Conditions: Kaposiform Hemangioendothelioma (KHE) Kasabach-Merritt Syndrome Tufted Angioma
Keywords: KHE Vascular anomaly Kasabach-Merritt Syndrome Tufted angioma hemangioendothelioma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

Brief summary:
In this research study we want to learn more about which treatment works better for patients diagnosed with a vascular tumor called Kaposiform Hemangioendothelioma (KHE) or other high risk vascular tumors such as Tufted Angioma (TA). In these tumors, the blood cells that help your blood clot called platelets become trapped in the tumor causing swelling, pain, and bruising. Vascular tumors can be life threatening. There are few medical treatments that will work to shrink the vascular tumor. Some doctors will use steroids and vincristine to try and shrink vascular tumors.

In this research study, the study doctor will compare two different drugs to see which one will work better to help shrink your vascular tumor. One of the drugs is vincristine. Vincristine is approved by the Food and Drug Administration (FDA) to treat people with cancer. Vincristine is used to stop the abnormal cells from growing such as cells that make up blood vessels.

The other drug to be used in this study is sirolimus. Sirolimus is currently approved by the Food and Drug Administration (FDA) to prevent transplanted organ rejection. Sirolimus is not approved by the FDA for treatment of vascular abnormalities and is considered experimental. Sirolimus belongs to a class of drugs call 'mTOR inhibitors'. mTOR (mammilian target of rapamycin) helps cells to grow and may also help blood vessels to grow in a more normal fashion. Sirolimus is currently being tested in patients with vascular tumors and cancer. In vascular tumors, we hope sirolimus will stop the blood vessel growth.

Funding Source: FDA - OOPD (Office of Orphan Products Development)

Detailed description:
Kaposiform hemangioendotheliomas (KHE) are extremely rare life threatening tumors which can be associated with Kasabach-Merritt Phenomenon consisting of profound thrombocytopenia and hypofibrinogenemia causing a significant risk of bleeding and an associated mortality rate as high as 20% to 30%. Despite the severity of potential complications, we lack uniform guidelines for the treatment and response to treatment of children and young adults with these tumors. KHE patients have been treated with a multitude of aggressive drug regimens without prospective evaluation of response or safety. Presently, vincristine is considered the standard of practice. We have treated a subset of these patients on study SIR-DA-0901 (FDA Grant# 5RO1FD003712-01). This study is a phase II trial assessing the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies. Although the numbers are small, the response has been extremely promising with excellent tolerability. There is pre-clinical and clinical data supporting the essential regulatory function of the PI3 kinase/AKT/mTOR pathway in vascular growth and organization which suggests a therapeutic target for patients with complicated vascular anomalies. The overall goal of this trial is to objectively assess the efficacy of sirolimus compared to vincristine for the treatment of patients with high risk KHE.

Hypothesis: Sirolimus treatment for children and young adults with Kaposiform hemangioendotheliomas will be more effective than vincristine, assessed by time to response in an induction period and provide equivalent safety parameters.

Study Rationale We propose a multi-center, phase II trial with participation from 8 sites. The study will consist of two phases. The first of these is an initial induction phase in which vincristine and steroids will be compared to sirolimus and steroids. Response in the induction phase will be assessed as time to hematologic response. At the end of induction phase, cross over can occur if there is failure to respond. Part 2 is a maintenance phase which will be 1 year in length. Continued safety and efficacy data will be collected during maintenance and there will be cross over at any time for patients who lose their response following induction. Failure will be defined as worsening of hematological parameters on two separate laboratory evaluations at any time during maintenance or if they meet the definition of progressive disease following response assessments. Formal response in maintenance will be evaluated by imaging studies, functional assessment, and quality of life as per study SIR-DA-0901. Present therapies are very limited and new therapies are desperately needed for this devastating disease. Based on our preliminary data, there is a very good rationale for sirolimus therapy in KHE patients and so a phase II trial is urgently needed to determine if this therapy is to become the new standard of care for KHE patients.

Our secondary aims will be addressing biomarker analysis. There are limited studies describing the biology of these tumors. Per study SIR-DA-0901 there is some preliminary data indicating the importance of VEGF-C and other upregulated markers in the mTor pathway. This needs to be further investigated especially in KHE patients. Furthermore there are no clear objective measurements to determine response data.

Arms:
arm 1: Induction phase: participants assigned to vincristine will receive vincristine weekly at a dose of 0.05mg/kg/dose IV (for participants less than 10kg) or a dose of 1.5 mg/m2/dose (for participants greater than 10kg) for 2 months.

Maintenance: if participants continue to receive vincristine weekly for 2 months, every 2 weeks for 5 months and every 3 weeks for 5 months. arm 2: Sirolimus will be administered at a dose of 0.8mg/m2/dose twice a day on a continuous dosing schedule throughout the trial for participants randomized to Sirolimus or for participants who fail vincristine may cross-over to the sirolimus arm.

Sirolimus trough levels will be maintained between 10-15 ng/ml.

Interventions: intervention 1: Vincristine intervention 2: Sirolimus
Intervention descriptions: intervention 1: Vincristine dose dependent upon weight. Weekly for 2 months (Induction); Weekly 2 months; every 2 weeks for next 5 months; every 3 weeks for 5 months (Maintenance) intervention 2: Continuous dosing to maintain trough level of 10-15ng/ml.

Protocol document:
Prot_SAP_000.pdf: 
This Protocol is for Research Purposes Only 
 
Protocol SIR-DA-1202 
Version  01/31/2018 
  
 
 
 
A Randomized Phase 2 Study of Vincristine versus Sirolimus to treat 
High Risk Kaposiform Hemangioendothelioma (KHE). 
 
 
 
 
 
 
Study Chair/Sponsor 
 
Denise M. Adams, M.D. 
300 Longwood Ave 
Fegan 3 (VAC)  
Boston, MA 02115 
Phone: 617-355-5226 
Pager: 5021 
Fax: 617-730-0752 
Email: denise.adams@childrens.harvard.edu 
 
 
 
Coordinating Center:  
Boston Children’s Hospital 
300 Longwood Avenue 
Boston, MA 02115 
 
Contact information:  
Yvonne Sheldon BSN, RN 
Project Management CTSU 
Phone: 617-919-6299 
Email: Yvonne.sheldon@childrens.harvard.edu
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Protocol SIR-DA-1202 
Version  01/31/2018 
 
 
 
 
AGENT 
Rapamune® (sirolimus) 
 
Provided by: 
 
Pfizer 
235 East 42nd Street 
New York, NY  10017 
 
IND#105046 
 
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Protocol SIR-DA-1202 
Version  01/31/2018 
TABLE OF CONTENTS 
 
PAGE 
1 
ABSTRACT .............................................................................................................. 6 
2 
OBJECTIVES (SCIENTIFIC AIMS) ......................................................................... 6 
 HYPOTHESIS: ............................................................................................................ 6 
2.1
 PRIMARY AIMS: ......................................................................................................... 6 
2.2
 SECONDARY AIMS: .................................................................................................... 7 
2.3
3 
BACKGROUND AND RATIONALE ........................................................................ 7 
 BACKGROUND AND SIGNIFICANCE: ............................................................................. 7 
3.1
 PI3 KINASE/AKT/MTOR SIGNALING PATHWAY AND VASCULAR MALFORMATIONS ...... 11 
3.2
 SIROLIMUS AND INHIBITION OF GROWTH .................................................................... 12 
3.3
 STUDY RATIONALE .................................................................................................. 12 
3.4
4 
RECRUITMENT, PAYMENT, CONSENT, STUDY ENROLLMENT PROCEDURES13 
 RECRUITMENT ......................................................................................................... 13 
4.1
 OBTAINING CONSENT .............................................................................................. 13 
4.2
 PROTECTING PEDIATRIC PARTICIPANTS .................................................................... 13 
4.3
 ENROLLMENT .......................................................................................................... 14 
4.4
5 
PATIENT ELIGIBILITY ........................................................................................ 14 
 INCLUSION CRITERIA ................................................................................................ 14 
5.1
 EXCLUSION CRITERIA .............................................................................................. 16 
5.2
6 
TREATMENT PROGRAM ..................................................................................... 17 
 STUDY SCHEMA ...................................................................................................... 17 
6.1
 RESEARCH DESIGN AND METHODS ........................................................................... 17 
6.2
 RANDOMIZATION ..................................................................................................... 18 
6.3
 INDUCTION .......................................................................................................... 18 
6.4
STEROID TAPER – ........................................................................................................... 18 
 ARM 1:  VINCRISTINE + STEROIDS (INDUCTION) ......................................................... 19 
6.5
 ARM 2:  SIROLIMUS + STEROIDS (INDUCTION) ............................................................ 19 
6.6
 HEMATOLOGIC RESPONSE ASSESSMENT –INDUCTION (ALL PARTICIPANTS) ................. 20 
6.7
 TREATMENT CHANGE (INDUCTION)............................................................................ 21 
6.8
 MAINTENANCE (12 COURSES) .............................................................................. 21 
6.9
 ARM 2:  SIROLIMUS ................................................................................................. 23 
6.10
 RESPONSE ASSESSMENT – MAINTENANCE (ALL PARTICIPANTS) ................................. 25 
6.11
 TREATMENT CHANGE (DURING MAINTENANCE) ......................................................... 25 
6.12
 DURATION OF THERAPY ........................................................................................... 25 
6.13
 DURATION OF FOLLOW-UP ....................................................................................... 26 
6.14
 OFF STUDY CRITERIA .............................................................................................. 26 
6.15
7 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE 
GUIDELINES ................................................................................................................ 27 
 SUPPORTIVE CARE - BOTH ARMS ............................................................................. 27 
7.1
 OTHER THERAPY FOR VASCULAR ANOMALY ............................................................... 27 
7.2
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 CONCOMITANT MEDICATIONS ................................................................................... 27 
7.3
8 
DOSE MODIFICATIONS/DOSE DELAYS ............................................................. 28 
 SIROLIMUS ARM ...................................................................................................... 28 
8.1
 VINCRISTINE ARM............................................................................................... 32 
8.2
9 
REQUIRED OBSERVATIONS ............................................................................... 33 
 ARM 1.  VINCRISTINE ............................................................................................... 33 
9.1
 ARM 2.  SIROLIMUS .................................................................................................. 34 
9.2
 PRE-STUDY ASSESSMENTS ...................................................................................... 36 
9.3
 TREATMENT ASSESSMENTS ..................................................................................... 36 
9.4
 OFF TREATMENT (COMPLETION OF STUDY DRUG ASSESSMENTS) ................................. 37 
9.5
 FOLLOW UP ASSESSMENTS ...................................................................................... 37 
9.6
 CORRELATIVE STUDIES (BIOMARKERS) - OPTIONAL SERUM AND TISSUE (ARCHIVAL) 
9.7
COLLECTION .................................................................................................................... 37 
10 
DRUG INFORMATION ...................................................................................... 39 
 SIROLIMUS (SEE CURRENT SIROLIMUS INVESTIGATIONAL BROUCHURE FOR FURTHER 
10.1
INFORMATION). ................................................................................................................ 39 
 VINCRISTINE (SEE PACKAGE INSERT FOR PRODUCT INFORMATION) ............................. 43 
10.2
 STEROIDS (PREDNISOLONE OR EQUIVALENT) – SEE PACKAGE INSERT FOR FURTHER 
10.3
INFORMATION .................................................................................................................. 44 
11 
RESPONSE ASSESSMENTS ............................................................................ 44 
 EVALUATION OF DISEASE RESPONSE:....................................................................... 44 
11.1
 DISEASE RESPONSE ................................................................................................ 47 
11.2
12 
ADVERSE EVENT REPORTING REQUIREMENTS ......................................... 48 
 DEFINITIONS ............................................................................................................ 48 
12.1
 DOCUMENTATION AND REPORTING OF NON-SERIOUS AES OR SARS ........................... 49 
12.2
 DOCUMENTATION OF SAES OR SERIOUS SARS ........................................................ 50 
12.3
 PARTICIPATING SITE RESPONSIBILITIES: ................................................................... 50 
12.4
 SPONSOR RESPONSIBILITIES TO BE PERFORMED BY THE COORDINATING CENTER (BCH):51 
12.5
 REPORTING OF PROTOCOL VIOLATIONS/DEVIATIONS AND UNANTICIPATED PROBLEMS . 52 
12.6
13 
STATISTICAL ANALYSIS PLAN ....................................................................... 52 
 SAMPLE SIZE AND POWER CALCULATION: .................................................................. 52 
13.1
 STATISTICAL ANALYSIS ............................................................................................ 55 
13.2
 ACCRUAL ................................................................................................................ 56 
13.3
 EVALUABLE FOR ADVERSE EFFECTS ........................................................................ 56 
13.4
 EVALUABLE FOR RESPONSE .................................................................................... 56 
13.5
14 
HUMAN SUBJECTS PROTECTION & DATA SAFETY MONITORING PLAN. 57 
 SOURCES OF MATERIAL ........................................................................................... 57 
14.1
 POTENTIAL RISKS .................................................................................................... 57 
14.2
 RECRUITMENT AND INFORMED CONSENT ................................................................... 57 
14.3
 IRB APPROVAL AND REQUIRED DOCUMENTATION ..................................................... 57 
14.4
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 PROTECTION AGAINST RISKS .................................................................................... 57 
14.5
 POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECT AND OTHERS ... 58 
14.6
 IMPORTANCE OF KNOWLEDGE TO BE GAINED ............................................................ 58 
14.7
 DATA AND SAFETY MONITORING PLAN ...................................................................... 58 
14.8
 STUDY MONITORING AND AUDITING .......................................................................... 58 
14.9
 
PRIVACY ............................................................................................................ 59 
14.10
 
CONFIDENTIALITY ............................................................................................... 59 
14.11
15 
REFERENCES .................................................................................................... 60 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES ...................................... 63 
APPENDIX II: LIST OF MEDICATIONS TO AVOID/ USE CAUTION WHEN TAKING 
SIROLIMUS (RAPAMUNE)- THIS TABLE IS NOT ALL INCLUSIVE .......................... 64 
APPENDIX III: STANDARD VASCULAR MRI PROTOCOL ........................................ 65 
APPENDIX IV: PARAMETERS FOR GRADING FUNCTIONAL IMPAIRMENTS ........ 66 
APPENDIX V: QOL INSTRUMENTS ............................................................................ 70 
APPENDIX VI  INVESTIGATOR’S SIGNATURE ....................................................... 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 
ABSTRACT 
 
Kaposiform hemangioendotheliomas (KHE) are extremely rare life threatening tumors that can be 
associated with Kasabach-Merritt Phenomenon consisting of profound thrombocytopenia and 
hypofibrinogenemia causing a significant risk of bleeding and an associated mortality rate as high as 
20% to 30%. Despite the severity of potential complications, uniform guidelines are lacking both for 
the treatment and response to treatment of children and young adults with these tumors. KHE 
patients have been treated with a multitude of aggressive drug regimens without prospective 
evaluation of response or safety. Presently, vincristine is considered the standard of practice 
although there is not a lot of data to support this. We have treated a subset of these patients on study 
SIR-DA-0901 (FDA Grant# 5RO1FD003712-01). This study is a phase II trial assessing the efficacy 
and safety of sirolimus for the treatment of complicated vascular anomalies. Although the numbers 
are small, the response has been extremely promising with excellent tolerability. There is pre-clinical 
and clinical data supporting the essential regulatory function of the PI3 kinase/AKT/mTOR pathway 
in vascular growth and organization that suggests a therapeutic target for patients with complicated 
vascular anomalies.  The overall goal of this trial is to objectively assess the efficacy of sirolimus 
compared to vincristine for the treatment of patients with high risk KHE. 
 
2 
OBJECTIVES (SCIENTIFIC AIMS) 
 
2.1 
Hypothesis: 
Sirolimus treatment for children and young adults with Kaposiform hemangioendotheliomas will be 
more effective than vincristine, assessed by time to hematologic response in an induction period and 
provide equivalent safety parameters.  
 
