologic 
assessment, Patient Reported Outcome Measurements (composite score) and Clinical Benefit 
Assessment. Disease Response is determined by the local institution/investigator and is defined 
below. 
Clinically meaningful response: 
A clinically meaningful response includes a substantial response, Intermediate response or stable 
disease at the timing of protocol assessment.  
 
Assessment of individualized response criteria after 6 cycles for primary endpoint and then every 
6 months. 
Substantial response: 
o Improvement in Radiologic assessment (if applicable) by 20% AND 
o Improvement in Global Health PROs by 3T-score points* AND 
o Improvement in at least 1 CBA as reported by the clinician AND 
o No clinically meaningful worsening in any measure 
Intermediate response: 
o Improvement in Radiologic assessment (if applicable) by 20% OR 
o Improvement in Global Health PROs by 3 T-score points* OR 
o Improvement in at least 1 CBA as reported by the clinicians AND 
o No clinically meaningful worsening in any measure 
Stable disease: 
o No clinically meaningful improvement or worsening from screening in   
• 
Radiologic assessment (if applicable), OR 
• 
Global Health PROs*, OR 
• 
CBA as reported by the clinician  

 
 
 
 
 
32 
Worsening disease: 
o Clinically meaningful worsening in   
• 
Radiologic assessment (if applicable) by 20%, OR 
• 
Global Health PROs by 3T-score points*, OR 
• 
CBA as reported by the clinician  
• 
Regardless of any concomitant improvement in other measures. 
*Prior review articles have indicated that a change of 2 to 6 T-score points is the minimum 
important change (MIC) for PROMIS measures. PROMIS leadership recommends 3 T-score 
points as the MIC29,30. 
 
 
8.3.3 Duration of Response 
Duration of Overall Response: The overall response (substantial or intermediate) duration is 
measured from the time of primary endpoint measurement (6 cycles) 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). 
Duration of Stable Disease: Stable disease is measured from the start of the treatment until 
the worsening disease criteria are met, or patient on evaluation has a substantial or intermediate 
response.   
9 
STATISTICAL CONSIDERATIONS 
This is a Phase II non-randomized study to evaluate alpelisib in children and young adults with 
PIK3CA and TIE-2/TEK activating variants in subjects. The primary efficacy endpoint is 
objective response at the end of cycle 6 and the primary safety endpoint is toxicity of alpelisib. 
Secondary endpoints include objective response at the end of cycle 12, safety and tolerability of 
alpelisib over time, duration of response, and biomarker measures. 
9.1 Sample Size and Power 
For the primary efficacy analysis of objective response at the end of cycle 6, we will test a null 
hypothesis of response of 60% against an alternative hypothesis of response rate of 80%. We will 
follow the Simon’s optimal two-stage design: an interim analysis will be conducted after 19 
subjects have been observed for response, and if 11 or fewer response is observed, the trial will 
be stopped for futility; otherwise the trial will continue to enroll a total of 53 evaluable subjects 
and at the end of the trial if 37 or more responses are observed, the treatment will be declared 
promising. This design provides >=90% power when the true response rate is 80% and yields a 
one-sided type I error of <=0.05 when the true response rate is 60%.  
For evaluating of toxicity, a sample size of 53 provides 93% probability to observe at least one 
toxicity event when the underlying true toxicity rate is 5%, so that we have good confidence to 
observe a rare toxicity type. In addition, this sample size provides a reasonable precision on the 
estimate of the toxicity rate. For example, with 10 observed toxicity events out of 53 subjects, 
the estimated toxicity rate is 19%, with the 95% exact confidence interval (CI) as 9% - 32%. 

 
 
 
 
 
33 
9.2  Safety monitoring 
We will monitor the incidence of severe toxicity that occurs during the first 2 courses and is 
associated with the treatment (Grade 4 infection, Pneumocysitis jirovecii pneumonia, Grade 2 
pneumonitis, Grade 4 rash, Grade 4 hyperglycemia, Grade 4 diarrhea, or Grade >2 allergic 
reaction).  An early stopping rule will be invoked to pause the study if there is evidence that the 
observed severe toxicity rate is higher than the acceptable rate of 10%. Specifically, if the lower 
bound of the two-sided 95% exact CI exceeds 10% then the stopping rule will be triggered. We 
will monitor severe toxicity continuously after five subjects are enrolled. Toxicity will be 
reviewed and if the number of subjects with a severe toxicity is equal or greater than the number 
indicated in the table below, accrual will be paused. Based on simulations, the stopping rule 
implies that the probability of early stopping will be 6% if the underlying true toxicity rate is 
10%, the probability of early stopping will be 65% if the underlying true toxicity rate is 20%, 
and the probability of early stopping will be 97% if the underlying true toxicity rate is 30%. 
 
Number of subjects  
Trial will be paused if the number of 
subjects with severe toxicity >=  
5-6 
3  
7-11 
4 
12-17 
5 
18-23 
6  
24-29 
7 
30-36  
8  
37-43 
9  
44-50 
10 
51-53 
11 
 
9.3 Statistical Analyses Plan 
For all the analyses, subjects who received any dose of alpelisib will be included in the analyses. 
The primary efficacy endpoint is objective response (including both response and partial 
response) at the end of cycle 6 and the primary safety endpoint is toxicity of alpelisib. We will 
use binomial distributions to estimate the response and the toxicity rates with their 95% exact 
CIs. For the secondary efficacy endpoint of response at the end of cycle 12, the response rate will 
also be calculated with 95% CI. For the secondary endpoint of duration of response, time from 
initial response to disease progression will be examined, and subjects will be censored at the last 
adequate disease assessment if no progression occurred by that time. We will use the log-rank 
tests and/or Cox proportional hazard regression to analyze the endpoint. Should the data suggest 
the violation of the proportional hazard assumption, we will consider an alternative method such 
as accelerated failure time model analysis.  
 

 
 
 
 
 
34 
Secondary data analyses will be performed for the secondary outcomes of longitudinal 
measurements of the radiologic assessment, PROMIS Patient Reported Outcome measurement, 
and Clinical Benefit Assessments, taken at screening, and at the end of cycles 6, 12, 18, and 24. 
The longitudinal data will be analyzed separately at each follow-up time point and together 
longitudinally. The paired t-test will be used to look at changes in these measures from pre-
treatment levels to the post-treatment level (follow-up at cycle 3) to evaluate the treatment’s 
short-term effects. Mixed effects models will be used for longitudinal analysis to evaluate 
changes in these measures over time. Should the data suggest the distributions of the 
measurements deviate from normal distributions, we will consider nonparametric alternatives 
such Wilcoxon signed rank test or transformation. Relationships between PROMs measures and 
other variables such as pain will be investigated using correlation analysis. Lastly, exploratory 
analyses will be performed for biomarker measures such as cell-free DNA. Descriptive statistics 
will be generated to summarize data.  
 

 
 
 
 
 
35 
10 DOSE MODIFICATION AND MANAGEMENT OF ADVERSE EVENTS 
10.1 Dose Modifications 
10.1.1 Dose Escalation 
Dose escalation for response optimization purpose is considered in this study. 
Dose escalation is allowed: 
Decision to escalate the dose for response optimization purpose will be done by the 
investigator based on local assessment of lesion response and overall clinical response. 
Escalation will be allowed, when: 
• 
The subject does not meet criteria for lesion response based on local assessment 
and there are no safety/tolerability concerns which may preclude from treatment 
continuation at a higher dose level. 
• 
The subject, in the opinion of the investigator, did not derive sufficient clinical 
benefit (based on overall clinical response assessed by the investigator) from 
previous treatment regardless of meeting criteria for lesion response and there are 
no safety/tolerability concerns which may preclude from treatment continuation 
at higher dose level. 
Dose escalation is allowed at a minimum of 12-week intervals. 
Subjects ages 6 years or older, dose escalations are possible from cycle 3 visit onwards as 
following: 
• Subjects 18 years or older: from 125 mg to 200 mg, from 200 mg to 250 mg once daily 
p.o.  
• Subjects aged 6-17: from 50 mg to from 125 mg, to 200 mg once daily p.o.  
 
Table 10-1 
Dose escalation for alpelisib ages 18+  
Alpelisib dose level 
Dose (18+) 
Number of tablets & strength  
Starting 
125 mg/day 
1 x 125 mg tablet 
Dose level 1 
200 mg/day 
1 x 200mg tablet 
Dose level 2 
250 mg/day 
1 x 200mg tablet + 1 x 50mg 
 
 
Table 10-2 
Dose escalation for alpelisib ages 6-17 
Alpelisib dose level 
Dose (Ages 6-17) 
Number of tablets & 
strength 
Starting dose 
50 mg/day 
1 x 50 mg tablet 
Dose level 1 
125 mg/day 
1 x 125 mg tablet 

 
 
 
 
 
36 
Dose level 2 
200 mg/day 
1 x 200 mg tablet 
 
10.1.2 Dose Reduction 
Dose reduction and/or interruption is allowed in all age groups at any time for reasons of 
tolerability and safety. 
Generally, when dose reduction is permitted as per toxicity management guidance, maximum 2 
consequent dose reductions are possible. When the subject experiences safety concerns at starting 
dose level, only one dose reduction is permitted. Depending on the dose of alpelisib, the 
investigator should follow the general guidance for alpelisib dose reductions sequential steps as 
described in Table 10-4 and Table 10-5. 
For subjects aged 2-5, if starting dose is not tolerated, dose reduction is not allowed. Subject will 
hold or completely stop the alpelisib in case of toxicities. 
Investigators should exercise caution and consider dose interruption for safety reasons, especially 
in subjects who experience adverse events of grade 3 and higher, regardless of their apparent 
relatedness to study medication, and in subjects experiencing recurrent or prolonged adverse 
events. This is particularly important for pediatric subjects. A combined approach of drug 
interruption with subsequent re-initiation of study medication at a reduced dose may be pursued. 
Dose interruption because of safety and/or other medically relevant reason may last up to 60 days, 
afterward the subject may restart study therapy. If a patient is off therapy for up to 60 days, the 
study chair needs to be notified.  
The sections below provide specific guidance for management and study drug modification in the 
event of: QTcF prolongation, skin toxicity, hyperglycemia, pneumonitis, diarrhea and 
stomatitis/oral mucositis. 
When minor or major surgical invasive procedure is planned, the investigator may make a 
decision to interrupt study medication based on clinical condition of the subject. 
Dose reduction sequential steps are described in the Table 10-4 and Table 10-5; guidelines and 
criteria for dose reduction/interruption/re-initiation are provided in the following Sections 
(10.1.3.1-10.1.3.7). 
 