2.2 
Primary Aims:  
2.2.1 To determine the efficacy of oral sirolimus as compared to intravenous (IV) vincristine for an 
induction period of 2 courses in patients with high risk KHE. For this purpose, 50 patients 
with high risk KHE will be randomized to either receive oral sirolimus or IV vincristine for 2 
courses.  Both treatment groups will also be placed on a defined weaning dose of steroids 
over the induction period (initial 2 courses). Time to hematologic response will then be 
assessed at the end of 2 courses.  Hematologic response will be defined as platelet count of > 
100,000/μl x 2 consecutive lab measurements or an increase of 2 times the baseline for 2 
consecutive lab measurements, whichever is greater, and a fibrinogen of > 150 mg/dl. 
(Baseline is initial laboratory evaluation without transfusions). 
 
 
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2.2.2 To determine the safety of oral sirolimus and IV vincristine in patients with high risk KHE.  
Toxicities will be assessed and recorded at specific intervals throughout therapy. Common 
Terminology Criteria for Adverse Events (CTCAE, version 4.0.3) will be used to categorize 
and grade all toxicities. Safety monitoring and stopping rules will be instituted to ensure that 
serious treatment-related toxicities are reported and study continuation re-evaluated.  
 
2.3 
Secondary Aims:  
2.3.1 To determine the efficacy of these agents in the maintenance phase in patients with high risk 
KHE. Maintenance phase will last for 1 year and treatment change may occur for any patient 
that loses their response. (See research plan for details). Formal disease response will be 
assessed at end of maintenance courses 6 and 12 using radiographic, clinical and quality of 
life measures. 
2.3.2 To determine the safety of these agents in the maintenance phase in patients with high risk 
KHE. Toxicities will be assessed and recorded at specific intervals throughout therapy. 
Common Terminology Criteria for Adverse Events (CTCAE, version 4.0.3) will be used to 
categorize and grade all toxicities with same monitoring. 
2.3.3 To assess biomarker/genomic analysis on serum and tissue in children and adults with high 
risk KHE. Biomarkers in serum will be tested at baseline, end of induction, end of 
maintenance courses 6 and 12. Tissue availability will be more limited and will only be 
available at one time point. 
 
3 
BACKGROUND AND RATIONALE 
 
3.1 
Background and Significance: 
Patients with Vascular Anomalies (VA) have a spectrum of diseases that can be broadly classified 
into vascular tumors and malformations (1, 2, 49) (Figure 1).  Vascular tumors grow and spread 
through a proliferative process while vascular malformations enlarge through expansion of a 
developmental anomaly, with little cellular proliferative activity. Growth and/or expansion of VA 
cause clinical problems such as disfigurement, chronic pain, coagulopathies and bleeding, organ 
dysfunction and occasionally death. Individuals with VA often experience progressive clinical 
symptoms with worsening quality of life. Although limited treatment options are available, their 
efficacy has not been validated in prospective clinical trials and is usually based on case reports. 
Thus there are no validated standards of care for these patients (3). 
 
Figure 1: Classification of Vascular Anomalies 
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Kaposiform hemangioendotheliomas (KHE) and tufted angiomas (TA) are rare tumors of vascular 
origin. There are no national registries documenting numbers of KHE patients but from extrapolating 
data at the 2 largest vascular anomaly centers in the U.S., the prevalence appears to be 0.91/100,000 
children with an estimated total number of diagnosed cases in the US of 760 in 2011. These tumors 
pose difficult dilemmas for the practitioner particularly in regards to there being limited treatment 
options and a lack of validated biological markers. For example, KHE and TA can cause a 
coagulopathy known as Kasabach-Merritt Phenomenon (KMP) which has a mortality rate of 20 – 
30% (4-7). A number of therapies have been reported via case reports but none have been uniformly 
effective. Steroids are often used as a first line therapy with varying results. (8, 9) Interferon has 
been used but has significant neurological side effects (10-12). Antifibrinolytic agents (e-
aminocaproic acid or tranexamic acid) have been used with mixed responses, as have antiplatelet 
agents such as aspirin, or dipyridamole (13).  Chemotherapy with agents such as cyclophosphamide, 
vincristine, and actinomycin has been used with variable responses as well (14-15).  Other medical 
options that have been used include radiation therapy, compression therapy, and embolization 
therapy. We initially reported a case of refractory KHE with KMP whose hematologic parameters 
responded to sirolimus (16). Since that time, other cases have been reported that have improved 
outcome, at least in the short term (17). 
 
We initially reported the use of sirolimus in the treatment of a 9 month old with refractory KHE with 
KMP on palliative treatment that had a hematologic recovery in 3 weeks to sirolimus and significant 
improvement in her clinical symptoms and quality of life (17). She began treatment in July 2007and 
has not suffered any long term effects. Since that time, other cases have been reported with excellent 
short term efficacy (18). Presently, 13 KHE patients are enrolled on SIR-DA-0901 (FDA Grant# 
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5RO1FD003712-04) (Figure 2 and Table 1). Twelve patients completed drug therapy and are in 
follow up. All twelve patients had a partial response to treatment (improvement of quality of life, 
organ function and radiologic imaging). Of the twelve patients who completed treatment, 8 were 
females and 5 were males. The average age at the start of treatment was 11 months with a range of 3 
weeks to 3 years. Eleven patients presented at the time of diagnosis with KMP. Of the eleven, 3 had 
resolution of KMP prior to starting study but all were on steroid therapy and unable to wean 
treatment because of reoccurrence of KMP. When sirolimus was started all of these patients were 
weaned off steroids without reoccurrence of KMP. Of the 8 patients with KMP at study initiation, all 
had resolution of KMP with an average time to hematologic recovery of 3 weeks. One patient with 
multifocal KHE of the bone without KMP was taken off of study secondary to disease progression. 
This patient had been given a “wash-out period” (removal from previous therapy for 2 weeks prior to 
starting protocol). She was in severe pain from the beginning of the study, and also had multifocal 
bone disease which is extremely rare and perhaps has a different clinical spectrum than unifocal 
KHE. The “wash out” requirement was subsequently removed from the study. There were limited 
Grade III or IV toxicities in this group of patients, none of which required dose reduction or 
withdrawal from study. There have been no drug related infections and no obvious long term effects. 
Although we are presently evaluating this data, our preliminary conclusion is that sirolimus appears 
to be an effective and well-tolerated agent for high-risk KHE patients who otherwise have very 
limited options for treatment.  
 
Figure 2.  One patient’s results with sirolimus. 
 
 
  
   
 
 
a.   Enrollment          b. 6 months on study    c. 12 months on study 
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Table 1. Summary of KHE patients on SIR-DA-0901 
Age at 
initiation 
of 
Sirolimus
Diagnosis
Location of 
Vascular 
Anomaly
Previous 
Treatment
Response 
time to 
KMP 
Resolution
Side Effects 
Grade III/IV 
Attributed to 
Sirolimus
Completed 
Study
Response
1
3 years
KHE with KMP 
initially 
Recovered at 
Start of Study
Retroperitoneal
Steroids, 
Vincristine, 
Actinomycin, 
Cytoxan
N/A
None
Yes
Yes
2
22 
months
KHE with KMP 
initially 
Recovered at 
Start of Study
Multifocal Bone
Steroids, 
Interferon, 
Vincristine
N/A
N/A
Withdrew Progressive 
Disease
3
9 weeks KHE with KMP
Left Leg and 
Inguinal Area
Steroids
2 weeks
None
Yes
Yes
4
18 
months
KHE with KMP
Chest, Pleura, 
Left arm
Steroids, 
Vincristine, 
Actinomycin, 
Cytoxan
2 weeks
None
Yes
Yes
5 2 months KHE with KMP
Left leg
Steroids
3 weeks
None
Yes
Yes
6
5 weeks KHE with KMP
Right Inguinal 
area, Buttocks, 
Back
Steroids
4 weeks
None
Yes
Yes
7
2 years
KHE
Right Mandible
Steroids
N/A
Grade III 
ANC
Yes
Yes
8
2 years
KHE with KMP
Left Forearm 
and Chest
Steroids, 
vincristine
3 weeks
Grade III 
ANC
Yes
Yes
9
4 weeks KHE with KMP Right Chest and 
Axilla
Steroids
1 week
None
Yes
Yes
10 5 months KHE with KMP
Right Chest, 
Neck and Axilla
Steroids
3 weeks
None
Yes
Yes
11
13 
months
KHE with KMP 
initially 
Recovered at 
Start of Study
Retroperitoneal
Steroids, 
Vincristine 
N/A
Grade III/IV 
Neutrophils
Yes
Yes
12 3 months
KHE with KMP 
initially 
Recovered at 
Start of Study
Left Forearm
Steroids
N/A
Grade III 
Triglycerides
Yes
Yes
13 8 months KHE with KMP
Left Leg 
None
4 weeks
None
Yes
Yes
 
 
 
Sirolimus treatment has already made a tremendous difference in the morbidity and mortality/quality 
of life of these patients. However, because the numbers are small, the use of sirolimus needs to be 
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tested in a larger number of patients and compared to what is currently considered to be the standard 
of practice (vincristine). If our hypothesis is correct this drug will be proven to be more effective 
than vincristine and we will be one step closer to official FDA approval of sirolimus as a first line 
agent for the treatment of high-risk KHE.    
 
3.2 
PI3 Kinase/AKT/mTOR Signaling Pathway and Vascular Malformations 
The PI3 kinase/AKT signaling pathway is critical to cell growth and survival and has been shown to 
govern normal vascular development, angiogenesis and even T cell differentiation (19). The 
mammalian target of Rapamycin (mTOR) integrates signals from the PI3 kinase/AKT pathway to 
coordinate cell growth and proliferation by regulating ribosomal biogenesis and protein synthesis 
(20) (Figure 4).   
 Figure 3: The mTOR pathway 
 
 
Activation of AKT results in the phosphorylation of TSC proteins leading to mTOR activation with 
resultant cellular growth and proliferation. In addition, enhanced mTOR signaling has been shown to 
increase expression of the vascular endothelial growth factor (VEGF), a key regulator of 
angiogenesis and lymphangiogenesis (21-24).  Disorders that lead to the inappropriate activation of 
the PI3 kinase/AKT/mTOR pathway would be predicted to result in tissue overgrowth with vascular 
anomalies. Indeed, there is preclinical and clinical data suggesting a critical role for this signaling 
pathway in vasculogenesis with disruptions that lead to hyperactivation of the pathway resulting in 
vascular pathology (25).  
 
The over-expression of Akt/PKB (a key mediator of resistance to apoptosis in the PI3K pathway) in 
mice is known to cause cutaneous vascular malformations in vivo (26).  Tie 2 receptor activating 
mutations have been associated with development of venous malformations through ligand-
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independent AKT activation leading to endothelial survival (27).  Several clinical studies have 
identified single gene mutations within the PI3 kinase/AKT pathway that are associated with 
vascular malformations and abnormalities of growth (28, 29).  Tuberous sclerosis (TS) and 
lymphangioleiomyomatosis (LAM) are caused by inactivating mutations in the tuberous sclerosis 
complex tumor suppressor proteins TSC1 and TSC2 leading to increased activation of mTOR and 
unrestrained growth/lesions like hamartomas and various skin abnormalities (30).  Loss of function 
mutations in the PTEN tumor suppressor gene, which inhibits the activation of Akt/PKB, are found 
in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, two disorders characterized by 
macrocephaly, vascular anomalies, excessive growth and hamartoma formation (31,32).  These 
studies provide compelling evidence for a critical role for the PI3 kinase/AKT/mTOR pathway in the 
regulation of vascular growth and organization and suggest a therapeutic target for patients with 
these disorders. 
 
3.3 
Sirolimus and Inhibition of Growth 
Sirolimus (Rapamycin) is a specific and potent inhibitor of mTOR. Inhibition is mediated through 
binding to the cellular protein receptor FKBP512. The exact mechanism of mTOR inhibition by the 
sirolimus-FKBP512 complex is not known, although it likely involves disruption of an effective 
signaling complex. Sirolimus has been used extensively as an immunomodulatory agent and in the 
treatment of patients with cancer. Single agent mTOR inhibition using a variety of mTOR inhibitors 
has resulted in objective radiographic responses in patients with low-grade astrocytomas (36), 
glioblastoma multiforme (37), renal cell carcinoma (33), mantle cell lymphoma (34), breast cancer 
(35), and sarcomas (36).  Sirolimus has been shown to be effective and safe in both adult and 
pediatric populations. More recently, mTOR inhibition by sirolimus has been shown to be an 
effective strategy in the treatment of patients with hamartoma syndromes. Patients with TS 
(Tuberous Sclerosis) and LAM (lymphangioleiomyomatosis) showed a nearly 50% reduction in the 
size of angiomyolipomas and LAM lesions with sirolimus treatment. Upon withdrawal of the drug, 
however, there was some regrowth of the lesions but they did not to return to their pretreatment 
baseline (37).  A recent case report of a patient with Proteus syndrome treated with sirolimus was 
also positive including some reversal of the manifestations of his tumors and malformations (38). 
 
3.4 
Study Rationale 
We propose a multi-center, phase II trial with participation from up to 12 sites.  The study will 
consist of two phases.  The first of these is an initial induction phase in which vincristine and 
steroids will be compared to sirolimus and steroids.  Response in the induction phase will be 
assessed as time to hematologic response.  At the end of induction phase, change of treatment can 
occur if there is failure to respond.  Part 2 is a maintenance phase which will be 1 year in length. 
Continued safety and efficacy data will be collected during maintenance and there may be a 
treatment change at any time for patients who lose their response following induction.  Failure will 
be defined as worsening of hematological parameters on two separate laboratory evaluations at the 
end of induction or at any time during maintenance, or if they meet the definition of progressive 
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disease following response assessments (or at the discretion of the PI).  Formal response in 
maintenance will be evaluated by imaging studies, functional assessment, and quality of life as per 
study SIR-DA-0901.  Present therapies are very limited and new therapies are desperately needed for 
this devastating disease.  Based on our preliminary data, there is a very good rationale for sirolimus 
therapy in KHE patients and so a phase II trial is urgently needed to determine if this therapy is to 
become the new standard of care for KHE patients. 
 
Our secondary aims will be addressing biomarker analysis.   There are limited studies describing the 
biology of these tumors.   Per study SIR-DA-0901 there is some preliminary data indicating the 
importance of VEGF-C and other upregulated markers in the mTOR pathway.  This needs to be 
further investigated, especially in KHE patients.  Furthermore there are no clear objective 
measurements to determine response data.   
 
4 
RECRUITMENT, PAYMENT, CONSENT, STUDY ENROLLMENT PROCEDURES 
 
4.1 
Recruitment  
Patients will be recruited from the various clinics of the investigative sites. Outside referrals will be 
accepted. The study is open to all eligible patients (0-31 years of age) regardless of gender or 
ethnicity. 
 
Upon coordinating center and institutional IRB approval or waiver, participating sites may post a 
summary of the study to their institutional web site including basic information such as study title, 
purpose of the study, protocol summary, basic eligibility criteria, study site location(s), and how to 
contact the study site for further information.  This trial will also be posted on clinicaltrials.gov. 
 
4.2 
Obtaining Consent 
Consent will be obtained by the PI or a sub-investigator on the trial.  Informed consent may be 
obtained in person or may be obtained via telephone per institutional policies.  Where deemed 
appropriate by the clinician and the child’s parents or guardian, the child will also be included in all 
discussions about the trial. The informed consent process includes consultation with the parents or 
legal guardian (for subjects less than 18 years old) and the subject to discuss the investigational 
nature and objectives of the trial, the procedures and treatments involved and their attendant risks 
and discomforts, and potential alternative therapies. The consent document will be provided in 
English. Non-English speaking participants will be consented using the institutional IRB approved 
process. 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements. 
 
4.3 
Protecting Pediatric Participants 
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To safeguard the participation of children in this study, Investigators will: 
• Obtain written parent/legal guardian permission 
• Obtain assent of children, as per institutional requirements 
• Whenever possible and appropriate, purposefully solicit that the child and 
parent/legal guardian are still willing to participate (e.g., when new information 
regarding the risks/benefits is available) 
 
4.4 
Enrollment 
Enrollment must take place within 30 days after obtaining written informed consent. If more than 30 
days elapse, re-consent in writing must be obtained prior to enrollment. 
 
 
After obtaining all required approvals and meeting the requirements outlined in the study’s Manual 
of Operations, participating sites may enroll eligible subjects on this clinical trial. Procedures for 
subject enrollment outlined in the Manual of Operations must be followed. 
 
Patients must be enrolled before treatment begins.  All eligibility requirements will be reviewed with 
the Study PI or designee prior to enrollment. 
 