Table 10-4  Dose reduction sequential steps for alpelisib in ages 18+ 
Alpelisib dose 
Reduced dose / Level -1 
Reduced dose / Level -2 
125 mg daily p.o 
50 mg daily p.o 
Not allowed 
200 mg daily p.o 
125 mg daily p.o 
50 mg daily p.o 
250 mg daily p.o 
200 mg daily p.o 
125 mg daily p.o 
 

 
 
 
 
 
37 
Table 10-5   Dose reduction sequential steps for alpelisib in ages 6-17 
Alpelisib dose 
Reduced dose / Level -1 
Reduced dose / Level -2 
50 mg daily p.o 
50 mg every other day p.o 
Not allowed 
125 mg daily p.o 
50 mg daily p.o 
50 mg every other day 
200 mg daily p.o 
125 mg daily p.o 
50 mg daily p.o 
 
10.2 Management of adverse effects 
10.2.1 Dose adjustments for QTcF prolongation 
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. When 
QTcF > 500 ms or > 60 ms change from baseline (≥ Grade 3) is detected on at least two 
separate ECGs, the investigator should follow criteria for interruption and re-initiation of 
study treatment as per Table 10-6 below. 
 
Table 10-6 Criteria for interruption and re-initiation of alpelisib treatment due 
to QTcF prolongation 
If QTcF > 500 ms or > 60 ms change from baseline (≥ Grade 3) is identified: 
• 
Assess the quality of the ECG recording and the QT value and repeat if needed 
• 
If deemed necessary, consult with a cardiologist (or qualified specialist) to 
confirm ECG 
diagnosis 
If QTcF prolongation is confirmed: 
• 
Interrupt study treatment 
• 
Determine the serum electrolyte levels (in particular hypokalemia, 
hypomagnesemia). If abnormal, correct abnormalities before resuming 
study drug treatment. 
• 
Review concomitant medication use for other causes for QT prolongation 
(refer to crediblemeds.org for known QT prolonging drugs), and for drugs 
with the potential to increase the risk of drug exposure related QT 
prolongation 
• 
Check study drug dosing schedule and treatment compliance 
• 
Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 ms or 
< 60 ms change from baseline 
After resolution to ≤ 480 ms / 60 ms change from baseline, re-introduce 
treatment at a reduced dose (if possible), and increase ECG 
monitoring 
If QTcF prolongation recurs (> 500 ms / 60 ms change from baseline, i.e., ≥ Grade 3) after treatment re-
introduction, discontinue subject from study.  

 
 
 
 
 
38 
10.2.2  Guidelines for the treatment of alpelisib induced skin toxicity 
Consultation with a dermatologist is highly recommended for better assessment and 
management of alpelisib-induced skin toxicity. Dermatologist consult is mandated for 
serious cutaneous reactions (i.e., fulfilling seriousness criteria for AE Reporting) and for 
severe cutaneous reactions like Stevens-Johnson-Syndrome (SJS), Toxic Epidermal 
Necrolysis (TEN), Erythema Multiforme (EM). Dose modification guidelines are 
described in Table 10-7.  
 
Table 10-7 Criteria for interruption and re-initiation of alpelisib treatment due 
to skin toxicity 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib 
Skin and subcutaneous tissue disorders 
Grade 1 (<10% body surface area (BSA) with 
active skin toxicity*) 
Maintain dose level 
Initiate topical corticosteroids 3-4 times daily, 
preferred compounds to use are triamcinolone, 
betamethasone as long as skin toxicity is active, 
for a duration of maximum 28 days. 
 
For subjects with symptoms like burning and/or 
pruritus add a non-sedating anti-histamine; 
consider adding a sedating anti-histamine at 
night.  
 
If active rash is not resolved within 28 days of 
appropriate treatment, consider adding low dose 
systemic corticosteroid 

 
 
 
 
 
39 
Grade 2 (10-30% BSA with active skin toxicity*) 
Maintain dose level 
Initiate topical corticosteroids 3-4x daily, 
preferred compounds to use are triamcinolone or 
betamethasone as long as skin toxicity is active, 
during max. 28 days 
 
Consider adding systemic corticosteroids in adult 
subjects. The optimal doses of systemic steroids in 
pediatric subjects should be defined individually 
after a consultation with a dermatologist according 
to the local label. 
 
If rash resolves to ≤ G1 within 10 days, the 
systemic corticosteroid may be discontinued. 
 
For subjects with symptoms like burning, stinging 
and/or pruritus add a non-sedating anti-histamine; 
consider adding a sedating anti-histamine at night 
Grade 3 (>30% BSA with active skin toxicity*) 
Omit alpelisib dose until rash /skin toxicity is no 
longer active but fading (G1), skin biopsy may be 
considered if part of local practice 
• Initiate topical corticosteroids 3-4x daily, 
preferred compounds to use are triamcinolone 
or betamethasone for at least 28 days 
• Add systemic corticosteroids 
If rash resolves to ≤ G1 within 10 days, systemic 
corticosteroid may be discontinued 
For subjects with symptoms like burning, stinging 
and/or pruritus add a non-sedating anti-histamine 
during day time; consider adding a sedating 
antihistamine at night 
Re-start alpelisib dose once rash/skin toxicity is no 
longer active but fading (G1): 
• at same dose in case of first occurrence, at 
reduced dose level in case of second 

 
 
 
 
 
40 
 
 
10.2.3 Guidelines for the treatment of alpelisib induced hyperglycemia 
Always consider consultation with a diabetologist, particularly for pediatric subjects, and 
recommend/reinforce lifestyle changes as per American Diabetes Association (ADA), i.e., exercise 
occurrence 
• If rash/skin toxicity still active in up to 10% 
BSA after more than 14 days, continue oral 
corticosteroid for at least 48 hours upon 
rechallenge with alpelisib; if rash and/or 
pruritus do not reoccur within 48 hours after 
re-challenge with alpelisib, systemic 
corticosteroid may be discontinued. 
• For subjects with symptoms like burning, 
stinging and/or pruritus an antihistamine 
regimen should be continued for a minimum of 
28 days after re-challenge 
with alpelisib 
Grade 4 (any % BSA associated with extensive 
superinfection, with IV antibiotics indicated; life-
threatening consequences) 
• Permanently discontinue subject from alpelisib 
• Mandated to consult a dermatologist. 
Photographs and skin biopsy** may be 
considered if part of local practice. Treatment 
may follow guidelines for Grade 3 above with 
the exception of rechallenge. Additional 
measures may be taken as per local treatment 
guidance 
Any Grade of Stevens-Johnson- 
Syndrome/Toxic Epidermal Necrolysis or 
other SJS/TEN-like severe skin reactions 
• Permanently discontinue subject from alpelisib 
• Consult dermatologist, ensure documentation 
by imaging like photographs and consider skin 
biopsy** if part of local practice. 
• Follow local treatment guidelines for SJS/TEN 
*“Active” skin toxicities: If there are no new lesions or new areas of involvement developing, and if 
lesion appearance is changing color from red to pale or light brown, it is likely the skin toxicity has 
begun to fade and is not to be considered “active” any longer. Treatment reduction can be considered 
for these areas. The appearance of skin toxicity may fade slowly, over 10 days or more but not 
requiring ongoing therapy. 
** Skin biopsy: skin biopsy can be performed as clinically indicated and assessed locally; no skin 
samples will be sent for central assessment 

 
 
 
 
 
41 
and dietary advice (e.g., small frequent meals, low carb, high fiber, balancing carbs over the course 
of the day. Three small meals and two small snacks rather than one large meal). 
The table below provides dose management recommendations. The preferred option for treating 
alpelisib-induced hyperglycemia, in subjects over 10 years old, is metformin, given its wide 
availability and well characterized safety profile. However, in case of intolerance, unavailability 
or unsuitability of metformin (e.g., in very young subjects), it is needed to consult a diabetologist 
to find the optimal individualized treatment for hyperglycemia, especially in pediatric subjects 
under 10 years old (where international or local guidelines may apply). Other insulin sensitizers 
such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors may be used for the treatment of 
alpelisib-induced hyperglycemia in adult subjects. Dose modification guidelines are described in 
Table 10-8. 
 
Table 10-8 Criteria for interruption and re-initiation of alpelisib treatment due to 
hyperglycemia 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib 
Grade 1 (> ULN - 160 mg/dL) [> ULN - 8.9 
mmol/L] 
For subjects with baseline values between >ULN 
– 140 mg/dL (ULN – 7.7 mmol/L) this applies 
only for findings > 140 mg/dL (7.7 mmol/L) 
Maintain dose level and remind subject 
on 
lifestyle changes. 
• If FPG < 140 mg/dl, consider 
adding metformin as per guidance 
below or in cooperation with 
diabetologist (for children<10 years 
old, a consultation with 
diabetologist to individualize 
treatment is required). 
• If FPG 140-160 mg/dl, 
start/intensify metformin as per 
guidance below or in cooperation 
with diabetologist (for children<10 
years old, a consultation with 
diabetologist to individualize 
treatment is required). 
Metformin 500 mg once daily with dinner. 
If no 
gastrointestinal (GI) intolerance after 
several days, increase to 500 mg bid, with 
breakfast and dinner. If tolerated, increase 
to 500 mg with breakfast, and 1000 mg 
with dinner. If tolerated, 1000 mg bid with 
breakfast and dinner. If not tolerated, 

 
 
 
 
 
42 
reduce to prior tolerated dose. 
Monitor FPG as clinically indicated and at 
least 
weekly for 8 weeks, then continue 
checking at least every two weeks until 
FPG is within baseline values. 
Grade 2 (>160 - 250 mg/dL) [> 8.9 - 13.9 
mmol/L] 
Maintain dose level and remind subject of 
lifestyle changes, exclude confounding 
factors like e.g., urinary tract infection, 
consider consultation with a diabetologist 
and start oral-antidiabetic treatment, e.g. 
metformin 500 mg bid with breakfast and 
dinner. 
If no GI intolerance, increase to 500 mg 
with 
breakfast, 1000 mg with dinner. If 
tolerated, 1000 mg bid with breakfast and 
dinner. If not tolerated, reduce to prior 
tolerated dose. Titrate to the maximum 
tolerated dose over a period of 3 weeks. 
If FPG is still rising on maximum tolerated 
dose of metformin or persistently 
>160mg/dl (>8.9 mmol/L), add an insulin-
sensitizer, e.g., pioglitazone 30 mg (max. 
dose). 
Monitor FPG as clinically indicated and at 
least 
weekly until FPG resolves to ≤ Grade 1 
• If FPG does not resolve to ≤ Grade 
1 within 21 days after institution of 
appropriate anti-diabetic treatment, 
reduce alpelisib by 1 dose level 
• Continue with anti-diabetic 
treatment and check FPG at least 
weekly for 8 weeks, then continue 
checking at least every 2 weeks, 
alert treating physician if 
FPG>250mg/dl 
Grade 3 (> 250 - 500 mg/dL) [> 13.9 - 27.8 
mmol/L] 
Omit alpelisib and confirm fasting status of 
the assessment. If non-fasting, re-check 
within 24 hours. 
Exclude confounding factors like e.g., 
urinary tract infection and consider 
consultation with a 

 
 
 
 
 
43 
diabetologist. 
Administer intravenous hydration and 
intervention for electrolyte/ketoacidosis/ 
hyperosmolar disturbances as clinically 
appropriate. Start metformin and titrate as 
outlined for Grade 2, add pioglitazone as 
outlined for Grade 2. Insulin may be used 
for 1-2 days until hyperglycemia resolves, 
however this may not be necessary in the 
majority of alpelisib-induced 
hyperglycemia given the short half-life of 
alpelisib. 
Monitor FPG as clinically indicated and at 
least twice weekly until FPG resolves to ≤ 
Grade 1. 
• If FPG resolves to ≤ Grade1 within 
3-5 days, while off program 
treatment and on metformin, re-start 
alpelisib and reduce by 1 dose level, 
continue with anti-diabetic 
treatment and check FPG at least 
weekly for 8 weeks, then continue 
checking at least every 2 weeks, 
alert treating physician if 
FPG>250mg/dl 
• If FPG does not resolve to Grade1 
within 3-5 days while off program 
treatment and on metformin, 
consult a diabetologist for 
management of diabetes is strongly 
recommended.  
If FPG does not resolve to ≤ Grade 
1 within 21 days after institution of 
appropriate anti-diabetic treatment 
in cooperation with diabetologist 
and exclusion of confounding 
factors e.g., urinary tract infection, 
permanently discontinue subject 
from alpelisib treatment. 
Grade 4 (> 500 mg/dL) [≥ 27.8 mmol/L] 
Omit alpelisib, confirm fasting status of the 
assessment. If non-fasting, re-check within 
24 hours. 
Exclude confounding factors (e.g., urinary 
tract 
infection). 
Should consult with diabetologist, initiate 
or intensify medication with appropriate 
anti-diabetic treatment (see Grade 3), re-

 
 
 
 
 
44 
check within 24 hours. 
• If grade improves then follow 
specific grade recommendations 
• If FPG is confirmed at Grade 4 and 
confounding factors could be 
excluded, permanently discontinue 
subject from alpelisib. 
 