Treatment must start within 7 calendar days after study enrollment. If more than 7 days elapse, the 
patient must be re-screened in order to enroll. 
 
 
5 
PATIENT ELIGIBILITY  
 
5.1 
Inclusion Criteria 
5.1.1 Diagnosis: All patients must have one of the following vascular anomalies as determined by 
clinical, radiologic and histologic criteria (when possible).  Biopsy strongly recommended 
(but not required) with suggested immunostains:  CD34, PROX-1 or D240, Glut-1 and MIB-
1. 
• Kaposiform Hemangioendotheliomas  
• Tufted Angioma  
 
High Risk Stratification:  In addition to the above diagnosis, all of the following criteria need 
to be met: 
• Kasabach Merritt Phenomenon defined at a platelet counts less than 100,000/µl 
and/or fibrinogen level < 150 mg/dl at the time of diagnosis 
5.1.2 Age: Patients must be 0 - 31 years of age at the time of study entry. Enrollment includes 
patients of both genders and all ethnic groups. 
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5.1.3 Organ function requirements:  
 
 
Adequate liver function defined as: 
• Total bilirubin ≤1.5 x ULN for age, and 
• SGPT (ALT) <5 x ULN for age, and 
• Serum albumin ≥2 g/dL. 
• Fasting LDL cholesterol of <160 mg/dL   
• Fasting triglyceride <400 mg/dl 
 
 
Adequate Bone Marrow Function defined as: 
• Peripheral absolute neutrophil count (ANC) ≥1000/µL 
• Hemoglobin ≥8.0 g/dL (may receive RBC transfusions) 
• No Platelet requirement 
     
 
      
 
Adequate Renal Function Defined as: 
   
• 
A serum creatinine based on age as follows: 
 
Age (Years) 
Maximum Serum 
Creatinine (mg/dL) 
≤5 
6  to ≤10 
11 to  ≤15 
>15 
0.8 
1.0 
1.2 
1.5 
 
 
 
• 
Urine protein to creatinine ratio (UPC) < 0.3 g/l 
 
5.1.4 Performance Status:  Karnofsky ≥ 50 (≥16 years of age) and Lansky ≥ 50 for patients <16 
years of age (Appendix I).   
5.1.5 Prior therapy  
a. Patients who have undergone surgical resection or interventional radiology 
procedures for disease control are eligible if they meet all inclusion criteria after 
surgery/procedure  
b. Surgery:  At least 2 weeks since undergoing any major surgery 
c. Radiation:  > 6 months from involved field radiation 
d. Prior steroid and vincristine therapy is permitted.  Patients may have received up to 2 
doses of vincristine prior to randomization.  
 
 
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5.2 
Exclusion Criteria 
5.2.1 Concurrent severe and/or uncontrolled medical disease that could compromise participation 
in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe 
malnutrition, chronic liver or renal disease, active upper GI tract ulceration). 
5.2.2 Patients who require medications that are strong inhibitors/inducers CYP3A4 enzyme 
activity, including anticonvulsants, (Appendix II) to control concurrent medical conditions 
are not eligible.   Patients who discontinue use of prohibited medications with a one week 
washout prior to start of study treatment are eligible.   
5.2.3 Known history of HIV seropositivity or known immunodeficiency. Testing is not required 
unless a condition is suspected. 
5.2.4 Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter 
the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome or small bowel resection). A gastric tube or nasogastric tube is 
allowed. 
5.2.5 Females who are pregnant or breast feeding. 
5.2.6 Males or females of reproductive potential may not participate unless they have agreed to use 
an effective contraceptive method during the period they are receiving the study drug and for 
3 months thereafter. Abstinence is an acceptable method of birth control.  
Females of childbearing potential will be given a pregnancy test within 7 days prior to 
administration of study treatment and must have a negative urine or serum pregnancy test. 
5.2.7 Patients who have received prior treatment with an mTOR inhibitor. 
5.2.8 Patients unwilling or unable to comply with the protocol or who in the opinion of the 
investigator may not be able to comply with the safety monitoring requirements of the study. 
5.2.9 Patients who currently have an uncontrolled infection, defined as receiving intravenous 
antibiotics. 
 
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6 
TREATMENT PROGRAM 
 
 
6.1 
Study Schema 
 
 
 
6.2 
Research Design and Methods 
A total of 50 patients will be enrolled over a 4 year period from up to 12participating institutions, 
targeting to yield a minimum of 45 evaluable patients by accommodating up to 10% non-evaluable 
rate, or 5 non-evaluable patients. Patients will be followed through an initial 14-course treatment 
period (2 courses of induction, 12 courses of maintenance), with 5-year follow up from time of 
enrollment for all patients who complete the study or have a response.  Patients will be randomized 
to receive vincristine plus a weaning dose of steroids or sirolimus plus a weaning dose of steroids.  
Initial treatment combined with steroids is essential as many patients will be started on steroids at 
their primary institutions and there is speculation in our present study that this initial combination 
may have some synergistic benefit.  This will provide consistency of treatment.  After induction, 
patients will then continue on a 1 year maintenance phase.  If patients fail to achieve hematologic 
response at the end of induction or lose their response during maintenance, a treatment change may 
occur.  Formal response in maintenance will be evaluated by imaging studies, functional assessment, 
and quality of life as per study SIR-DA-0901.  Failure at any time will be defined as worsening of 
hematological parameters on two separate laboratory evaluations.  
 
The number of study patients was determined from projections of eligible patients seen by 
multidisciplinary vascular anomalies centers over the past three years. Study participation is limited 
to those institutions that have the required patient volumes, infrastructure and significant 
multidisciplinary expertise in investigator initiated clinical trials.  
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6.3 
Randomization 
The initial treatment assignment will be made using a response adaptive randomization algorithm: 
patients will be randomized in a 1:1 ratio (with equal probability) for the first 10 and in a skewed 
ratio for the rest to favor the better performing treatment arm by adjusting the treatment allocation 
ratio based on response data observed on previously  accrued patients.  The response data observed 
on previously enrolled patients will be available in a real time and continuously analyzed by the 
study statistician for treatment assignment of each newly enrolled patient.  Clinical trial designs 
using such adaptive randomization algorithm are known to increase patient benefits over the course 
of trials without undermining the scientific rigor (39). We specifically will use the doubly adaptive 
biased coin design with a target allocation given by an urn model (40, 41).  
Because of the time it takes to measure treatment response, we will modify the dynamic 
randomization in the following manner.  Rather than using all previously enrolled patients response 
information to randomize the next patient, we will only base new randomization on the information 
from those previous patients who have had treatment response information available at the time of 
next randomization. Specifically, the probability of assigning a new patient to Sirolimus group is 
1
1+
𝑁𝑚,𝐴
𝑁𝑚,𝐵൬
1−𝑝ෝ𝑚,𝐴
1−𝑝ෝ𝑚,𝐵൰
2, where 𝑁𝑚,𝐴 and  𝑁𝑚,𝐵 are the number of numbers of patients who have been 
enrolled in Sirolimus and Vincristine respectively. 𝑝̂𝑚,𝐴 and 𝑝̂𝑚,𝐵 are respectively Sirolimus and 
Vincristine group observed response rates up to that time point. 
  
 
6.4 
INDUCTION 
 
Arm 1:  Vincristine + Steroid Taper 
 
Arm 2:  Sirolimus + Steroid Taper 
6.4.1 Steroid Taper – Steroids may be started prior to study enrollment.  All participants will 
continue to receive steroids during the Induction period.  The steroid (prednisolone or 
equivalent) taper will begin following enrollment during 2 courses of the induction period 
along with either vincristine or sirolimus.   
 
 
Steroid Taper Schedule 
 
 
 
Table 2 
Steroid Dose   
 
Duration 
2mg/kg/day divided BID 
2 weeks 
1.5 mg/kg/day divided BID 2 weeks 
1.0 mg/kg/day divided BID 2 weeks 
0.5 mg/kg/day QD 
1 week 
0.5 mg/kg/day QOD 
Every other Day – 1 
week 
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Stop 
 
 
6.5 
Arm 1:  Vincristine + Steroids (Induction) 
6.5.1 Administration - Vincristine will be administered weekly for 2 courses (one course is 28 
days) by central venous catheter (recommend PICC line) per institutional guidelines. 
Vincristine administration may be moved by one day per course.  The vincristine dose used 
for this study is based upon weight with 10 kg as a cut-off. 
 
 
Vincristine Dose 
• 0.05 mg/kg/dose IV – for participants less than or equal to 10 kg 
OR 
• 1.5 mg/m2/dose IV – for participants greater than 10kg 
 
6.6 
Arm 2:  Sirolimus + Steroids (Induction) 
6.6.1 Administration – Sirolimus will be administered at a dose of 0.8 mg/m2/dose for 
participants <6 months of age and 1mg/m2/dose for participants ≥6 months of age  twice a 
day on a continuous dosing schedule.  One course will be 28 days, measured by a 24 hour 
clock, rather than calendar days, to accommodate instances when the first dose of a course is 
the evening dose.  Previous studies support the role of therapeutic monitoring and dose 
adjustment, and the importance of twice daily dosing given the more rapid drug metabolism 
in pediatric patients (42).  Sirolimus will be administered as an oral (liquid) preparation in 
this study. 
6.6.2 Pharmacokinetically Guided Dosing – The target sirolimus trough level is 10-15ng/ml.  
Sirolimus dosing will be individually guided using real-time drug concentrations 
measurements in combination with a Bayesian population model-based target optimization 
approach (43) 
 
The dosing of sirolimus will be guided by pre-dose concentration measurements (trough) 
collected prior to either the AM or PM sirolimus dose.  Each participant will have sirolimus 
serum levels measured according to the timeline listed below.  Analysis for sirolimus level 
will occur at each participating site, or at a local laboratory using a validated assay approved 
by the study Pharmacologist.  Regardless of collection and analysis site, the study 
Pharmacologist (Sander Vinks, PharmD, PhD, FC at Cincinnati Children’s Hospital Medical 
Center (CCHMC)) or designee will perform all modeling and make recommendations for 
dose adjustment.  Trough levels will be taken as listed below:     
 
 
Table 3. 
Sirolimus  
Frequency of 
Action 
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Trough levels 
Loading Dose 
Anytime between 
Day 10-14* 
Continue Weekly trough level 
monitoring until 2 consecutive trough 
levels are stable**. 
Stable levels** 
Each course ***  
• If trough levels within target 
range – continue same sirolimus 
dose  
• If trough levels are outside of 
target range after consultation 
with study Pharmacologist – Dose 
Adjustment 
Dose adjustment 
7-14 days following 
dose adjustment 
Continue Weekly monitoring until 
trough levels are stable**. 
Toxicity 
At time of toxicity 
See section 8.1 
*  
Children up to age 2 will have loading dose trough sirolimus levels drawn beginning 
at Week 1 (Days 6-9) or, at the discretion of the investigator.  Trough levels may be 
drawn at 2 time points (12 hours apart) during Week 1 to determine an individualized 
PK (count business days only).   
**  
Stable Level is defined as 2 consecutive trough levels that are within target range.  
After the pharmacologist verifies the trough is within target range, the pharmacologist 
recommendation for the second level should be received within 7 business days. 
*** 
Trough levels are to be drawn at the beginning of each course (defined as first 5 days) 
if stable during the prior course (does not have to be repeated if trough level 
recommendation was obtained within 7 business days prior to start of next course). 
 
If unable to achieve a target trough sirolimus levels within 4 weeks, patients may be 
asked to have a mini-PK collection of 2 blood draws, in addition to a trough level, in 
order to better estimate the participant’s recommended dose.  The mini-PK collection 
will be at: 1 hour and 3 hours after a sirolimus dose. 
 
6.7 
Hematologic Response Assessment –Induction (all participants) 
During the induction phase, time to hematological recovery will be measured to assess response.  
Hematologic response will be defined as a platelet count >100,000/µl or an increase in platelet count 
of 2 times the baseline (whichever is greater) and fibrinogen of > 150mg/dl.  Hematologic response 
must be documented within 7 days prior to completion of induction course 2 or earlier if failure is 
suspected.  Platelet count and fibrinogen levels must meet these parameters on 2 consecutive lab 
measurements with a minimum of 1 day between evaluations.  Baseline is initial laboratory 
evaluation without transfusions; lab results performed outside of enrolling site may qualify as 
baseline as long as supporting documentation is provided.  Study treatment will be continued during 
the period of hematologic response assessment.  Hematologic response can NOT be assessed within 
24 hours of a platelet or cryoprecipitate infusion (Section 7.1). 
 
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6.8 
Treatment Change (Induction) 
Participants who fail to achieve hematologic response by the end of induction (2 courses of therapy) 
will change to the other treatment arm for the start of Maintenance.  Although participants are 
expected to finish their assigned induction period, a participant may switch treatment arm 
(change treatment) prior to the end of the induction period if it is in the best interest of the 
participant’s safety and well-being and hematologic failure is documented.   Such participant 
will be considered a treatment failure (a non-responder will be counted as failure and the 
participant will change to the other therapy, but will be counted in the intent to treat group).  
Treatment change is permitted one time during the study.  Maintenance should be initiated within 
one week following documentation of hematologic failure for patients who change treatment.  
Functional assessments (Appendix V) and Quality of Life Questionnaires will be repeated prior to 
start of new treatment arm.  These will serve as the baseline for the subsequent assessments obtained 
during maintenance. 
 
6.9 
MAINTENANCE (12 courses) 
 
Study treatment (all participants) will be continuous between the periods of Induction and 
Maintenance.    For participants who change treatments prior to start of maintenance, study treatment 
should begin within one week after documentation of hematologic failure. 
6.9.1 Arm 1:  Vincristine 
6.9.2 Administration – Participants randomized to Arm 1 and have achieved hematologic 
recovery as defined in Section 6.7 will continue to receive vincristine on the schedule 
outlined in Table 4.  Participants randomized to Sirolimus for induction and who have failed 
to achieve hematologic recovery as defined in Section 6.7 will change treatment to Arm 1 
and receive Vincristine as outlined in Table 4.  Vincristine will be administered by central 
venous catheter (recommend PICC line) per institutional policy during Maintenance for a 
total of 12 courses (48 weeks).    
 
Vincristine Dose 
• 0.05 mg/kg/dose IV – for participants less than or equal to 10 kg 
OR 
• 1.5 mg/m2/dose IV – for participants greater than 10kg 
 
Vincristine administration schedule:  
 
Vincristine will be administered weekly for 2 courses (Maintenance Courses 1-2).  After 2 
courses vincristine will be administered every two weeks for 5 courses (Maintenance Courses 
3-7).  Treatment will then be every 3 weeks for 5 courses (Maintenance Courses 8-12).  
Doses held/ missed for toxicity will not be made up.  Vincristine administration may be 
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moved by two days per course.   
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Table 4 
 
 
 
 
 
 
 
 
Frequency 
Every 2 weeks  (+/- 2 days) 
Course 
Course 3 
Course 4 
Course 5 
Course 6 
Course 7 
Week 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
Vincristine 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
Frequency 
Every 3 Weeks (+/- 2 days) 
Course 
Course 8 
Course 9 
Course 10 
Course 11 
Course 12 
Week 
29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 
Vincristine 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
 
 
6.9.3 Monitoring – Laboratory assessments and toxicity monitoring will occur as outlined in 
Section 9. 
 
6.10 Arm 2:  Sirolimus 
6.10.1 Administration – Participants randomized to Arm 2 for Induction and who have achieved 
hematologic recovery as defined in Section 6.7 will continue to receive sirolimus.  
Participants currently receiving sirolimus will continue at their current dose unless the criteria 
for dose adjustment as described in Section 6.10.3 are met.   
 
6.10.2 Sirolimus Administration for Treatment Change to Arm 2- Participants originally randomized 
to Arm 1 that fail to achieve hematologic recovery will then switch to Arm 2 and will be 
administered sirolimus at a dose of 0.8 mg/m2/dose for participants <6 months of age and 
1mg/m2/dose for participants ≥6 months of age twice a day on a continuous dosing schedule.  
Sirolimus dosing will be monitored pharmacokinetically to achieve serum trough levels for 
sirolimus between 10-15ng/ml.  
Frequency 
Duration – 48 weeks 
Weekly 
Maintenance Courses 1-2  (8 doses) 
Every 2 weeks 
Maintenance Courses 3-7 (10 doses) 
Every 3 weeks 
Maintenance Courses 8-12 (6 doses) 
Frequency 
Weekly (+/- 2 days)  
Maintenance Course 
Course 1 
Course 2 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
Vincristine 
• 
• 
• 
• 
• 
• 
• 
• 
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6.10.3 Pharmacokinetically Guided Dosing – The target sirolimus trough level is 10-15ng/ml.  
Sirolimus dosing will be individually guided using real-time drug concentrations 
measurements in combination with a Bayesian population model-based target optimization 
approach (43) 
 
The dosing of sirolimus will be guided by pre-dose concentration measurements (trough).  
Each participant will have sirolimus serum levels measured according to the timeline listed 
below.  Analysis for sirolimus level will occur at each participating site, or at a local 
laboratory using a validated assay approved by the study Pharmacologist.  Regardless of 
collection and analysis site, the study Pharmacologist or designee will perform all modeling 
and make recommendations for dose adjustment.  Trough levels will be taken as listed below:     
 
Table 5 
Sirolimus  
Frequency of 
Trough levels 
Action 
Loading Dose 
Anytime between 
Day 10-14* 
Continue Weekly trough level 
monitoring until 2 consecutive trough 
levels are stable**. 
Stable levels** 
Each course ***  
• If trough levels within target 
range – continue same sirolimus 
dose  
• If trough levels are outside of 
target range after consultation 
with study Pharmacologist – Dose 
Adjustment 
Dose adjustment 
7-14 days following 
dose adjustment 
Continue Weekly monitoring until 
trough levels are stable**. 
Toxicity 
At time of toxicity 
See section 8.1 
 
* 
 
Children up to age 2 will have loading dose trough sirolimus levels drawn 
beginning at Week 1 (Days 6-9) or, at the discretion of the investigator.  
Trough levels may be drawn at 2 time points (12 hours apart) during Week 1 to 
determine an individualized PK. 
**  
Stable Level is defined as 2 consecutive trough levels that are within target 
range. After the pharmacologist verifies the trough is within target range, the 
pharmacologist recommendation for the second level should be received within 
7 business days. 
*** 
Trough levels are to be drawn at the beginning of each course if stable during 
the prior course (does not have to be repeated if trough level recommendation 
was obtained within 7 days prior to start of next course). 
 
If unable to achieve a target trough sirolimus levels within 4 weeks, patients may be 
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asked to have a mini-PK collection of 2 blood draws, in addition to a trough level, in 
order to better estimate the participant’s recommended dose.  The mini-PK collection 
will be at: 1 hour and 3 hours after a sirolimus dose. 
 
6.11 Response Assessment – Maintenance (All Participants) 
The optimal measure of disease response in patients with complex vascular anomalies has not been 
established.  Current practice includes changes in physical exam, radiologic 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, as determined radiologically and clinical changes or quality of life measures.  
For these reasons we have elected to assess formal disease response using three distinct methods: 
1. Radiologic evaluation 
2. Clinical measures of disease (cytopenias, coagulopathies, other clinically relevant 
radiologic evaluation beyond the lesion of interest such as chest X-rays), and/or 
parameters for grading functional impairment – (Functional Assessment - Appendix 
V) 
3. Quality of life measures 
 
Formal Responses will be assessed three times during the study: prior to initiation of study treatment 
(baseline), and at the end of courses 6 and 12 following the start of Maintenance.  Disease 
assessments may be performed at any time during maintenance if clinically indicated.  Participants 
with disease worsening as defined as “progressive disease” or “loss of response” based upon any one 
of the above methods will be permitted to change treatment.  If worsened disease is based on 
laboratory parameters we suggest a repeat of laboratory evaluations to confirm.  Refer to Section 11 
for definitions of responses. 
 
6.12 Treatment Change (During Maintenance) 
Treatment change is permitted one time during the study.  If participant has changed treatment at the 
start of maintenance and has ‘progressive disease’ or ‘loss of response’, off treatment criteria will 
have been met.  If treatment change occurs during maintenance, treatment on the new arm will begin 
within 7 days of documentation of disease worsening.  Functional Assessment and Quality of Life 
measures are to be repeated at the time of treatment change unless performed within the last 7 days. 
 
6.13 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for up to 14 courses 
(inclusive of Induction and Maintenance) or until one of the following criteria applies: 
• Intolerable toxicity (leading to treatment interruption for more than 4 weeks) 
• Refusal of further protocol therapy by patient and/or parent/guardian 
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• Physician determines it is in the best interest of the patient 
• Progressive Disease or loss of response following change of treatment 
• End of Protocol defined therapy 
• Complete response to therapy* 
* If there is a Complete Response (CR) prior to completion of 12-24 weeks of therapy (3-6 
courses), all study drugs will be stopped.   
• Continuation of sirolimus or vincristine off study will be up to the patient’s primary physician.  
 
Participants who are off protocol therapy will be followed until they meet the criteria for Off Study 
(see below).  Follow-up data will be required unless consent is withdrawn. 
 
6.14 Duration of Follow-Up 
All patients who complete the study or have a response (defined as stable disease or better), 
regardless of treatment arm, will continue to be followed for growth and complications of the 
vascular tumor and therapy-related toxicities for a total of 5 years from the date of study enrollment.  
Following completion of study therapy, patients will be followed at a minimum interval of every 6 
months.    Follow up visits may occur at participants home institutions or they may return to the study 
site for their routine follow up care.  Participants should return to the study site on an annual basis 
during follow-up.   
 
Patients who stop study treatment early for any reason and did not have a documented response to 
sirolimus or vincristine (defined as stable disease or better) will be followed for 30 days from the last 
dose of study treatment or until toxicities resolve to baseline or less than or equal to Grade 1.   
 
6.15 Off Study Criteria 
• Death 
• Lost to follow-up 
• Withdrawal of consent for any further data submission 
• Complete Follow up as defined in Section 6.14 
• Five years from protocol enrollment 
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7 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
7.1 
Supportive Care - Both Arms 
Appropriate antibiotics, blood products, antiemetics and general supportive care are to be used 
as necessary.  
• All blood products will be leukocyte depleted and irradiated to prevent graft-versus-host 
disease.  Platelet transfusions have been associated with an increase in pain and 
lesion size in patients with KHE/ KMP lesions.  Platelet transfusions should be 
limited and only used if there is actual bleeding or prior to procedures.  Hematologic 
response can NOT be assessed within 24 hours of a platelet or cryoprecipitate infusion.   
• Good oral hygiene and mouth care are encouraged, as mucositis is a common toxicity. 
•  Infection Prophylaxis will be administered according to treating center’s institutional 
guidelines as immunosuppressed patients are susceptible to Pneumocystis carinii 
infection.   
• GFs that support platelet or white cell number or function can only be administered for 
culture proven bacteremia, clinical sepsis, or invasive fungal infection with neutropenia. 
• Constipation prophylaxis is highly recommended as constipation and abdominal cramps 
are common toxicities associated with vincristine. 
 
7.2 
Other therapy for vascular anomaly 
Interventional procedures may be used to treat symptomatic lesions provided it does not 
interfere with radiographic evaluation.  For any planned surgery, the treating investigator 
should consider holding sirolimus.  Discussion with the study chair is required. 
 
7.3 
Concomitant Medications 
7.3.1 Steroids - Steroid use in maintenance should be limited to physiologic replacement doses due 
to endocrine deficiencies, as a premedication for blood products and for short courses if 
medically indicated.  This should be discussed with study chair. 
 
7.3.2 Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and 
p-glycoprotein (P-gp). Inducers of CYP3A4 and P-gp may decrease sirolimus concentrations 
whereas inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations.  Co-
administration of Rapamune with strong inhibitors of CYP3A4 and/or P-gp (such as 
ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or 
strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) are not recommended. 
CYP3A4 – Known strong inducers and inhibitors of isoenzyme CYP3A4, as specified in 
Appendix II, must not be administered. If these treatments are administered, the patient will 
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be removed from protocol therapy.  The listing of medications in Appendix II lists 
medications to avoid/ use caution with when taking sirolimus.   
 
Enzyme inducing anticonvulsants: Patients may not be taking enzyme–inducing 
anticonvulsants, and may not have received these medications within 1 week of entry, as these 
patients may experience different drug disposition. These medications are listed in Appendix 
II.   
7.3.3 Vaccinations- Patients receiving immunosuppressants, including sirolimus and vincristine, 
should not be administered live vaccines.  All other vaccines are permitted and highly 
suggested.   
 
8 
DOSE MODIFICATIONS/DOSE DELAYS 
Patients entered on the trial will be carefully monitored for the development of sirolimus-related 
toxicities and vincristine-related toxicities. This study will utilize the CTCAE of the National Cancer 
Institute for reporting of AEs. A copy of the current version of the CTCAE version 4.03 can be 
downloaded from CTEP:   http://ctep.cancer.gov/reporting/ctc.html  
 
8.1 
Sirolimus Arm 
Any patient experiencing a Grade 3 or 4 toxicity that is possibly, probably, or definitely related to 
sirolimus should have the drug held and a sirolimus trough level obtained as soon as possible.  Other 
toxicities requiring dose adjustments will be defined based on categorization of toxicity and sirolimus 
trough levels.  
8.1.1 Hematological Toxicity - If a patient experiences ≥Grade 3 neutropenia (ANC <750), anemia 
(Hgb <8), the sirolimus will be withheld.  Patients should continue to be seen and have 
complete blood counts measured, in addition trough sirolimus levels will be obtained every 
week until recovery (≤Grade 1) is documented.  See section 8.1.3 Table 6 for details on 
sirolimus trough target adjustments.    
8.1.2 Non-Hematological Toxicity - During All Courses for toxicities attributable (possibly, 
probably, definitely) to sirolimus: 
If a patient experiences a non-hematological toxicity as defined below, sirolimus will be 
withheld.  Patients should continue to be seen and have appropriate labs/observations, in 
addition to trough sirolimus levels, obtained at least weekly until recovery (≤Grade 1) is 
documented. See section 8.1.3 Table 6 for details on sirolimus target adjustments.   
 
Sirolimus-related (possibly, probably, or definitely) toxicities Requiring Dose 
Adjustments/Interruptions or other interventions 
• Grade 3 or Grade 4 non-hematological toxicity (*) 
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• Grade >2 serum creatinine elevation 
• Grade >2 allergic reaction 
• Grade >2 hypertension 
• Grade ≥1 non-hematologic toxicities related to sirolimus that are intolerable to the 
patient 
• Any > Grade 2 non-hematological toxicity that persists for >7 days without resolution 
(return to less than Grade 2 or baseline) and is considered sufficiently medically 
significant or sufficiently intolerable by patients that it requires treatment interruption 
and/or dose reduction (see Table 6). 
(*) The only non-hematological toxicities that are excluded from requiring dose 
adjustments/interruptions or other interventions are the following: 
o Grade 3 nausea and vomiting of less than 3 days duration 
o Grade 3 transaminase elevations that return to levels that meet initial eligibility 
criteria within 7 days of study drug interruption and that do not recur upon study 
re-challenge with study drug 
o Grade 3 GGT elevation 
o Grade 3 lymphopenia 
8.1.3 Dose Modification Algorithm for Toxicity - All recommendations for dose modifications will 
be made by the coordinating center after analysis of blood samples for sirolimus levels at local 
laboratory.  New doses will be communicated to the treating institution by the CCHMC 
Pharmacologist or designee. The table below will be used to modify sirolimus dose for 
patients who develop toxicity.   
 
All toxicities should recover to baseline or < Grade 2 prior to resuming sirolimus dosing. 
 
Table 6 
Sirolimus Trough 
Levels at time of 
Toxicity 
Dose Adjustment  
 
 
Toxicities attributable to 
sirolimus (possibly, probably, 
or related) 
Other explanation for 
toxicity (i.e., viral infection) 
>15ng/mL  (target trough 
10-15ng/mL)* 
 Resume at modified dose for target 
trough goal of 10-15ng/mL 
Resume therapy at same dose 
(targeted trough level of 10-
15ng/mL) 
Between 10-15ng/mL 
25% sirolimus dose reduction – 
resume at target trough goal of 7-
10ng/mL 
Resume therapy at same dose 
(targeted trough level 10-
15ng/mL).   
>10ng/mL  (target trough 
7-10ng/mL)* 
Resume at modified dose for target 
trough goal of 7-10 ng/mL 
Resume at same dose (targeted 
trough level 7-10ng/mL) 
Between 7-10ng/mL 
50% sirolimus dose reduction – 
Resume at same dose (targeted 
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resume at target trough goal of 5-
7ng/mL 
trough level 7-10ng/mL) 
>7 (target trough 5-
7ng/mL)* 
Resume at modified dose for target 
rough goal of 5-7 ng/mL 
Resume at same dose (targeted 
trough level 5-7ng/mL) 
Between 5-7ng/mL 
Remove from treatment 
Remove from treatment 
* If sirolimus trough level is above target range at time of toxicity; therapy may resume when trough level 
is within target range. 
 
8.1.4 Interventions for Hyperlipidemia/Hypertriglyceridemia 
Hyperlipidemia has been reported as an AE in at least 10% of patients treated with Sirolimus.  
As per the recent American Heart Association Scientific Statement on Cardiovascular Risk 
Reduction in High Risk Pediatric Patients, Tier III (65) management of hyperlipidemia should 
occur for patients with a fasting LDL cholesterol > 160 mg/dL.  Age appropriate dietary 
restrictions should be enforced.  Consult with your pediatric dietary and/ or nutrition services.   
Table 7 
Event 
Action 
Hyperlipidemia 
Fasting LDL >160 mg/dL and 
Patient > 10 years old 
• 
Diet (Nutritionist counseling – 30% of calories from fat, avoidance of trans-
fats for 6 months) and exercise – Repeat Fasting LDL in 3 months.   
• 
If fasting LDL cholesterol is still >160 mg/dL, continue diet and exercise 
and initiate a triglyceride-lowering agent such as an HMG-CoA reductase 
inhibitor (pravastatin, atorvastatin, or fluvastatin).  Patients should avoid 
drugs that inhibit or induce CYP3A4.  Patients should be monitored 
clinically and through serum biochemistry for the development of 
rhabdomyolysis and other AEs as required in the product data sheets for 
HMG-CoA reductase inhibitors.  Continue to follow lipid panel every 8-12 
weeks and adjust statins as necessary. 
• 
If fasting LDL cannot be maintained < 160mg/dL despite medical 
intervention, or the patient cannot tolerate medical intervention, then the 
sirolimus target goal should be reduced to a target goal of 7-10 ng/mL. 
• 
If after 3 months, fasting LDL cholesterol is still >160 mg/dL, then the 
sirolimus target goal should be reduced again to a target goal of 5-7 ng/mL.  
• 
If after 3 months at this new target goal fasting LDL cholesterol is still >160 
mg/dL, then the patient must be removed from protocol therapy. 
 
Fasting LDL >160mg/dL and 
Patient <10 years old 
• 
Diet (Nutritionist Counseling <30% of calories from fat, avoidance of trans-
fats for 6 months).  Repeat Fasting LDL in 3 months. 
• 
If fasting LDL cholesterol is still >160mg/dL, continue diet and exercise 
and consider cholestyramine resin. 
• 
If fasting LDL cannot be maintained < 160mg/dL despite medical 
intervention, or patient cannot tolerate medical intervention, then the 
sirolimus target goal should be reduced to a target goal of 7-10ng/mL. 
• 
If after 3 months, fasting LDL cholesterol is still 160 mg/dL, then sirolimus 
target goal should be reduced again to a target goal of 5-7ng/mL. 
• 
If after 3 additional months at this new target goal fasting LDL cholesterol 
is still >160 mg/dL, then the patient must be removed from protocol 
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therapy.  
Triglycerides 
150-699 mg/dL 
• 
Nutritionist counseling for low simple-carbohydrate, low-fat diet. 
• 
If triglycerides remain 700mg/dL, sirolimus therapy may continue at current 
dose target. 
≥ 700 – 1000 mg/dL 
• 
Diet (nutritionist counseling) and exercise.  Repeat lab work in 3 months. 
• 
If patient is > 10 years old and fasting triglycerides still > 700 mg/dL and 
HDL is low, the patient should continue diet and exercise and consider 
fibrate or niacin cholestyramine resin. 
o 
If after 3 months, the fasting triglycerides are still > 700 mg/dL, then 
sirolimus target goal should be reduced to a target goal of 7-10 ng/mL.   
o 
If after 3 months the fasting triglycerides are still > 700 mg/dL, then 
sirolimus target goal should be reduced again to a target goal of 5-7 
ng/mL. 
o 
If after 3 months at this new target goal fasting triglycerides are still > 
700 mg/dL, then the patient must be removed from protocol therapy. 
• 
If patient is < 10 years old and fasting triglycerides are still > 700 mg/dL or 
patient cannot tolerate medical intervention, then sirolimus target goal 
should be reduced to a target goal of 7-10 ng/mL. 
o 
If after 3 months the fasting triglycerides are still > 700 mg/dL, then 
sirolimus target goal should be reduced again to a target goal of 5-7 
ng/mL. 
o 
If after 3 months at this new target goal fasting triglycerides are still > 
700 mg/dL, then the patient must be removed from protocol therapy. 
 