A diabetologist consultation should always be considered. 
In cases where there is rapidly increasing serum glucose suspicious of severe clinical 
presentation and/or diabetic ketoacidosis without obvious confounding factors, a diabetologist 
should be consulted with consideration of potential hospitalization and close monitoring. 
 
10.2.4 Guidelines for treatment of alpelisib induced pneumonitis 
An early consultation with a pulmonologist is recommended at any suspicion of 
pneumonitis for an appropriate evaluation and management. Dose modification 
guidelines are described in Table 10-9. 
Table 10-9 Management of pneumonitis related to alpelisib with or without 
other agents in combination 
 
Pneumonitis 
Recommended 
Investigations 
Management of 
Pneumonitis 
Program Treatment 
Modification 
Any Grade 
Obtain appropriate 
imaging (e.g., high 
resolution CT scan) 
Consider broncho- 
alveolar lavage (BAL) and 
biopsy, if clinically 
appropriate 
Infectious causes of 
interstitial lung disease 
should be ruled out 
Follow institutional 
practice for 
management of 
pneumonitis (e.g., 
Treatment with high 
dose corticosteroids; 
concurrent antibiotic 
therapy if infectious 
causes are suspected). 
Consultation with a 
pulmonologist is highly 
recommended 
Immediately interrupt 
alpelisib for any case 
of suspected 
pneumonitis. 
For all subjects with 
confirmed 
pneumonitis alpelisib 
should be permanently 
discontinued 
 
10.2.5 Guidelines for the treatment of alpelisib induced diarrhea 
Mild to moderate diarrhea has been reported in studies of single agent alpelisib. Severe diarrhea 
and its clinical consequences including dehydration and acute kidney injury, have been reported 
in subjects treated with alpelisib. Based on the severity of the diarrhea, alpelisib may require dose 
interruption, reduction, or discontinuation. 

 
 
 
 
 
45 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, subject education as well as proper management of alpelisib-induced diarrhea is 
mandatory. For pediatric subjects, early detection and treatment of diarrhea is particularly 
important to avoid dehydration, and consultation with a gastroenterologist is recommended. The 
investigators and care givers should ensure appropriate hydration and nutrition of the subjects 
experiencing diarrhea; standards of local practice to be applied. In pediatric subjects the 
investigator may consider immediate dose interruption and initiation of anti-diarrhea treatment at 
occurrence of the first episode of diarrhea, and should ensure, that subjects and care givers are 
guided how to control diarrhea in timely manner. Dose modification guidelines are described in 
Table 10-10. 
The following algorithm for treatment and management of diarrhea is based on Wadler et al 
1998 38, Kornblau et al 2000 39. 
 
Table 10-10 Criteria for interruption and re-initiation of alpelisib treatment 
due to diarrhea 
 
Worst toxicity-CTCAE Grade 
Dose Modifications for alpelisib 
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 
reduce 1 dose level 
 
Subject history of diarrhea 
• 
At baseline, the subject’s history of diarrhea should be reviewed and the subject 
(and caregiver) should be appropriately informed of potential alpelisib-induced 
diarrhea and its management 
• 
Review previous medical history of diarrhea within the last 12 months; laxative 
use, colon surgery abdominal and pelvic irradiation, nocturnal diarrhea, pain, 
ulcerative colitis and other diarrhea-inducing diseases/conditions 
• 
Stop all diarrheogenic agents, otherwise exclude from program 
• 
Instruct subjects regarding risk of developing diarrhea 
• 
Perform baseline clinical/laboratory studies (e.g., one could rule out 
carrier state of Salmonella spp., Clostridium difficile, Campylobacter spp., 
Giardia, Entamoeba, Cryptosporidium which can lead to opportunistic 
infections in immunosuppressed subjects) 
• 
Explain the frequency of diarrhea and its relationship to NCI CTCAE grading 
(Table 10-10). 
First report of diarrhea: 
• 
Obtain history of onset and duration of diarrhea 

 
 
 
 
 
46 
• 
Description of number of stools and stool composition (e.g., watery, blood, 
mucus in stool) 
• 
Assess subject for fever, abdominal pain, cramps, distension, bloating, 
nausea, vomiting, dizziness, weakness (i.e., rule out risk for sepsis, 
bowel obstruction, dehydration) 
• 
Obtain medication profile (i.e., to identify any diarrheogenic agents) and dietary 
profile (i.e., to identify diarrhea-enhancing foods) 
• 
Proactively look for occurrence of diarrhea. If no problems occur, instruct the 
subject and care-giver to call when a problem does arise 
Management of diarrhea  
General Recommendation 
• 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 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte®, 
Gatorade®, broth) 
• Eat frequent small meals (e.g., bananas, rice, apple sauce, toast) 
It is recommended that subjects are treated with loperamide (refer to the local label). Subjects and 
caregivers should be instructed on the use of loperamide in order to manage signs or symptoms of 
diarrhea at home. Subjects should be instructed to start oral loperamide at the first sign of loose stool 
or symptoms of abdominal pain (initial administration for adults: 4 mg, then 2 mg every 4 hrs to a 
maximum of 16 mg/day; for children below 12 years, depending on age: 1-2 mg up to 4 times a day). 
These instructions should be provided at each visit and the treating physician should ensure that the 
subject understands the instruction. At each visit, subjects should be specifically questioned regarding 
any experience of diarrhea or diarrhea related symptoms. If symptoms were experienced, then the 
treating physician 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 
stools or overt diarrhea. 
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 diphenoxylate 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. 
 

 
 
 
 
 
47 
Treatment of diarrhea CTCAE Grade 1 or 2 
Diarrhea CTCAE Grade 1 or 2 will be treated with standard loperamide (initial at first 
administration 4 mg, then 2 mg every 4 hrs. (maximum of 16 mg/day) or after each unformed 
stool). Dosage and dosage schedule for pediatric subjects should be individualized according to 
the local loperamide label. 
 
12-24 hours later: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12 hours 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 subject does not need hospitalization (see section Diarrhea workup 
below). 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, then 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 hours: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• 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 48hrs 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. 

 
 
 
 
 
48 
 
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 subjects 
condition (to rule out dehydration, sepsis, ileus) medical check and workup (see section 
Diarrhea workup below). 
Observe subject for response. 
 
After 12-24 hours: 
• If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 jig 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 
jig TID) should be administered. 
• To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 
2 weeks. Treatment should be continued only when diarrhea resolves. 
Diarrhea workup 
Perform appropriate tests.27  
Spot stool analysis 
• Collect stool separating it from urine (special containers, analysis 
immediately, exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immunosuppressed 
subjects), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic 
etc., possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is 
likely to be fragile with evidence of colitis and thus great care and caution must be 
exercised in undertaking these invasive procedures: 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and 
biopsy of proximal jejunum to assess extent of inflammatory jejunitis 

 
 
 
 
 
49 
• Sigmoidoscopy - reassessment of colitis 
 
Table 10-11   NCI CTCAE version 5.0 grading of diarrhea for subjects without 
Colostomy 
Toxicity 
Diarrhea 
Increase of < 
4 stools per 
day over 
baseline 
Increase of 
4-6 stools 
per day 
over 
baseline 
Increase of ≥ 7 
stools per day 
over baseline; 
incontinence; 
hospitalization 
indicated; 
limiting self-care 
Activity of Daily 
Living (ADL) 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Diarrhea is defined as: A disorder characterized by frequent and watery bowel movements. 
 
10.2.6 Guidelines for the treatment of alpelisib induced stomatitis/oral mucositis 
For pediatric subjects, early consultation with a dentist is recommended on 
suspicion of alpelisib-induced stomatitis for appropriate evaluation and 
management. Dose modification guidelines are described in Table 10-12. 
Table 10-12   Criteria for interruption and re-initiation of alpelisib treatment 
due   to stomatitis 
Worst toxicity- CTCAE Grade  
(value) 
Dose Modifications for alpelisib 
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 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). 
Second occurrence: hold until ≤ Grade 1 and reduce 1 
dose level. 
Grade 4 
Permanently discontinue subject from alpelisib 
 

 
 
 
 
 
50 
10.2.7 Guideline for treatment of alpelisib induced pancreatitis 
If acute pancreatitis is diagnosed, initiate appropriate treatment and follow dose modification 
guidelines described in the Table 10-13. 
Table 10-13 Criteria for interruption and re-initiation of alpelisib treatment 
due to pancreatitis. 
Worst toxicity-  
CTCAE Grade  
(value) 
Dose Modifications for alpelisib 
Grade 2 (enzymatic elevation or 
radiologic findings only) 
Maintain dose level. Initiate appropriate medical therapy and 
monitor as clinically indicated. 
Grade 3 
Omit dose until resolved to Grade ≤ 1, then resume 
treatment at decrease 1 dose level. Only 1 dose 
reduction is allowed. If toxicity recurs, permanently 
discontinue subject from alpelisib 
Grade 4 
Permanently discontinue subject from alpelisib 
 
10.2.8 Investigations: alpelisib dose modifications 
Recommendations for dose reduction or dose interruption of alpelisib in the management of 
changes in the investigations when they are considered adverse events are summarized in the Table 
10-14 and Table 10-15. 
Clinical judgment of the treating physician, including confirmation of laboratory values if deemed 
necessary, should guide the management plan of each subject based on individual benefit/risk 
assessment. 
• Dose reduction will be allowed after which treatment must be discontinued as 
indicated in Table 10-14 and Table 10-15. 
 