 
8.1.5 Toxicities Requiring Removal from Therapy – Sirolimus Arm only 
If patients experience any of the following toxicities regardless of relationship to sirolimus or 
current trough level will be removed from protocol therapy. 
 
Table 8 
Toxicity 
Criteria for Removal 
Renal Function 
If serum creatinine persistently increases (documented on at least 2 consecutive lab evaluations) 
to greater than 1.5X the baseline serum creatinine at trial entry, a creatinine clearance or GFR 
should be obtained. If the creatinine clearance or GFR is <70% of normal for age, regardless of 
attribution, the patient should be removed from protocol therapy. 
Infection 
Patients who develop a ≥ Grade 3 pneumocystis carinii pneumonia or systemic fungal infection, 
regardless of attribution, will be removed from protocol therapy. 
 
Malignancy 
Patients who develop lymphoma or other cancers, regardless of attribution, will be removed 
from protocol therapy. 
Pneumonitis 
Patients who develop ≥Grade 2 sirolimus-related pneumonitis (symptomatic but no 
intervention/oxygen therapy needed) will be removed from protocol therapy. 
 
Hypertension 
Patients who develop sirolimus-related >Grade 3 hypertension will be removed from protocol 
therapy. 
 
Allergic 
Reaction 
Patients who develop sirolimus-related >Grade 3 allergic reaction will be removed from 
protocol therapy. 
 
Rash 
Patients who develop sirolimus-related Grade 4 rash will be removed from protocol therapy. 
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Hyperlipidemia 
Hyperlipidemia (with LDL cholesterol >160mg/dL) not responsive to diet, exercise, and 
medical intervention for patients after 2 dose reductions, regardless of attribution, will be 
removed from protocol therapy. 
 
8.1.6 Other AE-related Criteria for Removal Therapy 
• Patients who experience a sirolimus-related toxicity requiring a dose 
modification/interruption after two target level reductions will be removed from protocol 
therapy. 
• Patients who experience a sirolimus-associated toxicity requiring a target level 
reduction/drug interruption whose toxicity does not recover within 4 weeks of stopping 
sirolimus will be removed from protocol therapy. 
8.2 
VINCRISTINE ARM 
8.2.1 Vincristine Dose Modifications 
Table 9 
Toxicity 
Grade 
Management/Dose Modification 
Neuropathic Pain 
Grade 3 or greater 
Hold dose.  When symptoms subside, resume at 50% 
previous dose, then escalate to full dose as tolerated.  
Severe peripheral neuropathies, with or without a 
positive family history, might suggest the need for a 
molecular diagnosis evaluation to rule out hereditary 
neuropathy syndromes. 
Vocal Cord paralysis 
Any Grade 
Hold Dose.  When symptoms subside, resume at 50% 
previous dose, then escalate to full dose as tolerated. 
Foot Drop, Paresis 
Grade 3 or greater 
Consider holding or decreasing dose.  These toxicities 
are largely reversible but over months to years; 
physical therapy may be beneficial. 
Jaw Pain 
Any Grade 
Treat with analgesics; do not modify vincristine dose. 
Hyperbilirubinemia (Direct 
Bilirubin mg/dL) 
<3.1 mg/dL 
Full dose 
3.1-5.0 mg/dL 
50% dose reduction 
5.1-6.0 mg/dL 
75% dose reduction 
>6.0 mg/dL 
Withhold dose and administer next scheduled dose if 
toxicity has resolved.  Do not make up missed dose. 
Constipation, Ileus, or 
Typhilits 
Grade 3 or greater  
Hold Dose.  Institute aggressive regimen to treat 
constipation if present.  When symptoms are less than 
or equal to Grade 2, resume at 50% dose and escalate 
to full dose as tolerated. 
Extravasation 
Discontinue the IV administration of the drug and institute appropriate measure 
to prevent further extravasation and damage according to institutional guidelines.  
Remaining dose may be introduced into another vein. 
For AEs not covered within section 8, it will be left to the investigator’s clinical judgment whether 
or not an AE is of sufficient severity to require that the subject to be removed from treatment.  A 
subject may also voluntarily withdraw from treatment due to what he or she perceives as an 
intolerable AE.  If either of these occurs, the subject will be given appropriate care under medical 
supervision until symptoms cease or until the condition becomes stable. 
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9 
REQUIRED OBSERVATIONS 
 
9.1 
Arm 1.  Vincristine 
 
STUDIES TO BE OBTAINED 
Pre-Study1 
Induction 
Maintenance 
Off 
treatment 
Follow-up5 
Informed Consent/Assent 
X 
 
 
 
 
Eligibility Checklist 
X 
 
 
 
 
Physical Assessments 
History 
X 
Weekly 
X2 
X 
X 
Physical Exam with vital signs 
(including T, P, RR, BP) 
X 
Weekly 
X8 
X 
X 
Height, weight, BSA 
X 
Weekly 
X8 
X 
X 
Performance Status (see 
protocol) 
X 
Weekly 
X2 
X 
X 
Concomitant Medications 
 
Weekly 
X2 
 
 
Laboratory Assessments2 
CBC, differential, platelets, 
fibrinogen, D-Dimer 
X 
X2 
X2 
X 
X 
Urinalysis9 
X 
X9 
X9 
X 
X 
Pregnancy test3 
X 
X3 
X3 
 
 
Electrolytes including BUN, 
Creatinine, glucose, blood 
chemistry including albumin, 
total protein, SGOT, SGPT, 
bilirubin (total and direct) 
X 
X2 
X2 
X 
X 
Study Drug 
Vincristine administration 
(Vincristine administration 
may be moved by one day per 
course.) 
 
Weekly 
X 8 
 
 
Diary Review 
 
X2 
X2  
X2 
 
Response Assessments4 
Hematologic response6 
 
X6 
 
 
 
Imaging analysis 
X1 
 
X4 
X 
 
Health-related quality of life and 
pain assessments4 
X 
 
X4 
X 
 
Functional Assessment 
(Appendix IV)4 
X 
 
X4 
X 
 
Correlative Studies7 
Serum and tissue samples 
X 
X 
X 
 
 
1. 
All studies to determine eligibility must be performed within 2 weeks prior to enrollment.  Imaging may occur within 3 weeks of 
start of study treatment. 
2. 
Physical Assessments and laboratory Assessments should be obtained at a minimum of the end of every course but may be 
repeated more frequently if clinically indicated. Participant Diary should be returned and reviewed at the end of every course. 
3. 
For females of childbearing potential; must occur within 7 days prior to start of treatment.  Pregnancy tests for females of 
childbearing potential will be repeated every 4 to 6 weeks.   
4. 
Response assessments occur pre-study and at the end courses 6 and 12 in maintenance.   Disease assessments may be performed at 
any time if clinically indicated.  Quality of life and Functional assessments are to be repeated at time of treatment change. See 
section 11. 
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5. 
Follow-up assessments will be performed every 6 months or more frequently if clinically indicated.  See Sections 6.14 and 9.6. 
6. 
Hematologic response occurs within 7 days of completion of Induction course 2.  This may occur sooner or if hematologic failure 
is suspected. Consecutive platelet count and fibrinogen levels must be drawn with a minimum of 1 day between evaluations.  See 
Section 6.7. Hematologic response can NOT be assessed within 24 hours of a platelet or cryoprecipitate infusion. See Section 7.1 
 
7. 
Optional archival tissue and Serum samples will be collected from consenting patients.  See Section 9.6 for time points. 
8. 
Physical exam occurs prior to administration of vincristine during maintenance.  Vincristine will be administered weekly x 2 
courses, q2weeks for 5 courses and q3 weeks for 5 courses.  Missed doses will be discussed with Sponsor Investigator..   
9. 
Urinalysis should be obtained every eight weeks.  
 
Arm 2.  Sirolimus 
 
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1. 
All studies to determine eligibility must be performed within 2 weeks prior to enrollment unless otherwise indicated below.  
Radiological assessments may be done within 3 weeks prior to enrollment. 
2. 
Physical Assessments and laboratory Assessments should be obtained at a minimum of the end of every course but may be 
repeated more frequently if clinically indicated.  
3. 
For females of childbearing potential; must occur within 7 days prior to start of treatment. Pregnancy tests for females of 
childbearing potential will be repeated every 4 to 6 weeks. 
4. 
Response assessments occur at baseline, end of maintenance courses 6 and 12.  Quality of Life and pain assessment and functional 
assessments are to be repeated at treatment change.  Disease assessments may be repeated if clinically indicated. See section 11.  
5. 
Follow-up assessments will be performed every 6 months or more frequently if clinically indicated.  See Sections 6.14 and 9.6. 
6. 
Hematologic response occurs within 7 days of completion of Induction course 2.  This may occur sooner if hematologic failure is 
STUDIES TO BE OBTAINED 
Pre-Study1 
Induction  
Maintenance 
Off-treatment 
Follow-
up5 
Informed Consent/Assent 
X 
 
 
 
 
Eligibility Checklist 
X 
 
 
 
 
Physical Assessments 
History 
X 
X2 
X2 
X 
X 
Physical Exam with vital signs 
(including T, P, RR, BP, SaO2) 
X 
X2 
X2 
X 
X 
Height, weight, BSA 
X 
X2 
X2 
X 
X 
Performance Status (see protocol) 
X 
X2 
X2 
X 
X 
Concomitant Medications 
 
X2 
X2 
 
 
Laboratory Assessments 
CBC, differential, platelets, 
fibrinogen, D-Dimer 
X 
X2 
X2 
X 
 
X 
Urinalysis10  
X 
X10 
X10 
X 
X 
Pregnancy3 
X 
X3 
X3 
 
 
Electrolytes including BUN, 
Creatinine, & fasting glucose, blood 
chemistry including albumin, total 
protein, alkaline phosphatase, uric 
acid, phosphorous & fasting serum 
lipid profile (triglycerides, total 
cholesterol, HDL and LDL),  
SGOT, SGPT, bilirubin(total and 
direct) 
X 
 
 
X2 
X2 
 
X 
 
X 
Study Drug Administration 
Sirolimus Administration (Oral) 
 
Continuous Dosing 
 
 
Sirolimus Diary Review11 
 
X11 
X11 
X 
 
Trough sirolimus levels 
 
X8 
X9 
 
 
Response Assessments4 
Hematologic response with  
fibrinogen and  D-dimer6 
 
X6 
  
 
 
Imaging analysis 
X1 
 
X4 
X 
 
Functional Assessment (Appendix 
IV) 
X 
 
X4 
X 
 
Health-related quality of life and pain 
assessments 
X 
 
X4 
X 
 
Correlative Studies7 
Serum and Tissue samples 
X 
X 
X 
 
 
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suspected.  Consecutive platelet count and fibrinogen levels must be drawn with a minimum of 1 day between evaluations.  See 
Section 6.7. Hematologic response can NOT be assessed within 24 hours of a platelet or cryoprecipitate infusion. See Section 7.1  
7. 
Optional archival tissue and Serum samples will be collected from consenting patients.  Sec Section 9.6 for time points. 
8. 
The first trough level should not be measured until week 2 (Day 10-14) to allow for loading to occur and to approach steady state 
concentrations. (For patients less than 2 years of age there is allowance for additional levels in the first week; any questions should 
be discussed with the Sponsor Investigator).  After any dose modification, subsequent sirolimus levels should be obtained 7-14 
business days after the dose adjustment.  If abnormal or dose is adjusted, sirolimus level must be repeated weekly until two 
consecutive trough levels are within target range (Stable levels). See Section 6.6.2 and Table 3. 
9. 
For participants continuing on Maintenance, continue sirolimus trough levels at the end of every course if stable.  For participants 
who switch to sirolimus arm at Maintenance, refer to Section 6.10.3, and Table 5 (Maintenance).   
10. 
Urinalysis should be obtained every eight weeks. 
11. 
Participant Diary should be returned and reviewed weekly. 
 
9.2 
Pre-study Assessments 
All entry/eligibility studies must be completed within 2 weeks prior to start of treatment (unless 
otherwise specified). The baseline radiologic study documenting disease status is required within 3 
weeks prior to start of study treatment.  Urine or serum pregnancy test must be available within 7 day 
prior to start of study treatment. 
 
9.3 
Treatment Assessments 
All assessments scheduled to be obtained during Induction and Maintenance must occur within (+/-) 
1 day if scheduled to occur weekly.   For assessments to be repeated at the end of courses, these 
must occur within (+/-) 4 days of scheduled day.   
 
The following assessments will occur while participants are receiving study drug. 
• Physical Assessments 
o Medical history  
o Physical exam with vital signs including temperature, pulse, respiratory rate, and 
blood pressure.  Oxygen saturation will be recorded for patients randomized to the 
sirolimus arm only. 
o Height, Weight, BSA 
o Performance Status – Karnofsky performance status for participants ≥ 16 years of age 
or Lansky Performance scale for participants < 16 years of age 
• Laboratory Assessments  
o CBC, Differential, Platelets, and fibrinogen and D-Dimer at assessment timepoints   
o Urinalysis 
o Pregnancy tests – serum or urine pregnancy tests may be performed if female is of 
childbearing potential.  Pregnancy test should be within 7 days prior to start of 
treatment.  Pregnancy tests will be repeated every 4 to 6 weeks for females of 
childbearing potential while receiving study treatment.   
o Chemistries  
 Arm 1 (Vincristine) – Electrolytes including BUN, creatinine, glucose, blood 
chemistry including albumin, total protein, SGOT, SGPT, bilirubin (total and 
direct). 
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 Arm 2 (Sirolimus) -  Electrolytes including BUN, creatinine, fasting glucose, 
blood chemistry including albumin, total protein, alkaline phosphatase, uric 
acid, phosphorous and fasting serum lipid profile (triglycerides, total 
cholesterol, HDL and LDL), SGOT, SGPT, and bilirubin (total and direct). 
o Any laboratory assessments may be performed more frequently if clinically indicated. 
• Disease Assessments – Baseline, at the end of maintenance courses 6 and 12. 
o Hematologic response – Occurs within 7 days of completion of Induction course 2.  
This may occur sooner if hematologic failure is suspected to assess response including 
platelet count and fibrinogen levels.  See Section 6.7 and 7.1 regarding platelet 
transfusions and cryoprecipitate infusions. 
o Imaging analysis at time of treatment change 
o Assessment of functional impairment (Appendix IV) – to be repeated at time of 
treatment change 
o Health-related quality of life and pain assessments – to be repeated at time of 
treatment change 
o Disease assessments may be repeated any time if clinically indicated. 
 
9.4 
Off treatment (completion of study drug assessments) 
Assessments as described in Section 9.1 and 9.2 are to be performed at time of study drug 
discontinuation for any reason.   
 
9.5 
Follow up Assessments  
All patients who complete the study or have a response (defined as stable disease or better), 
regardless of treatment arm, will continue to be followed for growth and complications of the 
vascular tumor and protocol therapy related toxicities for a total of 5 years from the date of study 
enrollment.  Following completion of study therapy, patients will be followed at a minimum interval 
of every 6 months.    Follow up visits may occur at participants home institutions or they may return 
to the study site at a minimum of every 6 months for their routine follow up care.  Participants should 
return to the study site on an annual basis for a follow up visit.  See section 6.14 for further 
information for follow-up criteria. 
 
9.6 
Correlative Studies (Biomarkers) - Optional Serum, plasma and Tissue (archival) 
collection 
Correlative molecular biology studies will be conducted as part of the current trial. All patients 
should be approached for consent to all of these biology studies.  Patients may participate in the 
treatment portion of this trial without consenting to the biology studies.  Following completion of 
biomarker analysis at CCHMC, any remaining samples will be stored in the vascular tissue repository 
at CCHMC with participant consent. 
 
Biomarker analysis 
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Biomarker analysis will be conducted on blood samples (serum and plasma) and tissue (when 
available) at baseline (blood and tissue), at the end of induction course 2, and at the end of 
maintenance courses 6 and 12 (following initiation of induction and maintenance).  The change in 
levels of these vascular markers will be analyzed in LeCras’ laboratory at CCHMC using ELISA.  
Analysis will include VEGF-A, -C, -D, Pleiotrophin, IGF-1, Endothelin-1, Thrombospondin and 
Angiopoietin-1, and-2 and future biomarkers of interest in this class of patients.  Control serum and 
plasma from age and sex matched non-malformation patients may be obtained from left-over clinical 
samples or tissue repository.  Tissue analysis (expression of the vascular markers) will include 
phosphorylated Akt, phosphorylated ERK-1/2, and mTOR and phosphor-S6 kinase, as well as 
biomarkers VEGF-A, -C, -D, Pleiotrophin, IGF-1, Endothelin-1, Thrombospondin and Angiopoietin-
1, and-2 and future biomarkers of interest in this class of patients.  There is limited information on 
biomarker analysis in this population of patients.   
9.6.1 Sample Collection 
Tissue:   
Archival tissue may be submitted to satisfy this correlative study.  In the event tissue is 
available at another institution, the enrolling site should work with the institution to obtain the 
tissue samples, either snap-frozen or in paraffin block, or as prepared slides (10 unstained 
sections, if available. Sites should contact the coordinating center if fewer sections are 
available for submission).  In the event no archival tissue is available and the patient has a 
cutaneous lesion, if consent is indicated on the study consent form, a 6 mm punch biopsy may 
be obtained to satisfy this correlative study.   
Processing:  For patients undergoing punch biopsy, the coordinating center should be 
contacted prior to the procedure to obtain further processing instructions. 
Labeling: All tissue samples should be labeled with the subject’s study ID number, initials, 
and the date of collection. 
Shipping: See shipping instructions on the tissue specimen transmittal form.   
9.6.2 Blood Biomarkers analysis: 
Time point: Baseline, at end of induction and end of maintenance courses 6 and 12. 
Sample collection: 1-6 ml of blood will be collected in a serum and plasma separator tubes   
 
 
Processing: 
• 
Specimens collected at CCHMC need to be received at LeCras’ laboratory within 45 
minutes of being drawn. 
• 
Serum collection and processing: Collect 1-6 ml blood in serum separator tube (red top). 
Centrifuge at 1800xG for 15 minutes. Transfer serum to a 2-5 ml polypropylene cryogenic 
vial. Freeze and store at -80℃ until shipped.  
• 
Plasma collection and processing: Collect 1-6 ml blood in a plasma separator tube (sodium 
citrate tube). Centrifuge at 1800xG for 15 minutes. Transfer plasma to a new tube and 
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repeat centrifugation 1800xG for 15 minutes. Transfer plasma to a 2-5ml polypropylene 
cryogenic vial. Freeze and store at -80℃ until shipped 
• 
Due to blood volume limits, collect blood for clinical labs, then biomarker samples with 
serum as first priority then plasma. 
• 
Polypropylene cryogenic vials will be provided to participating institutions. 
Labeling: All samples should be labeled with the subject’s study ID number, initials, the date 
of collection and time point (baseline, end of induction, and end of maintenance courses 6 and 
12 
Shipping: See shipping instructions on the serum and plasma specimen transmittal form.  
Frozen serum and plasma samples should be shipped frozen on dry ice overnight by FedEx or 
another overnight service. Please email tracking number and time/date/place of shipping to: 
HVMCresearch@cchmc.org.   
Ship frozen serum/plasma samples in dry ice by FedEx or other overnight carrier; First 
Priority Overnight to:  
Megan Metcalf 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Ave. 
MLC 7015 
Cincinnati, OH 45229 
Pager: (513) 736-3010 
 
 
10 DRUG INFORMATION 
 
10.1 Sirolimus (Investigational Brochure). 
Sirolimus (Rapamune) is a macrocyclic lactone produced by Streptomyces hygroscopicus. In 
cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12). The sirolimus: 
FKBP-12 complex binds to and inhibits the activation of the mammalian Target of Rapamycin 
(mTOR), a key regulatory kinase. Following administration of sirolimus oral solution, 
sirolimus is rapidly absorbed, with a mean time-to-peak concentration of approximately 1 
hour (range 1-3 hours). The systemic availability of sirolimus was estimated to be 
approximately 14% after the administration of sirolimus oral solution. The mean 
bioavailability of sirolimus after administration of the tablet is about 27% higher relative to 
the oral solution. Sirolimus oral tablets are not bioequivalent to the oral solution; however, 
clinical equivalence has been demonstrated at the 2-mg dose level. Sirolimus is extensively 
metabolized by O-demethylation and/or hydroxylation to at least seven major metabolites. 
The parent drug contributes to more than 90% of the activity. The main route of elimination is 
through the feces (91%). The mean t 1/2 increased from 79 ± 12 hours in subjects with normal 
hepatic function to 113 ± 41 hours in patients with impaired hepatic function. Males have a 
12% lower clearance of sirolimus than females after oral solution administration. No 
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differences were demonstrated between black and non-blacks.  After administration of the oral 
solution and tablets with a high fat meal, the maximum concentration was reduced, and the 
time to maximum concentration was increased. The total exposure to drug (AUC) was also 
increased. Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-
glycoprotein (P-gp). Sirolimus is extensively metabolized by the CYP3A4 isozyme in the 
intestinal wall and liver and undergoes counter-transport from enterocytes of the small 
intestine into the gut lumen by the P-gp drug efflux pump. Sirolimus is potentially recycled 
between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. 
Therefore, absorption and subsequent elimination of systemically absorbed sirolimus may be 
influenced by drugs that affect these proteins. Drugs that stimulate or inhibit p-450 enzymes 
will alter clearance of sirolimus and close attention to potential drug interactions is crucial. 
10.1.1 Product Description: 
For the purposes of this study, only sirolimus oral solution, containing 1 mg/mL sirolimus, 
will be used.  
Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl 
alcohol, chloroform, acetone, and acetonitrile. The inactive ingredients in Rapamune® Oral 
Solution are Phosal 50 PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, 
ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Rapamune Oral Solution 
contains 1.5% - 2.5% ethanol. 
10.1.2 Solution Preparation and Storage:   
Each Rapamune Oral Solution carton, NDC 0008-1030-06, contains one 2 oz (60 mL fill) 
amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for 
fitting into the neck of the bottle, sufficient disposable amber oral syringes and caps for daily 
dosing, and a carrying case.  
Rapamune Oral Solution bottles should be stored protected from light and refrigerated at 2°C 
to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used within one 
month. If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) 
for a short period of time (e.g., not more than 15 days).  
An amber syringe and cap are provided for dosing, and the product may be kept in the syringe 
for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 
2°C to 8°C (36°F to 46°F). After dilution, the preparation should be used immediately.  
Rapamune Oral Solution provided in bottles may develop a slight haze when refrigerated. If 
such a haze occurs, allow the product to stand at room temperature and shake gently until the 
haze disappears. The presence of this haze does not affect the quality of the product.  
10.1.3 Route of Administration:  
Sirolimus may be taken either with or without food. Patients should be advised to take their 
sirolimus at the same time of the day and at the same time in relation to meals. Patients may 
not take sirolimus with grapefruit juice. It is recommended that the oral solution be added to at 
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least two ounces (60 mL) of water or orange juice immediately prior to consumption in order 
to hide the taste. This solution should be stirred vigorously and then consumed. The container 
may then be refilled with a minimum of 4 oz of additional water or orange juice, stirred 
vigorously, and immediately consumed.  Special attention must be paid to avoiding foods and 
drugs that will affect CYP3A4. (See Appendix II) 
10.1.4 Drug interactions  
Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and 
p-glycoprotein (P-gp). Inducers of CYP3A4 and P-gp may decrease sirolimus concentrations 
whereas inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations.  
Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp - Avoid concomitant use of 
sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., 
ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of 
CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should 
be considered.  
Grapefruit Juice - Because grapefruit juice inhibits the CYP3A4-mediated metabolism of 
sirolimus, it must not be taken with or be used for dilution of Rapamune.  
Inducers or Inhibitors of CYP3A4 and P-gp - Exercise caution when using sirolimus with 
drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of Rapamune and/or 
the co-administered drug may need to be adjusted.  
Refer to Appendix II for prohibited medications. 
Immunosuppressants may affect response to vaccination. Therefore, during treatment with 
Rapamune, vaccination may be less effective. The use of live vaccines should be avoided; live 
vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral 
polio, BCG, yellow fever, varicella, and TY21a typhoid.  
 
10.1.5 Toxicity 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Headache (L), 
hypertension (L), nausea, 
immunosuppression (L), 
diarrhea, constipation, fever 
Chest pain, insomnia, 
dysphagia, vomiting, dyspnea 
Hypotension, asthma, increased cough, 
flu like syndrome, tachycardia, 
anorexia, sensitivity reactions 
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Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Tremor (L), renal 
dysfunction, elevated 
creatinine/BUN, anemia, 
asthenia, pain (abdominal, 
back, pain), hyperlipidemia, 
hypercholesteremia, 
hypertriglyceridemia, 
hyperglycemia, peripheral 
edema, weight gain, 
arthralgia 
Elevated LFTs, UTI, URIs, 
mild thrombocytopenia, 
leukopenia, 
hyper/hypokalemia (L), 
hypophosphatemia, rash, 
hives, pruritis, hyperuricemia, 
delayed wound healing, 
hypomagnesaemia (L) 
Gastritis, esophagitis, flatulence, CNS 
abnormalities: (confusion (L), 
somnolence (L), depression (L), 
anxiety, anxiousness, paresthesias, 
emotional labiality, hypo/hypertonia, 
dizziness, neuropathy, hypesthesia, 
nervousness), infections (bacterial, 
fungal, viral–sepsis, cellulitis, herpes 
simplex & zoster, EBV, mycobacterial, 
sinusitis, pharyngitis, abscess, 
pneumonia, bronchitis, peritonitis), 
pleural effusions, pleural edema, 
hypoxia, thrombosis, thrombophlebitis, 
myalgia 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
Acne 
Skin ulcer, hirsutism (hypertrichosis) 
(L), gingival hyperplasia, abnormal 
vision, ear pain, cataracts, otitis, 
tinnitus, hemorrhage, ileus, chronic 
renal dysfunction, renal tubular 
necrosis, post-transplant diabetes 
mellitus (L), CHF, ascites, 
thrombocytopenic purpura (hemolytic- 
uremic syndrome), arthrosis, bone 
necrosis, osteoporosis 
Late: 
Any time after 
completion of 
treatment 
Lymphoproliferative disorders, skin 
malignancies 
Unknown 
Frequency and 
Timing: 
Sirolimus was embryo/feto-toxic in rats at dosages of 0.1 mg/kg and above (approximately 0.2 to 
0.5 the clinical doses adjusted for body surface area). Embryo/feto toxicity was manifested as 
mortality and reduced fetal weights (with associated delays in skeletal ossification). Sirolimus is 
excreted in trace amounts in milk of lactating rats. It is not known whether sirolimus is excreted in 
human milk. 
(L) Toxicity may also occur later. 
10.1.6 Therapeutic Drug Monitoring  
Monitoring of sirolimus trough concentrations is recommended for all patients, especially in 
those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less 
than 40 kg, in patients with hepatic impairment, when a change in the Rapamune dosage form 
is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors.  
Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy. 
Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and 
laboratory parameters.  
 
The above recommended 24-hour trough concentration ranges for sirolimus are based on 
chromatographic methods. Currently in clinical practice, sirolimus whole blood 
concentrations are being measured by both chromatographic and immunoassay 
methodologies. Because the measured sirolimus whole blood concentrations depend on the 
type of assay used, the concentrations obtained by these different methodologies are not 
interchangeable.  Adjustments to the targeted range should be made according to the assay 
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utilized to determine sirolimus trough concentrations. Since results are assay and laboratory 
dependent, and the results may change over time, adjustments to the targeted therapeutic 
range must be made with a detailed knowledge of the site-specific assay used. Therefore, 
communication should be maintained with the laboratory performing the assay. A discussion 
of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, 
April 2000.  
10.1.7 Supplier:   
For this study, sirolimus (oral solution) will be supplied by Pfizer and is considered an 
“investigational” drug. 
10.1.8 Return and Retention of Study Drug – 
Study drug supplies may be destroyed on site per institutional policies.  Documentation of 
destruction will be collected during on-site monitoring visits and provided to the coordinating 
center at the conclusion of the study. 
 
10.2 Vincristine (See Package Insert for product information) 
10.2.1 Supplier – commercial supplies are to be used for vincristine. 
10.2.2 Source and Pharmacology 
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, 
disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. 
The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; 
however, the range of the terminal half-life in humans is from 19 to 155 hours. The liver is the 
major excretory organ in humans and animals; about 80% of an injected dose of vincristine 
sulfate appears in the feces and 10% to 20% can be found in the urine. The P450 cytochrome 
involved with vincristine metabolism is CYP3A4. Within 15 to 30 minutes after injection, 
over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not 
irreversibly bound. It is excreted in the bile and feces. There is poor CSF penetration. 
10.2.3 Administration  
Vincristine is to be prepared and administered per institutional policies and the package insert 
recommendations.  It is extremely important that the intravenous needle or catheter be 
properly positioned before any vincristine is injected. Leakage into surrounding tissue during 
intravenous administration of vincristine may cause considerable irritation. If extravasation 
occurs, the injection should be discontinued immediately and any remaining portion of the 
dose should then be introduced into another vein. Local injection of hyaluronidase and the 
application of moderate heat to the area of leakage will help disperse the drug and may 
minimize discomfort and the possibility of cellulitis.  
 
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The World Health Organization, the Institute of Safe Medicine Practices (United States) and 
the Safety and Quality Council (Australia) all support the use of minibag rather than syringe 
for the infusion of vincristine. The delivery of vincristine via either IV slow push or minibag 
is acceptable. Injection of vincristine sulfate should be accomplished as per institutional 
policy. Vincristine must be administered via an intact, free-flowing intravenous needle or 
catheter. Care should be taken that there is no leakage or swelling occurring during 
administration.  The solution may be injected either directly into a vein or into the tubing of a 
running intravenous infusion. When dispensed the container or syringe containing 
vincristine must be enclosed in an overwrap bearing the statement “DO NOT REMOVE 
COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. 
FOR INTRAVENOUS USE ONLY.” 
10.2.4 ADVERSE REACTIONS 
Prior to the use of this drug, patients and/or their parents/guardian should be advised of 
the possibility of untoward symptoms.  
In general, adverse reactions are reversible and are related to dosage. The most common 
adverse reaction is hair loss; the most troublesome adverse reactions are neuromuscular in 
origin. 
When single, weekly doses of the drug are employed, the adverse reactions of leukopenia, 
neuritic pain, and constipation occur but are usually of short duration (i.e., less than 7 days). 
When the dosage is reduced, these reactions may lessen or disappear. The severity of such 
reactions seems to increase when the calculated amount of drug is given in divided doses. 
Other adverse reactions, such as hair loss, sensory loss, paresthesia, difficulty in walking, 
slapping gait, loss of deep-tendon reflexes, and muscle wasting, may persist for at least as 
long as therapy is continued. Generalized sensorimotor dysfunction may become 
progressively more severe with continued treatment. Although most such symptoms usually 
disappear by about the sixth week after discontinuance of treatment, some neuromuscular 
difficulties may persist for prolonged periods in some patients. Regrowth of hair may occur 
while maintenance therapy continues. 
 
10.3 Steroids (Prednisolone or equivalent) – See package insert for further information 
10.3.1 Supplies – Commercial supplies of steroid are to be used for this study. 
 