After treatment is resumed at a lower dose: 
• If the same toxicity reoccurs with the same severity, treatment must be discontinued. 
• Once the AE has resolved and alpelisib dose has been reduced, the investigator may 
consider a dose re-escalation only if it may be needed to provide optimal clinical 
benefit (based on overall response assessment) and if there are no safety/tolerability 
concerns which may preclude from treatment continuation at higher dose level. 

 
 
 
 
 
51 
 
Table 10-14 
Criteria for interruption and re-initiation of alpelisib treatment: 
Investigations (hematologic) 
 
Worst toxicity-CTCAE Grade (value) 
Dose Modifications for alpelisib 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
• Maintain dose level. 
• Maintain dose level and 
monitor as clinically indicated. 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
• Omit dose until resolved to ≤ 
Grade 1, then resume at the next 
Grade 4 (ANC < 0.5 x 109/L) 
• Omit dose until resolved to ≤ 
Grade 1, then resume at the next 
lower dose level. 
Febrile neutropenia (ANC < 1.0 x 109/L, with a 
single temperature of ≥ 38.3 °C or a sustained 
temperature of ≥ 38 °C for more than one hour ) 
• Omit dose until 
resolved, then decrease 1 
dose level. Discontinue 
from study in the event 
of recurrence 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
• Maintain dose level. 
• Maintain dose level and monitor as 
clinically indicated. 
Grade 3 (PLT < 50-25 x 109/L) 
• Omit dose until resolved to ≤ 
Grade 1, then resume at the next 
Grade 4 (PLT < 25 x 109/L) 
• Omit dose until resolved to ≤ 
Grade 1, then resume at the next 
lower dose level. 
 
 
Table 10-15   Criteria for interruption and re-initiation of alpelisib treatment: 
Investigations (other) 
 

 
 
 
 
 
52 
Worst toxicity-CTCAE Grade 
(value) 
Dose Modifications for alpelisib 
Investigations (Renal) 
   Serum creatinine 
< 2 x ULN 
Maintain dose level. 
2 – 3 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then decrease 1 dose 
level. 
Grade 3 (> 3.0 – 6.0 x ULN) 
• Permanently discontinue subject from study 
Grade 4 ( > 6.0 x ULN) 
• Permanently discontinue subject from study 
Investigations (Hepatic) 
Isolated total Bilirubin elevation (for subjects with Gilbert 
Syndrome these dose modifications apply to changes in direct 
Grade 1 (>ULN - 1.5 x ULN) 
• No dose adjustment is required. 
Initiate appropriate medical therapy 
and monitor as clinically indicated. 
Grade 2 (> 1.5 - 3.0 x ULN) 
• Interrupt dose until recovery to Grade ≤ 
1 and resume at the same dose if resolved 
in ≤ 14 days or resume at the next lower 
dose level if resolved in > 14 days. 
Grade 3 (>3.0 - 10.0 x ULN) 
• Interrupt dose until recovery to Grade 
≤ 1, then resume at the next lower dose 
level. 
Grade 4 (>10.0 x ULN) 
• Permanently discontinue. 
Isolated AST or ALT elevation 
Grade 1 (>ULN - 3.0 x ULN) 
Grade 2 (>3.0 - 5.0 x ULN) 
• No dose adjustment is required. 
Initiate appropriate medical therapy 
and monitor as clinically indicated. 
Grade 3 (>5.0 - 20.0 x ULN) 
• Interrupt dose until recovery to Grade 
≤ 1, then resume at the next lower dose 
level. 
Grade 4 (>20.0 x ULN) 
• Permanently discontinue. 
Investigations (Metabolic) 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
• Maintain dose level. 
Grade 2 (> 1.5 - 2.0 x ULN) 
• Maintain dose level. 

 
 
 
 
 
53 
Grade ≥ 3 (> 2.0 x ULN) 
• Omit dose until resolved to baseline, then 
• If resolved in ≤ 14 days, maintain dose 
level. 
• If resolved in > 14 days, then 
decrease 1 dose level. Note: 
• In cases of isolated amylase elevations 
only, dosing may be maintained 
provided amylase fractionation 
demonstrates that pancreatic amylase is 
≤ Grade 1. Monitor total amylase (and 
continue to assess fractionated amylase) 
Note: Withhold study treatment for acute onset of new or progressive unexplained 
abdominal symptoms, such as severe pain or vomiting; and perform diagnostic 
procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology. 
  
Investigations (any other)  
Other adverse events 
Grade 1 or 2 
• 
Maintain dose level. 
Grade 3 
Omit dose until resolved to ≤ Grade 1, 
then decrease 1 dose level. 
Grade 4 
Permanently discontinue subject from 
alpelisib. 

 
  
 
 
54 
 
10.3 Follow-up for toxicities 
All subjects must be followed up for safety (adverse events and serious adverse events) for 30 
days following the last dose of study treatment (alpelisib). 
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event 
or a clinically significant laboratory value must be followed until resolution or stabilization of 
the event, whichever comes first. Further guidelines and recommendations for the 
management of specific study treatment induced toxicities are provided below. 
10.4 Criteria for Removal from Protocol Therapy and Off Study Criteria  
10.4.1  Criteria for Removal from Protocol Therapy  
a) Intolerable toxicity (leading to treatment interruption >4 weeks)  
b) Worsening disease at any time at the discretion of the investigator  
c) Refusal or withdraw of consent for further protocol therapy by parent/guardian/LARor 
subject  
d) Physician determines it is in subject’s best interest  
e) Completion of planned therapy  
f) Non-compliance with protocol requirements (e.g., unexcused missing more than one 
scheduled study visit or missing > 15% of doses of study drug)  
 
Subjects who are off protocol therapy are to be followed (as indicated) until they meet the 
criteria for Off Study (see below). For subjects who withdrawal due to AE, the medical 
condition will be tracked for at least a month after discontinuing the study drug or until 
resolution of the AE.  
 
Follow-up data will be required until one of the following off study criteria is met.  
 
10.4.2 Off Study Criteria  
a) Death  
b) Lost to follow-up  
c) Withdrawal of consent for any further follow up data submission 
d) Completion of protocol defined follow-up period. 
 
10.5 Adverse Reporting Requirements  
10.5.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
 

 
  
 
 
55 
10.5.2 Definition of an Adverse Event 
 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily 
have to have a causal relationship with the treatment.  An AE can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 
 
10.6 Routine Reporting Procedures for All AEs 
Grade 2 dose modifying and above AEs will be collected from the time the first dose of 
study treatment is administered until 30 days following discontinuation of study treatment. 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during the course of this study (including Serious Adverse Events (SAEs)) will be 
reported to the IRB of record in accordance with  the IRB of record’s SOPs and required 
timelines. AEs that are not serious but that are notable and could involve risks to subjects 
will be summarized in narrative or other format and submitted to the IRB at the time of 
continuing review. External SAEs that are both unexpected and related to the study 
intervention will be reported promptly after the investigator receives the report per the IRB 
of record’s SOPs.  
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence. Appropriate questions include: “How are you feeling?” or, “How does your 
child seem to feel?”  “Have you had any (other) medical problems since your last 
visit/contact?” or, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?” 
 
Grade 2 dose modifying and above AEs (including serious AEs) will be noted in the study 
records and on the case report form with a full description including the nature, date and 
time of onset, determination of non-serious versus serious, intensity (mild, moderate, 
severe), duration, causality, and outcome of the event. 
The severity of toxicities will be graded in accordance with the Common Terminology 
Criteria for AE (CTCAE) version 5.0. If an adverse event is not covered by one of the 
available CTCAE Adverse Event descriptions, and the Investigator deems it medically or 
clinically significant to document, the applicable “Other” category can be used.  

 
  
 
 
56 
Observed or volunteered AEs Grade 2 attributed to study drug and all Grade 3 and higher 
AEs, regardless of suspected causal relationship to study drug, will be recorded as AEs in 
the CRFs.  
 
10.7 Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• 
death, 
• 
a life-threatening event (at risk of death at the time of the event),  
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant disability/incapacity, or 
• 
a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea which persists for several hours may be considered severe nausea, but 
would not be an SAE.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
 
10.8 Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs 
Laboratory results from non-pediatric institutions or laboratories often have significantly 
different lab reference ranges, not specific for age. In the event of a greater than ±10% 
difference in the reference range for a specific lab result, either CHOP or other nationally 
recognized pediatric standards may be used to determine the grade of the laboratory value.  
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements) including 
those that worsen from baseline, and events felt to be clinically significant in the medical 
and scientific judgment of the investigator are to be recorded as an AE or SAE, in 
accordance with the definitions provided. In addition, an associated AE or SAE is to be 
recorded for any laboratory test result or other safety assessment that led to an intervention, 
including permanent discontinuation of study treatment, dose reduction, and/or dose 
interruption/delay. However, any clinically significant safety assessments that are associated 
with the underlying disease, unless judged by the investigator to be more severe than 
expected for the subject's condition, are not to be reported as AEs or SAEs. 

 
  
 
 
57 
 
 
 
10.9 Relationship of SAE to study drug or other intervention 
An assessment of the relationship between the AE and the medical intervention. CTCAE 
does not define an AE as necessarily “caused by a therapeutic intervention”. After naming 
and grading the event, the clinical investigator must assign an attribution to the AE using the 
following attribution categories: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
to the intervention 
Unlikely 
The AE is doubtfully related to 
the intervention 
Related to investigational agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 
For all collected AEs, the clinician who examines and evaluates the subject will determine the 
adverse event’s causality based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below: 
 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained 
by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(de-challenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary.  
 
Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time sequence to administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Rechallenge information is not required to 
fulfill this definition.  
 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an adverse drug event may rate only as 

 
  
 
 
58 
“possibly related” soon after discovery, it can be flagged as requiring more information and 
later be upgraded to “probably related” or “definitely related”, as appropriate. 
 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which 
other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
subject’s clinical condition, other concomitant treatments).  
 
Unrelated: The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician.  
 
10.10 
Treatment Dose Modifications and Guidelines for Adverse Event 
Reporting specific to study drug  
Dose modifying hematological and non-hematological toxicities are defined differently.  
Dose modification or discontinuation of trametinib for toxicity is considered a dose 
modifying toxicity. Guidelines for management and dose modifications are also provided for 
the toxicities of special interest. 
Alpelisib Dose Modification Schedule for Adverse Events 
Grade (CTC-AE)* 
Schedule 
Grade (CTC-AE)* Dose Modifications 
Grade 1 or Grade 2 (Tolerable) 
Continue treatment and monitor as clinically 
indicated. 
Grade 2 (Intolerable) or Grade 3 
Interrupt therapy until toxicity is grade 0-1and reduce 
by one dose level when resuming therapy. 
Grade 4 
Discontinue permanently, or interrupt therapy until 
Grade 0 to 1 and 
Reduce by one dose level when resuming therapy. 
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 
(CTC-AE) 
 
10.11 
IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of record of all on-site unanticipated, serious 
Adverse Events that are related to the research activity. Other unanticipated problems related 
to the research involving risk to subjects or others will also be reported promptly. Written 
reports will be filed with the IRB of record and in accordance with the timeline below. 

 
  
 
 
59 
External SAEs that are both unexpected and related to the study intervention will be 
reported promptly after the investigator receives the report.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 business days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
 
10.11.1 
Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
10.12 
Investigator Reporting of a Serious Adverse Event to 
Coordinating Center. 
Any serious adverse event that is life threatening or causes death(as defined in section 10.7 
above) whether anticipated or not, must be reported to the coordinating center (CHOP) 
within one business day of the investigator becoming aware of the event (expedited 
reporting).  Events that are not life-threatening and do not result in death, must be reported 
within 7 business days of discovery. If only limited information is initially available, follow-
up reports are required until resolution. The original SAE Form must be kept on file at the 
study site. 
Reporting will be conducted in full accordance with all applicable Institutional Research 
Policies and Procedures and all applicable Federal and state laws and regulations including 
45 CFR 46, and the Good Clinical Practice: Consolidated Guideline approved by the 
International Conference on Harmonization (ICH).   
10.13 
Medical Emergencies 
For any medical emergencies, the Investigator or her physician designee will be responsible 
for investigating the emergency and resolving issues surrounding the emergency. Study 
teams and medical personnel associated with the subject will proceed accordingly to provide 
best care. 

 
  
 
 
60 
10.14 
Reporting of Study Treatment Errors Including Misuse/Abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded 
on the appropriate CRF irrespective of whether or not they are associated with an AE/SAE. 
Study treatment errors and uses outside of what is foreseen in the protocol, including misuse 
or abuse, will be collected and reported in the safety database irrespective of it being 
associated with an AE/SAE within 24 hours of Investigator’s awareness. 
 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
 

 
  
 
 
61 
11  STUDY ADMINISTRATION 
11.1 IRB Approval 
The Children’s Hospital of Philadelphia (CHOP) Institutional Review Board (IRB) will 
serve as the reviewing IRB for this multi-center study. All participating sites have agreed to 
adhere to the single IRB (sIRB) Policy (https://grants.nih.gov/grants/guide/notice-
files/NOT-OD-16-094.html) and to rely on CHOP as the sIRB.  
The CHOP IRB will serve as a Privacy Board to fulfill the requirements of the Health 
Insurance Portability and Accountability Act (HIPAA) Privacy Rule (45 CFR 164.512(i)) 
for use or disclosure of protected health information for research purposes. The CHOP IRB 
has extensive experience with providing IRB oversight for external institutions and complies 
with the registration requirements for both the Office for Human Research Protections 
(OHRP) and the U.S. Food and Drug Administration (FDA) (IRB00000316 and 
IRB00000317). Prior to initiating the study, all participating sites will sign an 
authorization/reliance agreement that will clarify the roles and responsibilities of the sIRB 
and participating sites. 
When the CHOP IRB serves as the reviewing IRB for other sites, it will need information 
from each relying institution about local context, consent form requirements (i.e. injury 
compensation language), applicable state/local laws and any local conflict of interest 
determinations. The CHOP IRB will provide approval notices and approved informed 
consent documents customized with the site Principal Investigator name, contact 
information and any other site-specific wording (i.e. injury compensation, HIPAA) for each 
relying institution. 
As the sIRB, the CHOP IRB will communicate with the overall Principal Investigator 
through eIRB, which CHOP investigators also use for all other IRB submissions at CHOP. 
Communication with relying sites and their Principal Investigators will occur through the 
same system. This avoids the need to have the overall Principal Investigator collect the 
information from all of the relying sites and submit them to the CHOP IRB. eIRB provides 
the ability for Principal Investigators from each relying institution, after a simple registration 
process, to log in and provide site-specific documents and information (i.e. annual reports, 
site-specific recruitment materials) to the CHOP IRB. The CHOP IRB, in turn, will post 
site-specific packages (i.e. approval letters, stamped consent forms) for the use of the relying 
site Principal Investigators. 
11.2 Data Collection and Management 
The CASTOR system will be used as a central resource for data processing and 
management. Data transfer agreements will be in place with each site and the coordinating 
center to allow for data collection. CASTOR is a web application and back-end database 
model designed to support data capture for research studies. CaNVAS has a license with 
CASTOR that is housed on a password protected server and therefore afforded the same 
protections as other sensitive clinical systems. CASTOR was developed specifically around 
HIPAA-security guidelines with features such as data encryption. It provides an intuitive 
interface for data entry with data validation, audit trails for tracking data manipulation and 

 
  
 
 
62 
export procedures, automated export procedures for seamless data downloads to common 
statistical packages, including SAS and procedures for importing data from external 
sources. Standard operating procedures will be used to guide all data management 
activities, such as the naming and identification of variables, data cleaning and handling of 
missing data. Participating site data will be entered directly into the CASTOR database. 
Data entry screens will be designed to incorporate range checks and concurrent checks to 
minimize errors.  
 
11.2.1 Protection Against Risks 
All sites will obtain institutional review board approval for this study. Subject’s risks of 
participating in research will be kept to a minimum with measures to protect confidentiality 
and planned interim analysis for safety monitoring.  
 
Best of care will be provided to subjects in the event of toxicities associated with treatment. 
Subjects and, as applicable, parents/guardian/LAR, will be provided appropriate contact 
number(s) for treating physicians at the clinical site in accordance with institutional IRB 
guidelines.  
 
11.2.2 Drug Accountability  
Adequate records of study drug receipt and disposition will be maintained at each study site 
by the investigational drug pharmacy. Records of receipts, investigational drug orders, 
dispensing records, and disposition forms will be examined during the course of the study. 
The purpose of these records is to ensure regulatory authorities that the investigational new 
drug will not be distributed to any person who is not a study subject under the terms and 
conditions set forth in this protocol.  The study medication is to be prescribed by the 
Investigator or designee and may not be used for any purpose other than that described in 
this protocol. Supplies returned by subjects will be destroyed once returned quantities are 
documented. Unused supplies that expire during the study as well as those that are unused or 
partially used at study completion will be destroyed according to site specific SOPs. 
11.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. 
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and 
any recipient researchers (including others at CHOP) before sharing a of any Protected 
Health Information (PHI). 
Electronic documentation will be username and password encrypted. 

 
  
 
 
63 
 
11.4 Regulatory and Ethical Considerations 
11.4.1 Data and Safety Monitoring Plan 
• 
Principal Investigator  
The PI will have responsibility for monitoring the overall safety during the study and they or 
a designated appropriately clinically trained member of the study team will personally be at 
all of the study visits. In addition, the study coordinator will be involved in all studies and 
will also monitor for safety. All adverse events will be reported to the IRB in a timely 
fashion in compliance with all applicable regulations. 
• 
Data Safety Monitoring Board (DSMB): The DSMB will be made up of representatives who 
are independent of the study sponsor and investigators.  
The investigators place the highest priority on ensuring the safety of subjects participating in 
clinical trials. Every interventional trial conducted through CaNVAS includes a plan for safety 
and data monitoring. 
This study will be reviewed by the CHOP Data and Safety Monitoring Board (CHOP DSMB). 
A summary of the CHOP DSMB activities are as follows:  
• Review the clinical trial for data integrity and safety  
• Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as 
any others requiring expedited reporting as defined in this protocol. (Grades 4 & 5 
events must be reported to the DSMB within 5 calendar days of study staff’s 
knowledge.) 
• Review all DSM reports  
• Submit a summary of any recommendations related to study conduct  
• Terminate the study if deemed unsafe for subjects  
A copy of the CHOP Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The board will 
review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary.  
Any available DSMB letters will be submitted to the IRB of record as required. 
11.4.2 Audits 
Auditing is essential to ensure that research conducted is of the highest quality and meets 
regulatory agency standards.   
In accordance with ICH GCP and the audit plan, Regulatory authorities, the IRB, and/or 
sponsor may request access to all source documents, data capture records, and other study 
documentation for audit or inspection. Direct access to these documents must be guaranteed 
by the investigator, who must provide support at all times for these activities including; 

 
  
 
 
64 
review of subject and study related records, and compliance with protocol requirements as 
well as ICH GCP and applicable regulatory policies. 
The key sponsor contact, monitors, auditors or regulatory inspectors are responsible for 
verifying source documents and records assuring that subject confidentially is respected.   
The monitor is responsible for source document verification of case report forms (CRF) data 
at regular intervals during the study. Protocol adherence, accuracy and consistency of study 
conduct and data collection with respect to local regulations will be confirmed.   
By signing the investigator agreement, the investigator agrees to cooperate with the monitor 
to address and resolve issues identified during monitoring visits.   
All data will be collected in an electronic CRF system. All entries must be completed in 
English. Concomitant medications and AEs will be coded. For further details surrounding 
the completion of CRFs, please refer to the CRF completion guidelines.  
11.5 Risk Assessment 
TIE2/PIK3CA pathway Driven Vascular Anomalies are serious conditions with limited 
approval for pharmacological treatment targeting the underlying cause of the disease. 
Current therapy includes debulking surgery, amputation, and/or endovascular occlusive 
procedures which mainly addresses symptoms and complications of the disease. There is a 
high unmet medical need for an effective systemic treatment.  
The main risks of this study are from alpelisib administration. The safety profile of alpelisib 
observed in EPIK-P1 was consistent with the mechanism of action of alpelisib and compares 
favorably with prior experience in clinical studies and post marketing exposure in the 
oncology setting. The most common AEs are Diarrhea (reported in 15.8% of all patients), 
hyperglycemia (12.3%) and aphthous ulcer (10.5%). All events were of grade 1/2 in severity 
and were effectively managed with appropriate treatment. No AEs led to treatment 
discontinuation and no deaths were reported during the study40.  
 
11.6 Potential Benefits of Trial Participation 
Alpelisib is considered to be a promising treatment option for pediatric and adult subjects 
with a confirmed TIE2/PIK3CA variant. Treatment with alpelisib related to variant(s) in 
TIE2/PIK3CA gene may provide a clinical benefit compared to available treatment options. 
The participants enrolled in this study will receive alpelisib as active treatment for their 
disease. Based on published clinical data (Venot et al 2018)16 and recent results from EPIK-
P140 study, treatment with alpelisib is expected to be tolerated with a manageable safety 
profile. 
11.6.1 Risk-Benefit Assessment 
The low frequency and generally mild severity of AEs with alpelisib treatment suggest good 
tolerability and an acceptable and manageable safety profile in pediatric and adult subjects. 