 
11 RESPONSE ASSESSMENTS 
 
 
11.1 Evaluation of Disease Response: 
 
Patients will be assessed at the baseline (prior to induction) and 6 and 12 courses after start of 
maintenance.   
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The optimal measure of disease response in patients with complex vascular anomalies has not been 
established. Current practice includes changes in physical exam, radiologic 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 radiologically and clinical changes or quality of life measures. For 
these reasons we have elected to assess disease response using three distinct methods:  
11.1.1 Response by Imaging: 
For each imaging assessment time point (at baseline and end of maintenance courses 6 and 
12), initial radiologic response will be reviewed by each site’s radiologist.  If the radiologist 
identifies an area of possible disease progression while evaluating the imaging, the imaging 
will be reviewed by the identified site study radiologist prior to dispensing drug. 
 
MRI should be used as the radiologic study of choice.  MRI will be performed using a 1.5 or 
3.0 Tesla system with standard MRI protocols (Appendix III) to assess vascular anomaly 
response.  In rare cases where the patient may have a contraindication to MRI, contrast-
enhanced CT should be performed. 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 the target lesion at baseline and during follow up.  To improve reliability and 
consistency of response assessments all imaging will be centrally reviewed at BCH. Screening 
scan will be sent to BCH immediately for review to confirm eligibility.  All scans will be sent 
by disc at the end of maintenance for assessment.  If there is any question about radiologic 
disease response at any time during maintenance, the scans will be reviewed by the site 
radiologist and BCH study radiologist.   
11.1.2 Quality of Life Assessments (QOL): 
This study will evaluate the effects of disease and treatment with sirolimus on the health 
related quality of life (HRQOL) in children and young adults. QOL measurements in this 
population are complicated by the range of age of affected individuals (infants to young 
adults) and the lack of validated QOL scales for patients with vascular anomalies. However, 
there exist generic scales used to quantitate QOL in pediatric and adult patients with good 
reliability and validity for a variety of chronic diseases.   
 
The Pediatric Quality of Life Inventory (PedsQL 4.0) will be used to assess the QOL of 
children from 3 to 18 years of age. (46) The infant PedsQL is a tool to assess QOL in patients 
under the age of 2 years.  The PedsQL is a brief standardized multidimensional pediatric QOL 
scales consisting of both child self-report and parent proxy-report measures and includes 
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generic and disease specific modules. It consists of a 23-item core measure of global QOL 
that has four subscales: physical functioning, emotional functioning, social functioning, and 
school functioning. Based on the standard error of the mean, Varni has also defined minimum 
changes in total score as clinically meaningful (4.4 change in the child self-report and 4.5 
change in the parent proxy report). Changes in total scores with maintenance therapy will be 
used to quantitate the effects of this drug on health related quality of life in the pediatric 
population. A brief description of the QOL scales being used in this protocol is attached in 
Appendix V. 
 
The Functional Assessment of Chronic Illness Therapy (FACIT) system will be used to assess 
health-related QOL (47) in adult patients (19-31 years of age).  Specifically, this study will 
utilize a 27-item generic core (FACT-G) that includes 4 core subscales - physical well-being, 
emotional well-being, social well-being, and functional well-being. The FACT-G is a brief, 
reliable, and valid QOL measure, which is sensitive to clinical change and has been used with 
patients with cancer and a variety of other chronic illnesses (48).  Based on the standard error 
of the mean, the minimally clinically important difference in FACT-G scores is 3.99.   
 
Quality of Life assessments will be used in determining disease response as outlined in 
section11.2.  For Peds-QL, the patient’s self-report will be used when appropriate.  If the 
patient’s self-report is not available or other circumstances such as developmental delays, 
mental retardation, psychosis, or other apparent psychiatric issue, that in the opinion of the 
investigator would impair the subject’s ability to complete the scale accurately, then the proxy 
report will be used instead at the discretion of the investigator.  Likewise, a proxy-report will 
be used over the patient’s self-report as appropriate based on the developmental age of the 
patient.  This determination will be made by the investigator at the baseline QOL time point 
and will remain consistent for all other QOL time points.   In the event that there is neither a 
consistent parent nor proxy report, the QOL assessments will not be used as a measure of 
disease response. 
 
Pain will be assessed as an exploratory outcome and is not part of the response criteria for this 
study. Minimal clinically meaningful values have not been established for these variables; 
however given the importance of pain from the patient’s perspective, we will include its 
assessment. Pain will be measured using the FLACC pain questionnaire for infants and older 
subjects unable to complete their age appropriate pain questionnaire, the PedsQL Pediatric 
Pain Questionnaire (49) for children and the short-form McGill Pain Questionnaire (50) for 
adults. 
11.1.3 Clinical criteria and functional impairment: 
The degree of impairment of organ function caused by the vascular anomalies has been used 
historically to assess disease response to therapy. Currently, there are no validated scales, 
specific to vascular anomalies, to assess functional impairment. We therefore, have developed 
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a system of measurement which can be used across centers in a standardized manner 
(Appendix IV). This instrument has been adopted from the measures of organ function that 
have been validated in the quantification of AEs resulting from medical therapies or 
procedures (Common Terminology Criteria for AEs) and is currently in use In SIR-DA-0901 
We will use these objective measures to quantify specific organ dysfunction resulting from 
vascular anomaly.  
     
11.2 Disease Response  
Response will be established by changes in at least 1 parameter at 6 and 12 courses after the initiation 
of maintenance using the following criteria: 
 
Disease response – Complete Response (CR) and Partial Response (PR) 
• CR 
o No evidence of disease on radiologic imaging and 
o No evidence of organ dysfunction due to disease and 
o Normalization of QOL criteria* 
• PR 
o > 20 % reduction in volume by radiologic imaging, or 
o Improvement in target organ dysfunction by at least one grade, or 
o Improvement of proxy-report PedsQL by > 4.5; FACT-G by > 3.99* 
 
 
 
Progressive disease 
• > 20 % increase in target lesion volume by radiologic imaging, or 
• Worsening in target organ dysfunction by at least one grade, or 
• Worsening of Peds proxy-report PedsQL by > 4.5; FACT-G by > 3.99* 
 
 
Stable disease: None of the above 
 
Formal Responses will be assessed two times during maintenance at the end of courses 6 and 12 
following start of Maintenance.  Disease assessments may be performed at any time during 
maintenance if clinically indicated.  Disease worsening as defined as “progressive disease” or “loss of 
response” based upon any one of the above methods will be permitted to cross-over.  If worsened 
disease is based on laboratory parameters we suggest a repeat of laboratory evaluations to confirm. 
 
* In the event there is an apparent discrepancy between the patient or parent proxy PedsQL score 
with either the investigator’s assessment of target organ dysfunction or response evident 
radiographically, the patient will remain on protocol therapy at the investigator’s discretion.   In 
these particular instances, at the time of planned data analysis, the study statistician will 
determine if the patient should remain evaluable for overall response for the study. 
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Treatment will be continued until one of the criteria for removal from protocol therapy is met as 
outlined in section 6.13. 
 
12 ADVERSE EVENT REPORTING REQUIREMENTS 
 
12.1 Definitions  
12.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal laboratory 
finding, symptom, or disease temporally associated with the use of a drug) in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not related to 
the medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an 
AE (e.g., surgical insertion of central line) need not be considered AEs and should not be 
recorded as an AE.  Disease progression should not be recorded as an AE, unless it is 
attributable by the investigator to the study therapy. 
12.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that 
the drug is the cause.   Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration of the 
following factors: temporal relationship of the AE to study drug exposure, known mechanism 
of action or side effect profile of study treatment, other recent or concomitant drug exposures, 
normal clinical course of the disease under investigation, and any other underlying or 
concurrent medical conditions.  Other factors to consider in considering drug as the cause of 
the AE: 
• Single occurrence of an uncommon event known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• One or more occurrences of an event not commonly associated with drug exposure, 
but otherwise uncommon in the population (e.g., tendon rupture); often more than 
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once occurrence from one or multiple studies would be needed before the sponsor 
could determine that there is reasonable possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that indicates the 
events occur more frequently in the drug treatment group than in a concurrent or 
historical control group 
12.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not consistent 
with the applicable product information (e.g., package insert/summary of product 
characteristics for an approved product).  Unexpected also refers to AEs or SARs that are 
mentioned in the package insert as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation.   
 
12.1.3.1 
Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of existing 
hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience when, 
based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  For reporting purposes, also consider the 
occurrences of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as administration of 
chemotherapy, central line insertion, metastasis interventional therapy, resection of primary 
tumor, or elective surgery, will not be considered serious adverse events. 
 
12.2 Documentation and reporting of non-serious AEs or SARs 
The severity of toxicities will be graded in accordance with the Common Terminology Criteria for 
AE (CTCAE) version 4.0.3.  Grade 2 AEs deemed possible, probable or definitely attributed to study 
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medication and all Grade 3 and higher AEs, regardless of suspected causal relationship to study drug, 
will be recorded as AEs in the CRFs. 
 
For non-serious AEs or SARs, documentation must begin from day 1 of study treatment and continue 
through the 30 day follow-up period after treatment is discontinued.  
   
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 BCH or other nationally recognized pediatric standards may be 
used to determine the grade of the laboratory value. 
 
Collected information should be recorded in the Case Report Forms (CRF) for that patient.  Please 
include a description of the event, its severity or toxicity grade, onset and resolved dates (if 
applicable), and the relationship to the study drug.    Documentation should occur at least once a 
course.  
 
Refer to the Manual of Operations for this clinical trial for more detail instructions regarding adverse 
event reporting. 
 
12.3 Documentation of SAEs or Serious SARs  
SAEs and Serious SARs will be recorded from the time of informed consent until 30 days after 
completion of study treatment.   
12.3.1 SAE and Serious SAR reporting in the Follow Up Period 
In the event that during the 5-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 patient continued therapy on 
marketed off-label sirolimus) attributable to sirolimus, 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.  
 
12.4 Participating Site Responsibilities:  
12.4.1 SAE/Serious SAR Reporting 
All SAEs and Serious SARs, regardless of attribution or expectedness, must be reported to 
BCH verbally to coordinating center and Denise Adams within 24 hours of site awareness and 
followed with a FDA MedWatch 3500a Form.  For participating sites, this form must be 
submitted to BCH within 3 days of learning of the event.  
 
MedWatch 3500a Reporting Guidelines: In addition to completing appropriate patient 
demographic and suspect medication information, the report should include the following 
information within the Event Description (section 5) of the MedWatch 3500a form: 
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•       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 sending by secure email or 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.) 
12.4.2 IRB Reporting Requirements: 
Participating sites are required to notify their local IRBs according to institutional reporting 
policies. 
 
12.5 Sponsor Responsibilities to be performed by the Coordinating Center BCH: 
12.5.1 FDA:   
o 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.   
o Unexpected, Serious Suspected Adverse Reactions 
If an investigator or BCH deems that an event is both a serious SAR and unexpected, 
the FDA will be notified 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.  The serious 
SAR 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.     
12.5.2 BCH IRB and:  BCH DSMB: 
The sponsor will report any unexpected life threatening event or death (grade 4 or 5) adverse 
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event to the BCH IRB and BCH DSMB center program DSMB within 72 hours after the 
sponsor is made aware of the event.   
12.5.3 Unexpected Grade 3 serious adverse events at least possibly attributable to the research will 
be reported to the BCH IRB per institutional policies. 
12.5.4 Pfizer Reporting Requirements: 
Notify Pfizer Drug Safety of all SAEs using the safety reporting form provided by Pfizer.  
Pfizer: Fax: (866) 997-8322   
 
12.6 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. 
  
 
13 STATISTICAL ANALYSIS PLAN   
 
13.1 Sample size and power calculation:  
This is a two treatment arm randomized multi-center two-phase (induction/maintenance) clinical trial 
using the doubly adaptive biased coin design with a target allocation given by an urn model (40, 41) 
to continuously skew the randomization ratio to favor the better performing treatment arm. Patients 
will be randomized to receive either sirolimus or vincristine in the beginning of induction phase, and 
will be switched to the treatment they were not initially assigned to only if they fail to attain 
hematologic response (an increase of platelet count of >100,000 /µl  or an increase in platelets of 2 
times the baseline, whichever is greater, and a fibrinogen > 150 mg/dl; platelet and fibrinogen levels 
must meet these parameters on two consecutive lab measurements with a minimum of one day 
between evaluations). The primary efficacy endpoint is attainment of hematologic response by the 
end of the induction period.  
 
We plan to enroll n=50 evaluable patients over a 4 year period from up to 8 participating institutions. 
In the study SIR-DA-0901 we observed the median time to hematologic response was 3 weeks and 
we anticipate 74%~90% response rate for the sirolimus treatment arm, whereas 20%~40% for the 
vincristine, depending on the underlying time to response mechanism and preliminary data. Based on 
a computer simulation study and assuming a response rate difference of 40% or greater, we anticipate 
the proposed sample of n=50 in total under the doubly adaptive biased coin design will provide 
73%~90% power to detect a significant higher hematologic response rate of the sirolimus treatment 
arm.  The simulation study also suggests that on average ≥20% more patients will be treated with the 
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more efficacious sirolimus treatment arm compared to the conventional fixed design.  
 
In this adaptive design we will not conduct an interim analysis or stop the trial early. The adaptive 
design will treat more subjects with the sirolimus treatment arm by design in the case that the 
sirolimus treatment arm is more efficacious. We also do not expect any serious adverse events 
attributable to sirolimus. Therefore, futility may be the only legitimate reason to stop the trial early. 
However, the small total sample size limits the power of the interim analysis to test for the futility of 
sirolimus and splitting the type I error rate between the interim and the final analysis will lead to 
reducing the power of the final analysis without any substantial chance of early stopping for futility.  
An early stopping rule will be invoked to prevent further accrual of patients onto the study in the 
event that Sirolimus or Vincristine is associated with a higher than acceptable rate of severe toxicity 
(10%) with severe toxicity (defined as Grade 4 infection, pneumocystis carinii pneumonia, Grade 2 
pneumonitis, Grade 4 rash, Grade 4 hypertension, or Grade >2 allergic reaction) identified during the 
Induction period (the first 2 courses). We adopt a dynamic stopping rule based on cumulative number 
of patients enrolled into each treatment group.  Enrollment to a treatment will be stopped, if the 
number of severe toxicity AE reaches a threshold defined in the table.  This threshold is defined such 
that the 95% lower confidence bound of severe toxicity exceeds acceptable 10% rate, for either of the 
treatment groups.  The stopping rule has high probability of stopping early if the probability of severe 
toxicity is moderately great (≥20%) and low probability of stopping if the underlying probability of 
severe toxicity is ≤10%. 
A graph is also given below to visually show threshold as a function of total number enrolled in a 
particular treatment group.  If the cumulative number of aforementioned severe toxicity AE reaches 
or exceeds the red line, the enrollment to that treatment will be stopped.  New enrollment to the study 
will only be into the other group at that point.  
 