 
  
 
 
65 
This represents an acceptable risk benefit assessment where the benefits of treatment 
outweigh the risks.  
11.7 Recruitment Strategy 
Subjects will be recruited primarily through the CaNVAS member institutions with 
consideration given to outside provider referrals.  Subjects with complex lymphatic 
anomalies and diminished quality of life due to condition with suspected or known Ras-
pathway variants will be referred by their primary vascular anomalist, geneticist, or provider 
to the CaNVAS member institution.  Recruitment will also include listing through 
clinicaltrials.gov for subjects cared for outside of the member network and at CaNVAS 
member sites as documented in the protocol.  
There is no concern for ability to recruit this subject population given current and ongoing 
trends in requests for treatment of subjects with trametinib. 
11.8 Informed Consent/Assent and HIPAA Authorization 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate 
in the study and continues throughout the individual’s study participation. Extensive 
discussion of risks and possible benefits of this therapy will be provided to the subjects and 
their families. Consent forms describing in detail the study interventions/products, study 
procedures and risks are given to the subject and written documentation of informed consent 
is required prior to starting intervention/administering study product. 
Consent forms will be IRB-approved and the subject (and parent/guardian/LAR, if necessary) 
will be asked to read and review the document. Upon reviewing the document, the investigator 
will explain the research study to the subject or parent/guardian/ LAR and answer any 
questions that may arise. In accordance with 46 CR 46.111, the subject will sign and date the 
informed consent document prior to any procedures being done specifically for the study.  
A witness should only sign when required, institutional IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or 
note to file) the relationship to the subject and why a witness signed. (i.e., “Although not 
required, the subject’s spouse was present during the consenting process and signed as the 
witness.” Or “Although not required, hospital staff was present for consenting process and 
signed as a witness.”) 
The subjects will have the opportunity to discuss the study with their surrogates or think about 
it prior to agreeing to participate. The subjects may withdraw consent at any time throughout 
the course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. The 
rights and welfare of the subjects will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. If 
there are changes to the consent form, all revisions will be reviewed with study subject at the 
next appropriate opportunity. Subjects that require re-consenting will be defined in the IRB 
approved amendment submission. The process for obtaining informed consent will again be 

 
  
 
 
66 
performed. Study subjects will not be re-consented for continuing reviews. The protocol will 
follow the institutional IRB’s policy for subjects who demonstrate limited English proficiency 
or limited literacy.  
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that 
the consent has been signed and that all questions have been answered to the subject’s 
satisfaction after adequate time for review of the consent. It is also documented that a copy of 
the consent is given to the subject. The original consent is kept with the subject’s study file, 
and a copy of the signed consent is sent to the Medical Records Office to be scanned into the 
legal medical record. A copy will also be given to the subject. 
11.8.1 Waiver of Consent 
Waiver of consent is not requested.  
45 CFR 46.116(d) An IRB may approve a consent procedure which does not 
include, or which alters, some or all of the elements of informed consent set forth in 
this section, or waive the requirements to obtain informed consent provided the IRB 
finds and documents that: 
(1) the research involves no more than minimal risk to the subjects; 
(2) the waiver or alteration will not adversely affect the rights and welfare of the 
subjects; 
(3) the research could not practicably be carried out without the waiver or 
alteration; and 
(4) whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
 
11.9 Payment to Subjects/Families 
Reimbursement is not provided as part of this protocol.  
 
 
 
12 REPORTING OF PROTOCOL VIOLATIONS/DEVIATIONS AND 
UNANTICIPATED PROBLEMS  
Any protocol violations, deviations, or unanticipated problems should be documented and 
reported according to the coordinating center’s Manual of Operations. See the Manual for 
more detailed instructions.  
 
In addition, each participating site should report protocol deviations/violations or 
unanticipated problems according to their site’s policies, procedures and applicable 
regulations.  
 

 
  
 
 
67 
13 COORDINATING CENTER RESPONSIBILITIES:  
 
13.1  SAE/SAE Reporting  
All SAEs, regardless of attribution or expectedness, must be reported using a FDA 
MedWatch 3500a Form. For participating sites, this form must be submitted to the 
coordinating center within 24 hours of learning of the event. Participating sites are required 
to notify their local IRBs according to institutional reporting policies.  
MedWatch 3500a Reporting Guidelines: In addition to completing appropriate subject 
demographic and suspect medication information, the report should include the following 
information within the Event Description (section 5) of the MedWatch 3500a form:  
• Treatment regimen (dosing frequency, combination therapy)  
• Protocol description (and number, if assigned)  
• Description of event, severity, treatment, and outcome, if known  
• Supportive laboratory results and diagnostics  
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication  
Follow up information to a safety report should be submitted as soon as the relevant 
information is available. Additional information may be added to a previously submitted 
report by any of the following methods:  
• Adding to the original MedWatch 3500a report and submitting it as follow-up  
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500a form  
• Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e. D.O.B., initial, subject number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up information 
is being submitted (The subject identifiers are important so that the new information is 
added to the correct initial report.)  
 
13.2 SAE reporting in the Follow Up Period  
In the event that during the 1-year follow up period the Investigator identifies what is 
believed to be a new (unexpected) long-term risk or short-term risk (in the event the subject 
continued therapy on study drug) attributable to the study drug, this SAE must be reported to 
the Sponsor and to the site’s IRB consistent with any Unanticipated Problem reporting 
policy, as this would be a new risk directly related to any subject that might be participating 
in the research.  
 
13.3 Sponsor Responsibilities to be performed by the Coordinating 
Center:  
To ensure subject safety, every SAE, regardless of causality, occurring after the 
subject has provided informed consent and until 30 days after the last study visit 
must be reported to Novartis Patient Safety (clinicalsafetyop.phuseh@novartis.com) 

 
  
 
 
68 
immediately, without undue delay, but under no circumstances later than within 24 
hours of obtaining knowledge of the events. 
 
All follow-up information for the SAE including information on complications, 
progression of the initial SAE and recurrent episodes must be reported as follow-up 
to the original episode immediately, without undue delay, but under no 
circumstances later than within 24 hours of the Investigator receiving the follow-up 
information. 
 
Any SAEs experienced after the 30-day period should only be reported 
to Novartis Safety if the Investigator suspects a causal relationship to study 
treatment. 
 
To ensure subject safety, each pregnancy occurring after signing the informed 
consent must be reported to Novartis Patient Safety 
(clinicalsafetyop.phuseh@novartis.com) within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
 
13.3.1 Unexpected Fatal or Life-Threatening Suspected Adverse Reaction 
Reports  
Notify the FDA as soon as possible but no later than 7 calendar days after the sponsor’s 
initial receipt of the information. Either the sponsor or the investigator can make the 
determination of life-threatening. (Food and Drug Administration: Fax: (800) FDA – 0178)  
 
13.3.2 Unexpected, Serious Suspected Adverse Reactions  
 
Any suspected adverse reaction that is both serious and unexpected, per 21 CFR 
312.32(c)(1)(i), only if there is evidence to suggest a causal relationship between the 
drug and the adverse event, must be reported to the FDA as soon as possible but no later 
than 15 calendar days after the sponsor determines the information qualifies for reporting. 
(Food and Drug Administration: Fax: (800) FDA – 0178) The following must be reported:  
a. Single Occurrence – event is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). See SOP Form 32-
1.3-001 Adverse Event Reporting for the Sponsor: Single Occurrence.  
 
b. Multiple Occurrences – event occurs one or more times and is not commonly associated 
with drug exposure but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture).  
c. Aggregate Analysis of Specific Events Observed in the Clinical Trial – analysis of events, 
e.g., known consequences of the underlying disease or condition under investigation or other 

 
  
 
 
69 
events that commonly occur in the study population independent of drug therapy, that 
indicates those events occur more frequently in the drug treatment group than in a 
concurrent or historical control group.  
 
 
13.3.3 Serious Adverse Event Reporting Procedures to the CHOP IRB  
 
The Sponsor will report any unexpected life-threatening event or death (Grade 4 or 5) 
adverse event to the CHOP IRB and within 24 hours after the Sponsor is made aware of the 
event.  
Unexpected Grade 3 adverse events at least possibly attributable to the research will be 
reported to the CHOP IRB only at the time of the annual progress report.  
 
14 PUBLICATION 
Authorship of publications from data generated in study will be determined based on the 
uniform requirements for manuscripts submitted to biomedical journals (as outlined in the 
International Committee of Medical Journal Editors December 2013) which states:  
• Authorship should be based on  
o Substantial contributions to the conception or design of the work, acquisition of 
data, analysis, or interpretation of data for the work AND  
o Drafting the article or revising it critically for important intellectual content; 
AND  
o Final approval of the version to be published; AND  
o Agreement to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work re 
appropriately investigated or resolved  
When a large, multicenter group has conducted the work, the group will identify the 
individuals who accept direct responsibility for the manuscript. This individual will fully meet 
the criteria for authorship defined above.  
Funding, collection of data or general supervision of the research alone or in combination does 
not qualify an individual for authorship.  
Any publication, in any form, that is derived from this study must be submitted to CaNVAS 
for review and approval. The study contract between the institution, principal investigator, 
Co-investigator and CaNVAS or its delegate will outline the requirements for publication 
review. 

 
  
 
 
70 
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APPENDICES 
APPENDIX I: PERFORMANCE SCORES 
 
 
 
 

 
  
 
 
76 
APPENDIX II: PROMIS 
 

 
  
 
 
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APPENDIX III: BLOOD SAMPLING 
Blood will be collected into the following tubes: 
1. Blue top (sodium citrate) for plasma – 4.5 mL tube 
2. Red top for serum – 6.0 mL tube 
3. Purple top (EDTA) for DNA – 6.0 mL tubes 
4. Cell- free (cf) DNA  collection tube – 8.5ml tubes 
5. Tubes will be filled to capacity if possible and the order of 
priority if blood volume is limited is 1-5.  
 
For blood-derived plasma and serum (tubes 1. and 2), the plasma and serum must be 
separated as soon as possible and frozen at -70F. Tubes should be shipped on dry ice 
overnight to the biorepository.  EDTA tubes (#3) and cfDNA tubes *#4) can be shipped by 
FedEx or other express services in room temperature to: Division of Pulmonary Biology, 
Cincinnati Children’s Children’s Hospital R40153333 Burnet Avenue, Cincinnati 45229.  
 
Samples sent to Dr. Hakon Hakonarson’s lab should be sent to: 
Center for Applied Genomics (CAG) 
Leonard Madlyn Abramson Research Center 
3615 Civic Center Blvd, Lab 1014, 10th Floor 
Attn: James Snyder 
 
 
 
 
 
 
 
 

 
  
 
 
96 
APPENDIX IV: RADIOLOGY 
Protocol 
Name 
Sequences 
Est 
time 
Coverage/ 
Contrast 
Tech 
notes 
Nursing/Child 
Life notes 
Sedation/Anest
hesia notes 
Supporting 
evidence 
VASCULAR 
MALFORMATI
ON,  
EXTREMITY 
 
Radiologist must define coverage 
area either based on localizer or 
prior studies. 
1. 
Cor/Sag** T1 FSE 
2. 
Cor/Sag** STIR 
3. 
Axial T2 FS radial k-
space filling sequence 
4. 
Axial VIBE pre-
contrast 
5. 
Cor** time-resolved 
angiography (Temp. 
res.: 2.5 s; 20 phases) 
6. 
Axial VIBE post-
contrast. 
7. 
If lesion is peri-
articular or intra-
articular: sagittal 3D 
GRE (DESS) to see 
hemosiderin deposition 
in synovium. 
8. 
Axial DWI, b=0, 150, 
300, 600, 800 
 
**Planes must be prescribed to 
allow optimum visualization of 
the lesion 
 
 
 
5 min 
5 min 
5 min 
4 min 
3 min 
4 min 
 
 
 
 
 
5 min 
(31 
min) 
ROI 
 
Radiologist 
must define 
coverage area 
either based on 
localizer or 
prior studies. 
 
Contrast: 
Standard 
(gadavist) 
 
If focal 
lesion, 
place 
marker 
over site. 
Planes 
must be 
prescribed 
to allow 
optimum 
visualizati
on of the 
lesion; 
discuss 
with 
radiologist
. 
 
Study time:  
30 minutes (non-
sedated) 
45 minutes 
(sedated) 
 
Position:  
Always supine 
 
Music/video: 
Always possible 
(According to 
magnet) 
 
IV site/size:  
No preference  
 
Power injection:  
Mandatory 
 
NPO: N/A 
 
Oral prep: N/A  
 
Medications: 
none 
 
Sedation/Anest
hesia:  
Second PIV for 
contrast 
 
Protocols 
from Boston 
Children’s 
and Sick 
KIds 
 
Chest Vascular 
Malformation  
 
1. 
Coronal T1 FSE 
2. 
Coronal STIR  
3. 
Axial T2 FS BLADE  
4. 
Axial T1 FS volume-
interpolated GRE 
***Dynamic Contrast*** 
3 m  
5 m  
4 m  
30 s 
 
From/To:  
Include the 
entire lesion 
(might extend 
into neck 
and/or 
abdomen) 
Contrast: 
Temp 
resolution 
for TWIST 
if inside 
the 
thoracic 
cage 
(outside 
can be 
Study time:  
1 hour  
 
Position:  
Always supine 
Sedation/Anest
hesia:  
Second PIV for 
contrast 
 
Flors L, 
Leiva-Salinas 
C, Maged 
IM, et al. MR 
imaging of 
soft-tissue 
vascular 
malformation
s: diagnosis, 
classification, 
and therapy 

 
  
 
 
97 
5. 
Coronal time-resolved 
MR angiography 
(Temp Res: 2.5 s; 20 
phases) 
6. 
Axial T1 FS volume-
interpolated GRE GD+ 
7. 
Coronal T1 FS spoiled 
GRE GD+ 
8. 
Axial DWI, b=0, 150, 
300, 600, 800 
***OPTIONAL*** 
Delay Axial T1 FS spoiled GRE 
GD+ 
3 m 
 
30 s 
3 m  
(19’) 
3 m 
5 m 
(27’) 
Standard 
(gadavist) 
 
 
higher 
~3.5) 
 
Breath holds: 
None 
 
Music/video: 
Always possible 
(According to 
magnet) 
 
IV site/size: no 
preference  
 
Power injection:  
Always 
 
NPO: N/A 
 
Oral prep: N/A  
 
Medications: 
none 
 
follow-up. 
Radiographic
s. 
2011;31(5):1
321‐1341 

 
  
 
 
98 
VASCULAR 
MALFORMATI
ON, BODY 
1. Axial T1 FSE 
2. Axial T2 FS radial k-
space filling sequence  
3. Axial T1 FS stack 
stars volume-
interpolated GRE 
pre-contrast 
4. Cor time-resolved 
MRA (Temp. res.: 2.5 
s; 20 phases) 
5. Axial T1 FS stack 
stars volume-
interpolated GRE 
post-contrast 
Axial DWI, b=0, 150, 300, 600, 
800 
3 min 
4 min 
 
30 s 
 
3 min 
 
30 s 
 
 
5 min 
 
5 min 
(21 
min) 
From: lung 
bases 
Through: 
pelvis 
Contrast: 
Standard 
(gadavist) 
 
Coach 
breath 
holding 
If focal 
lesion, 
place 
marker 
over site. 
Arms up 
whenever 
possible  
 
Study time:  
30 minutes (non-
sedated) 
45 minutes 
(sedated) 
 
Position:  
Always supine 
 
Breath holds:  
Up to 30 seconds 
(practice and let 
tech know if 
child is able) 
 
Music/video: 
Always possible 
(According to 
magnet) 
 
IV site/size:  
No preference  
 
Power injection:  
Mandatory 
 
NPO: N/A 
 
Oral prep: N/A  
 
Medications: 
none 
 
Sedation/Anest
hesia:  
Second PIV for 
contrast 
 
Protocols 
from Boston 
Children’s 
and Sick 
KIds 
 
MRL 
1. T2 SPACE coronal 
2. Coronal TWIST* 
3. Post Gd coronal 3D 
IR FLASH 
(sequential after each 
access injection) 
*With slow injection of Gd into 
sequential access sites (nodes, 
liver, and mesentery) 0.2 
 
Chest & abd 
TWIST with 
1-1.5 mm 
slices, every 
8-12 s for 30 
phases 
 
IRFLASH 
with 
 
 
 
European 
Radiology 
(2019) 
29:5190–
5196 

 
  
 
 
99 
mmol/kg diluted to allow 
appropriate volume 
respiratory 
navigation 
Brain 
1. Axial diffusion  
2. T1 3D GRE 
volumetric / MPRAGE 
Sag, with axial 
reformations  
3. TSE T2 axial  
4. FLAIR axial 
5. TSE T2 coronal 
6. Pre-gad SE T1 axial 
with fat sat 
7. TWIST MRA 
8. Post-gad SE T1 axial 
with fat sat 
 
 
 
 
 
 
 
Face 
1. HASTE ax & cor 
2. Sag T1 
3. Ax T2 fat sat 
4. Ax STIR 
5. Ax diffusion 
6. Cor T2 
7. Pre-gad ax T1 FS 
8. Axial TWIST  
9. Post gad Sag, Ax & 
Cor T1 fat sat 
 
 
 
 
 
 
Neck 
1. HASTE ax & cor (not 
done on follow up 
studies) 
2. Sag T1 
3. Ax STIR 
4. Ax diffusion 
5. Cor fat sat T2 Dixon 
6. Axial TWIST  
7. Post gad Ax & Cor T1 
fat sat Dixon 
 
 
 
 
 
 
Orbits 
1. Small FOV sag & ax 
T1 thin section  
2. TSE T2 Ax (with fat 
sat ) 
3. TSE T2 Cor with fat 
sat 
4. Ax diffusion 
5. Pre-gad ax T1 FS 
6. Axial TWIST 
7. Post gad SE T1 ax & 
cor with fat sat thin 
sections 
 
 
 
 
 
 
 

 
 
 
 
 
100
APPENDIX V: MEDICATIONS TO BE USED WITH CAUTION 
List of CYP450 substrates to be used with caution 
Category 
Drug names 
CYP2C9 substrates 
Narrow Therapeutic index substrates of 
CYP2C9 
(S)-Warfarin and other coumarin-derivative 
anticoagulants 
Sensitive substrates of CYP2C9 
Benzbromarone, Celecoxib, Glimepiride, 
Glipizide, 
(R)/(S)-Ibuprofen, Lornoxicam, Meloxicam, 
Piroxicam, 
Tolbutamine, (S)-Warfarin 
CYP2B6 substrates 
Narrow Therapeutic index substrates of 
CYP2B6 
Meperidine 
Sensitive substrates of CYP2B6 
Bupropion, Efavirenz 
Selected CYP3A4 substrates 
Narrow Therapeutic index substrates of CYP3A 
Alfentanil, Diergotamine, Ergotamine, Fentanyl, 
Pimozide, Quinidine 
Sensitive substrates of CYP3A 
Alfentanil, Atazanavir, Atorvastatin, Darunavir, 
Lumefantrine, Midazolam, Simvastatin, 
Triazolam 
CYP3A4 substrates which are known or 
potential 
auto-perpetrators 
Clarithromycin, Conivaptan, Encorafenib, 
Erythromycin, Diltiazem, Mifepriston, Ribociclib, 
Telthromycin, Troleandomycin, Verapamil 
* Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increase in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious concerns (e.g. Torsades 
de Pointes, QT prolongation). 
** Sensitive substrates: Drug that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-
administered 
with a known potent inhibitor. 
CYP3A4 substrates which are auto-perpetrators: Based on Novartis internal assessment. 
 
 

 
 
 
 
 
101
APPENDIX VI: PROHIBITED MEDICATION  
List of prohibited medication 
Category 
Drug Name 
Strong CYP3A Inducers 
Apalutamide, Avasimibe1, Carbamazepine, 
Enzalutamide, Ivosidenib, Lumacaftor, Mitotane, 
Phenobarbital, Phenytoin, Rifabutin, Rifapentine, 
Rifampin (Rifampicin), St. John's wort (hypericum 
perforatum)1 
BCRP inhibitors - 
Evidence for DDI potential shown in vivo 
Protease Inhibitors (e.g., Atazanavir/ritonavir1,2, , 
Lopinavir/ritonavir1,2, Tipranavir/ritonavir1,2, 
Tipranavir2 , Paritaprevir2), 
Elvitegravir/cobicistat1,2, Curcumin1,2, 
Cyclosporine1,2, Daclatasvir1,2, Ledipasvir2, 
Eltrombopag1,2, 
Gefitinib2, Lapatinib1, Pantoprazole1,2 
1 Herbal product 
1 Lee et al 2015 
2 Novartis PK Sciences DDI List (January, 2018) 
 

 
 
 
 
 
102
APPENDIX VII: MEDICATION DIARY 
 
  
 

 
 
 
 
 
103
 
APPENDIX VIII: ROAD MAP 
 

 
 
 
 
 
104
 
APPENDIX IX: CLINICAL BENEFIT OF ASSESSMENT 
Clinical Benefit Assessment (CBA) 
Please assess each pertinent criterion for your patient. Each patient should 
have at least 2 pertinent criteria to be placed on study. Pertinent criteria 
should be Grade 2 or greater for each criteria category chosen. Base your 
assessment on the last 7 days of the patient’s clinical status. Your 
assessment should be based on the patients underlying vascular anomaly 
diagnosis, not side effects of the drug. Grade 5 for all criteria is death. 
 
Cardiac: 
Grade 0 
Normal 
Grade 1 
Mild asymptomatic diagnostic finding; no intervention required 
Grade 2 
Moderate asymptomatic or symptomatic diagnostic findings; outpatient 
interventions (cardiac medications) 
Grade 3 
Symptomatic, requiring intervention; hospitalization; responsive to 
therapy 
Grade 4 
Symptomatic, requiring aggressive intervention; not responsive to 
therapy  
 
Pulmonary: 
Grade 0 
Normal 
Grade 1 
Mild asymptomatic diagnostic finding; no intervention required 
Grade 2 
Moderate symptomatic diagnostic finding, outpatient interventions 
(medications, O2, CPAP etc.) 
Grade 3 
Symptomatic, requiring intervention, hospitalization; responsive to 
therapy 
Grade 4 
Symptomatic, requiring aggressive intervention; hospitalization; not 
responsive to therapy 
 
 

 
 
 
 
 
105
Skin: 
Grade 0 
Normal 
Grade 1 
Asymptomatic clinical changes of color, texture, warmth 
Grade 2 
Symptomatic skin lesions without breakdown 
Grade 3 
Skin breakdown with bleeding; pain and or infection 
Grade 4 
Life-threatening consequences; major invasive intervention indicated 
 
Proptosis/enophthalmos:  
Grade 0 
Normal 
Grade 1 
Asymptomatic, intervention not indicated  
Grade 2 
Symptomatic and interfering with function, but not interfering with ADL 
Grade 3 
Symptomatic and interfering with ADL 
Grade 4 
Loss of vision  
 
Obstruction of Visual Axis:  
Grade 0 
No obstruction of visual axis 
Grade 1 
Eyelid dysfunction a symptomatic but not interfering with ADL; no 
astigmatism 
Grade 2 
Symptomatic; interfering with ADL; causing amblyopia or astigmatism 
Grade 3 
Intervention indicated (medical and or surgical) 
Grade 4 
Loss of vision 
 
Obstruction of airway: 
Obstruction of: (select one or more) 
• Bronchus 
• Larynx 
• Pharynx 
• Trachea 

 
 
 
 
 
106
 
Grade 0 
No obstruction of airway 
Grade 1 
Asymptomatic obstruction on exam, endoscopy, or radiograph 
Grade 2 
Symptomatic (e.g., noisy airway breathing), but causing no respiratory 
distress;  
medical management and/or IR intervention indicated 
Grade 3 
Interfering with ADL; stridor or endoscopic intervention indicated (e.g., 
stent,   
laser, IR intervention, surgical removal, may need Tracheotomy) 
Grade 4 
Life-threatening airway compromise; tracheotomy or intubation 
indicated, need for ventilatory support 
 
Hemorrhage/Bleeding From VA: 
Grade 0 
No hemorrhage/bleeding from VA 
Grade 1 
Mild without transfusion, no anemia 
Grade 2  
Moderate without transfusion but anemia, or interference of ADL 
Grade 3 
Transfusion indicated, procedural intervention required and or hospitalization 
required 
Grade 4 
Catastrophic bleeding, requiring major non-elective intervention 
 
Thrombotic Event from VA: 
Grade 0  
No thrombotic event from VA 
Grade 1 
Phleboliths present on clinical or radiographic exam but asymptomatic 
Grade 2 
Phleboliths present on clinical or radiographic exam and symptomatic. 
Superficial phlebitis requiring medical management (anti-inflammatory 
agents or prophylactic anticoagulation. 
Grade 3 
Superficial phlebitis requiring medical management (treatment 
anticoagulation); Deep/Large Venous Thrombosis without Acute 
decompensation but in need of medical management 
Grade 4  
Life threatening Venous Thrombosis with Acute decompensation 
requiring intensive intervention and hospitalization 
 

 
 
 
 
 
107
Localized intravascular Coagulopathy (LIC) from VA: 
Grade 0  
No LIC 
Grade 1 
Normal Fibrinogen, normal platelet count, mildly elevated D-dimer (> 
normal less than 2x normal) 
Grade 2 
Mildly decreased fibrinogen (<150 mg/dl/ > 100 mg/dl), normal-low 
normal platelet count (> 100 10*3/ul), AND/OR moderately elevated 
D-dimer (> 2x normal, Less than 3 x normal) 
Grade 3  
Moderately decreased fibrinogen (< 100 mg/dl/>50 mg/dl), moderately 
decreased platelet count (<100 10*3/ul/>50 10*3/ul), AND/OR 
moderately elevated D-dimer (same as above   
Requiring medical intervention but no replacement except during 
procedures 
Grade 4  
Significantly decreased fibrinogen (<50 mg/dl), 
moderately/significantly decreased platelet (< 100 10*3/ul), AND/OR 
critically elevated D-dimer requiring medical (> 4 x normal).  
Requiring intervention and replacement 
 
Grading System for severity of Kaposiform Lymphangiomatosis (KLA) and 
Kasabach Merritt Syndrome (KMP) like coagulopathy: 
Grade 0 
KLA without KMP 
Grade 1 
KLA with KMP without bleeding or blood product support 
Grade 2 
KLA with KMP with no active bleeding or DIC, intermittently receiving 
blood product support secondary to low numbers or need for 
procedures 
Grade 3 
KLA with KMP with active bleeding, bruising and needing blood 
product support 
Grade 4 
KLA with KMP/DIC/bleeding requiring aggressive medical care 
(mechanical ventilation, pressor support) 
 
Grading of Hematological product support (Any Diagnosis): 
Grade 0 
No need for blood product support 
Grade 1 
One of the following hematological supports: PRBC, platelets, 
fibrinogen (cryoprecipitate) 

 
 
 
 
 
108
Grade 2 
Two of the following hematological supports: PRBC, platelets, 
fibrinogen (cryoprecipitate) 
Grade 3 
All three of the following hematological supports: PRBC, platelets, 
fibrinogen (cryoprecipitate) 
Grade 4 
All three of the following hematological supports: PRBC, platelets, 
fibrinogen (cryoprecipitate), AND at least one other means of 
hematological support (including factor support) 
 
Grading of Thrombocytopenia (no transfusion within 1 week): 
Grade 0 
Normal platelet count 
Grade 1 
plat < 100 10*3 /ul without bleeding 
Grade 2 
plat < 50 10*3/ul without bleeding 
Grade 3 
plat < 20 10*3/ul without bleeding 
Grade 4 
Any thrombocytopenia with clinically significant bleeding 
 
Grading of Fibrinogen: (no transfusion within 3 weeks): 
Grade 0 
Normal fibrinogen 
Grade 1 
Fibrinogen < 150 mg/dl without bleeding 
Grade 2 
Fibrinogen < 100 mg/dl without bleeding 
Grade 3 
Hypofibrinogenemia < 50 mg/dl without bleeding 
Grade 4 
Hypofibrinogenemia with clinically significant bleeding 
 
Neurologic/Compression by paraspinal/spinal VA: 
Grade 0  
No neurologic/compression by paraspinal/spinal VA 
Grade 1  
Asymptomatic radiologic findings only 
Grade 2  
Symptomatic, but not interfering with ADL 
Grade 3  
Symptomatic and interfering with ADL needing intervention (medical, 
surgical, IR intervention) 

 
 
 
 
 
109
Grade 4  
Life-threatening; disabling; immediate intervention indicated 
(IR/surgical)  
 
Neurologic CSF Leak (spinal or intracranial): 
Grade 0 
No CSF leak 
Grade 1 
Asymptomatic radiologic findings only 
Grade 2 
Symptomatic, but not interfering with ADL 
Grade 3 
Symptomatic and interfering with ADL needing intervention (medical, 
surgical, IR intervention 
Grade 4 
Life-threatening, disabling, immediate intervention indicated (IR 
surgical) 
 
Liver dysfunction: 
Grade 0  
Normal 
Grade 1  
Asymptomatic 
Grade 2  
Jaundice 
Grade 3  
Asterixis 
Grade 4  
Encephalopathy 
 
Abdominal compartment syndrome: 
Grade 0  
No abdominal compartment syndrome 
Grade 1  
Hepatomegaly 
Grade 2  
Mild hepatomegaly and abdominal distention 
Grade 3  
Moderate hepatomegaly and abdominal distention 
Grade 4  
Impairment of urine output or respiratory distress 
Grade 5  
Death 
 

 
 
 
 
 
110
Bone involvement of VA: 
Grade 0  
No bone involvement of VA 
Grade 1  
Asymptomatic, radiologic findings only 
Grade 2  
Symptomatic, but not interfering with ADL, medication/intervention 
may be needed 
Grade 3  
Altered ADL secondary to symptoms: pain, fracture 
Grade 4  
Complete loss of function 
 
Effusions caused by VA (pleural, cardiac, ascites): 
Grade 0 
No effusions caused by VA (pleural, cardiac, ascites) 
Grade 1 
Asymptomatic, radiologic findings only 
Grade 2 
Symptomatic, but not requiring immediate intervention 
Grade 3 
Requiring intervention, fluid removal, tube drainage, fluid replacement 
Grade 4 
Requiring ventilation or more aggressive surgical support 
 
Lymphedema caused by VA: 
Grade 0 
No lymphedema caused by VA 
Grade 1 
Intermittent swelling, when swelling skin will “pit”, Relief and reduction 
with elevation 
Grade 2 
Tissue is firmer, less pitting, no relief with elevation 
Grade 3 
Hard (fibrotic) skin, thickening of surface, Increase in circumference 
Grade 4 
 All of the above with skin breakdown with or without infection 
 
AVM Skin Involvement: 
Grade 0 
No skin discoloration or stain 
Grade 1 
Skin discoloration or stain, warmth, shunting on Doppler 
Grade 2 
Enlargement, pulsation-thrill, bruit with or without minor ulceration or 
pain 

 
 
 
 
 
111
Grade 3 
Moderate ulceration, bleeding, or pain 
Grade 4 
Severe ulceration, bleeding, pain, or other significant morbidity  
 
 
Physical Disability: 
Grade 0    
No disability 
Grade 1  
Mildly impaired, Performs ADLs 
Grade 2  
Moderately impaired, Needs help with some ADLs 
Grade 3  
Severely impaired, needs help with all ADLs 
Grade 4  
Unable to perform any intentional physical activity 
 
Protein Losing Enteropathy (PLE) 
Grade 0    
No PLE 
Grade 1  
Mildly abnormalities in lab work (Albumin, TP, Alpha -1 anti-trypsin 
etc.) 
Grade 2  
Moderate abnormalities in lab work, no replacement needed, may 
need low-fat diet 
Grade 3  
Significant impairment in lab work, need for replacement, strict low-fat 
diet, MRL intervention 
Grade 4  
Hospitalization, Requiring replacement and intervention (MRL with 
treatment, surgical procedures) 
 
Hypoglycemia 
Grade 0    
No hypoglycemia 
Grade 1  
Mildly impaired, Episodes but limited intervention 
Grade 2  
Moderately impaired, Need for frequent interventions 
Grade 3  
Severely impaired, need for frequent glucose monitoring and IV 
replacement 
Grade 4  
Hypoglycemic events requiring hospitalization 
 

 
 
 
 
 
112
Seizures 
Grade 0    
No need for antiepileptic medication  
Grade 1 
Seizures controlled on medication 
Grade 2  
Seizures partially controlled on medication 
Grade 3  
Seizures poorly controlled needing medication adjustment  
Grade 4  
Seizures uncontrolled or inadequately controlled on medication 
requiring hospitalization 
 
ADL = Activities of Daily Life 
KMP = Kasabach-Merritt Phenomenon 
VA = Vascular Anomalies (vascular tumors and vascular malformations) 
VM = Vascular Malformations 
KLA = Kaposiform lymphangiomatosis 
 
Open Endend Questions 
1. How has your vascular anomaly gotten better since starting on medication? It is 
okay to write “none” if nothing has gotten better. 
a. How has the rest of your health gotten better since starting on medication in 
this study? It is okay to write “none” if nothing has gotten better. 
2. How has your vascular anomaly gotten worse since starting on medication? It is 
okay to write “none” if nothing has gotten worse. 
a. How has the rest of your health gotten worse since starting on medication in 
this study? It is okay to write “none” if nothing has gotten better. 
3. What else would you like us to know about your experience taking this medication