 
Number of 
patients 
enrolled to a 
particular 
treatment 
group 
Stop enrollment If at 
least this many 
patients experienced 
severe toxicity AE 
cumulatively 
Probability of 
stopping at this stage 
if the true toxicity 
rate is 10% 
Probability of 
stopping at this stage 
if the true toxicity 
rate is 20% 
2 
2 
0.01 
0.04 
3 
2 
0.028 
0.104 
4 
3 
0.004 
0.027 
5 
3 
0.009 
0.058 
6 
3 
0.016 
0.099 
7 
3 
0.026 
0.148 
8 
3 
0.038 
0.203 
9 
4 
0.008 
0.086 
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10 
4 
0.013 
0.121 
11 
4 
0.019 
0.161 
12 
4 
0.026 
0.205 
13 
4 
0.034 
0.253 
14 
4 
0.044 
0.302 
15 
5 
0.013 
0.164 
16 
5 
0.017 
0.202 
17 
5 
0.022 
0.242 
18 
5 
0.028 
0.284 
19 
5 
0.035 
0.327 
20 
5 
0.043 
0.37 
21 
6 
0.014 
0.231 
22 
6 
0.018 
0.267 
23 
6 
0.023 
0.305 
24 
6 
0.028 
0.344 
25 
6 
0.033 
0.383 
26 
6 
0.04 
0.423 
27 
6 
0.047 
0.461 
28 
7 
0.018 
0.322 
29 
7 
0.022 
0.357 
30 
7 
0.026 
0.393 
31 
7 
0.031 
0.429 
32 
7 
0.036 
0.465 
33 
7 
0.042 
0.5 
34 
7 
0.048 
0.534 
35 
8 
0.02 
0.401 
36 
8 
0.024 
0.434 
37 
8 
0.027 
0.467 
38 
8 
0.032 
0.5 
39 
8 
0.037 
0.532 
40 
8 
0.042 
0.563 
41 
8 
0.048 
0.593 
42 
9 
0.021 
0.469 
43 
9 
0.024 
0.5 
44 
9 
0.028 
0.53 
45 
9 
0.032 
0.559 
46 
9 
0.036 
0.588 
47 
9 
0.041 
0.616 
48 
9 
0.046 
0.642 
49 
10 
0.022 
0.528 
50 
10 
0.025 
0.556 
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Table 10. Threshold to stop enrollment if number of patients experienced pre-defined severe 
 toxicity AE reaches or exceeds 
 
 
 
 
13.2 Statistical analysis  
We will summarize response and safety event rates by sample proportions and use exact binomial 
distributions to test for a significant difference in the event rates. We will also use the Kaplan-Meier 
estimator to estimate the distribution of time to hematologic response and use the log-rank test to test 
for a significant difference in the distributions. Secondary endpoints include efficacy and safety 
endpoints measured in the maintenance phase when some patients will switch treatment arms. As 
only non-responders or those who lose response will be only allowed to switch, this is not a cross-
over trial and efficacy after switching will be separately measured and compared. Quality of life 
(QOL) measure data will be analyzed by observing changes in total scores. Different QOL test 
batteries will be used depending on the patient age and we will use standardized changes in total 
scores by the known standard deviation of the test batteries. 
Patients enrolled
# Patients with severe toxicity AE
0
5
10
15
20
25
30
35
40
45
50
2
4
6
8
10
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There will be two data analysis sets, one for per-protocol analysis and one for intent to treat analysis 
in order to account for any patients who stop treatment early. 
 
Per Protocol Analysis; 
The initial response in Induction analyses: Only patients who have completed the 2 courses of 
induction will be considered evaluable for response, for per-protocol analysis.  The Maintenance 
phase analyses:  Only patients who have completed 6 courses of therapy and finished the end of 
course 6 evaluations will be considered evaluable for response, for per-protocol analysis. 
 
Intent-to-treat analysis data set: 
All patients who received at least first 14 days of therapy (sirolimus or vincristine) will be included in 
the ITT data set.  Those who terminated earlier than 2-course induction phase will be considered non-
responders in ITT analysis.  (The non-responder patients will change over to the other treatment and 
begin maintenance in that other treatment.) 
Comparisons of early dropout rates (prior to 2 courses) will be compared between the two treatment 
arms. 
 
13.3 Accrual 
Infants to young adults up to 31 years of age with Kaposiform hemangioendothelioma or tufted 
angioma requiring systemic therapy will be eligible for this study. Children with vascular anomalies 
are usually otherwise healthy except for the presence of the vascular anomaly and any resulting organ 
dysfunction. 
 
Anticipated number of patients to be enrolled 
 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, not 
of Hispanic 
Origin 
 
Hispanic 
White, not 
of Hispanic 
Origin 
 
Other or 
Unknown 
 
Total 
 
Female 
1.6 
2.5 
4.2 
2.5 
14.2 
 
25 
 
Male 
1.6 
2.5 
4.2 
2.5 
14.2 
 
25 
 
Total 
3.2 
5 
8.4 
5 
28.4 
 
50 
  
13.4 Evaluable for Adverse Effects 
Patients will be considered evaluable for adverse effects provided they have received at least the first 
14 days of therapy (sirolimus or vincristine). 
 
13.5 Evaluable for Response 
Initial response in induction: Only patients who have completed the 2 courses of induction will be 
considered evaluable for response.   
Maintenance:  Only patients who have completed 6 courses of therapy and finished the end of course 
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6 evaluations will be considered evaluable for response. 
 
14 HUMAN SUBJECTS PROTECTION & DATA SAFETY MONITORING PLAN 
 
14.1 Sources of Material  
If not contraindicated, tissue samples from the vascular tumor will be obtained before enrollment to 
ensure correct diagnosis. Blood tests will be obtained at study entry, at specific interval during 
treatment and at times required for the best care. In addition, results of blood work, evaluations 
including radiologic imaging, and adverse advents will be recorded at the treatment center and 
reported to BCH as coordinating center in a coded fashion. The treating physician at the clinical 
center will keep a list linking codes with patient identifying information in accordance with their 
institutional IRB guidelines. The Sponsor and BCH will not have access to identifying information 
from participating institutions. 
 
14.2 Potential Risks  
The primary risk to the subjects from participation in this trial is from sirolimus and/or vincristine 
toxicity. Risk of toxicity has been correlated with serum levels of sirolimus. All participants will 
have serum levels measured regularly to guide appropriate dosing and to minimize drug toxicity. 
Vincristine toxicity will be closely monitored and dose will be adjusted as needed. Participants 
enrolled on this trial will be carefully monitored for the development of toxicities, with guidelines 
for dose modifications, discontinuation of drug, and stopping rules in place.  
 
14.3 Recruitment and Informed Consent  
Patients may be recruited from the Dermatology, Oncology, Surgery, and Vascular Anomalies clinics 
at the participating institutions. The investigational nature and objectives of this trial, the procedures, 
and treatments involved and their attendant risks and discomforts and benefits, as well as potential 
alternative therapies will be carefully explained to the patient or the patient’s parents or guardian if 
he/she is a child, and a signed informed consent document will be obtained. Consent will be obtained 
by the site PI or an associate investigator on the trial. Where deemed appropriate by the clinician and 
the child’s parents or guardian, the child will also be included in all discussions about the trial.  
Requirement for documentation of assent will be determined by the local IRB.    
 
14.4 IRB Approval and Required Documentation 
This is a multi-institutional trial; BCH will require evidence of local IRB approval of the protocol 
prior to allowing for accrual of patients at that institution. This trial will be conducted in compliance 
with the protocol, Good Clinical Practice (GCP) and the applicable regulatory requirements.   
 
14.5 Protection against Risks  
We will obtain institution review board approval at all participating sites. Patient’s risks of 
participating in research will be kept to a minimum with measures to protect confidentiality and 
planned interim analysis for safety monitoring. Confidentiality will be maximized by coding patient 
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information prior to transfer to the principle investigator. The treating physician at the clinical center 
will keep a list linking codes with patient identifying information in accordance with their 
institutional IRB guidelines. The principal investigators will not have access to identifying 
information. Best of care will be provided to patients in the event of toxicities associated with 
treatment. Parents will be provided appropriate contact number(s) for treating physicians at clinical 
sites in accordance with institutional IRB guidelines. 
 
14.6 Potential Benefits of the Proposed Research to the Subject and Others 
This is the first clinical trial to prospectively assess and compare the effectiveness and safety of two 
treatment options for patients with Kaposiform hemangioendotheliomas. There will be potential for a 
direct benefit for patients with KHE as this will determine the optimum therapy option for these 
patients. The instruments developed in this study will be beneficial for future trials for this 
population. Finally, the participating institutions will develop a working collaboration that could 
provide the framework for future clinical trials in patients with rare vascular diseases. 
 
14.7 Importance of Knowledge to be Gained  
The knowledge gained by this study will help to determine a standard treatment for patients with 
these rare tumors. Response criteria developed in this study could be utilized for future trials.  
 
14.8 Data and Safety Monitoring Plan 
The Pediatric DSMB at Boston Children’s Hospital consists of individuals with recognized expertise 
in oncology, neurology, gastroenterology, conduct of clinical trials, and biostatistics. The DSMB 
meets a minimum of twice per year.   Approximately 4 weeks before each meeting of the DSMB, the 
study chair or designee will be responsible for preparing study reports for review by the DSMB. The 
DSMB will provide recommendations to change the study or to continue the study unchanged. 
 
The trial PI and clinical coordinator will review the study progress regularly.  Patients entered on the 
trial and adverse events will be reviewed to ensure that the study is implemented as outlined in the 
protocol. Quarterly reports will be generated by BCH to assess completeness of data. There will be 
monthly phone conferences between BCH and the local Principal Investigators to address QA issues. 
 
14.9 Study Monitoring and Auditing 
This study will be monitored in accordance with the BCH Program Data Safety Monitoring Plan for 
Phase I, Pilot, and Phase II Studies.  Monitoring and auditing procedures as outlined in BCH Program 
Data Safety Monitoring Plan will be followed to ensure that the entire 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 Boston Children’s Hospital.   
 
Verification of eligibility and appropriate documentation of informed consent will be performed for 
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all subjects enrolled into the study by BCH coordinating center.  Monitoring of timeliness of Adverse 
Event and Serious Adverse Event reporting will be done as events are reported to the coordinating 
center.  Case report forms for each subject enrolled into the study will be monitored for completeness 
and quality.   
 
14.10 Privacy 
Data provided must be treated in strictest confidence. No information provided from individual 
patient’s records may be discussed with anyone other than those individuals mentioned in the 
collaborative research agreement. Data may not be released in any form except as provided in the 
agreement. 
 
14.11 Confidentiality 
Each subject enrolled will, from that point forward, be identified by a unique identifier (study subject 
number). This study subject number will also be used for any research specimens collected and 
shipped to analysts outside each study site. All records generated will be stored in a locked office 
area, only accessible to study personnel. Clinical information will be accessed, according to HIPAA 
requirements, by study personnel to complete study documents, as needed.  
  
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Sclerosis Complex or Lymphangioleiomyomatosis. N Engl J Med. 2008;358: 140-151. 
38. Marsh DJ, Trahair TN, Martin JL, et al. Rapamycin treatment for a child with germline PTEN 
mutation. Nat Clin Prac Oncol.2008;5(6):357-361. 
39. Gallo et al. 2006, Adaptive designs in clinical drug development--an Executive Summary of the 
PhRMA Working Group, Journal of Biopharmaceutical Statistics, 2006, May;16(3):275-83.  
PMID:16724485. 
40.  Hu F, Zhang LX Asymptotic properties for doubly adaptive biased coin designs of multi-
treatment clinical trials. Annals of Statistics, 2004, Vol. 32(1):268-301. 
41. Jeffrey R Eisel and Michael B. Woodroofe. Central limit theorems for doubly adaptive biased 
coin designs,  Annals of Statistics Volume 23, Number 1 (1995), 234,254. 
42.  Jelliffe RW, Schumitzky A, Bayard D, et al. Model-based, goal-oriented, individualised drug 
therapy. Linkage of population modeling, new 'multiple model' dosage design, bayesian feedback 
and individualised target goals. Clin Pharmacokinet.1998;34(1):57-77. 
43.  Marquet P. Clinical application of population pharmacokinetic methods developed for 
immunosuppressive drugs. Ther Drug Monit 2005;27(6) 727-32. 
44. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life 
Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 
2001;39(8):800-12. 
45. Cella D, Nowinski CJ. Measuring quality of life in chronic illness: the functional assessment of 
chronic illness therapy measurement system. Arch Phys Med Rehabil 2002;83(12 Suppl 2):S10-7. 
46. Cella DF, Tulsky DS, Gray G et al. The Functional Assessment of Cancer Therapy scale: 
development and validation of the general measure. J Clin Oncol 1993;11(3):570-9. 
47. Varni KW. The Varni/Thompson pediatric pain questionnaire. I. Chronic musculoskeletal pain in 
juvenile rheumatoid arthritis. Pain 1987;Jan. 28(1):27-38. 
48.  Melzack R. The short form McGill Pain Questionnaire. Pain 1987;Aug 30(2);191-197. 
49. Wassef, M., Blei, F., Adams, D., Alomari, A., Baselga, E., Berenstein, A., Burrows, P., Frieden, 
I. J., Garzon, M. C., Lopez-Gutierrez, J. C., Lord, D. J., Mitchel, S., Powell, J., Prendiville, J., 
Vikkula, M. Vascular Anomalies Classification: Recommendations From the International 
Society for the Study of Vascular Anomalies. Pediatrics. 2015 Jul 1; 136(1): e203-14. . 
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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence of disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in physically strenuous activity. 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal activity 
or do active work. 
70 
Both greater restriction of and less time spent in play 
activity. 
60 
Required occasional assistance, but is able to care 
for most of his/her needs. 
60 
Up and around, but minimal active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance and frequent 
medical care. 
50 
Gets dressed, but lies around much of the day; no active 
play, able to participate in all quiet play and activities. 
40 
Disabled, requires special care and assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization indicated.  
Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  Death not 
imminent. 
20 
Often sleeping; play entirely limited to very passive 
activities. 
10 
Moribund, fatal processes progressing rapidly. 
10 
No play; does not get out of bed. 
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APPENDIX II: LIST OF MEDICATIONS TO AVOID/ USE CAUTION WHEN 
TAKING SIROLIMUS (RAPAMUNE)- THIS TABLE IS NOT ALL INCLUSIVE 
 
• Avoid* and/or Use caution** when Using Sirolimus (Rapamune) and the following 
medications:  
• (If these medications are medically necessary please consult a pharmacist prior to 
starting) 
•  
Azole Antifungals*: 
Ketoconazole, voriconazole, 
posaconazole, fluconazole, 
itraconazole, clotrimazole 
Antibiotics*: 
Rifampin, Rifabutin, 
Erythromycin, 
telithromycin, 
clarithromycin, fusidic acid, 
troleandomycin**, 
rifapentine** 
Antiepileptics**:  
carbamazepine, 
phenobarbital, phenytoin, 
fosphenytoin, 
oxcarbazepine, 
primidone**, stiripentol** 
Protease 
inhibitors/antiretrovirals:** 
Ritonavir, indinavir, 
boceprevir, telaprevir, 
efavirenz, lopinavir, 
saquinavir, amprenavir, 
delavirdine 
Blood Pressure agents**: 
Diltiazem, verapamil, 
nicardipine, amiodarone 
Kinase Inhibitors*: 
Crizotinib, tofacitinib, 
dabrafenib 
Miscellaneous Medications*: 
Conivaptan, enzalutamide, 
mifepristone, nefazodone, 
natalizumab, pimecrolimus, 
tacrolimus, cyclosporine 
 
Use Caution**: 
Bromocriptine, Cimetidine, 
metoclopramide, danazol, 
dipyrone, leflunomide, 
lomatipide, mitotane,  
Food/herbal agents: 
Grapefruit juice* 
Echinacea** 
St. John’s Wort** 
Steroids 
Dexamethasone, 
hydrocortisone, 
prednisone, prednisolone, 
methylprednisolone 
-make sure you are aware 
patient is on both due to 
immunosuppression.   
-no drug interaction 
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APPENDIX III: STANDARD VASCULAR MRI PROTOCOL 
 
 
 
 
 
Trunk and extremities 
Localizer 
Cor T1 
Ax 2D TOF (no sat bands) 
Sag or Cor STIR 
Ax T2 FSE with fat suppression 
DWI 
Ax T1 with fat suppression pre-contrast 
Cor, Sag and Ax T1 with fat suppression post-contrast 
 
 
 
             
 
 
 
 
 
 
 
 
 
 
 
Head and Neck 
Localizer 
Sag T1 
Sag T2 FSE with fat suppression 
Ax and Cor STIR 
Ax 2D TOF (no sat bands) 
DWI  
Ax T1 with fat suppression pre-contrast 
Cor and Ax T1 with fat suppression post-contrast 
 
 
 
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APPENDIX IV: PARAMETERS FOR GRADING FUNCTIONAL IMPAIRMENTS 
 
Cardiac: 
Grade 0 
Normal 
Grade 1 
Mild asymptomatic diagnostic finding; no intervention required 
Grade 2 
Moderate asymptomatic diagnostic finding; no intervention required 
Grade 3 
Symptomatic, requiring intervention; responsive to therapy 
Grade 4 
Symptomatic, requiring intervention; not responsive to therapy;  
 
 
ventricular assist device or heart transplant indicated 
Grade 5 
Death 
 
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; infection 
Grade 4 
Life-threatening consequences; major invasive intervention indicated  
Grade 5 
Death 
 
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  
Grade 5 
Not applicable 
 
Obstruction of Visual Axis:  
Grade 0 
No obstruction of visual axis 
Grade 1 
Eyelid dysfunction Asymptomatic but not ADL; no astigmatism 
Grade 2 
Symptomatic; interfering with ADL; causing amblyopia or astigmatism 
Grade 3 
Surgical intervention indicated, amblyopia 
Grade 4 
Loss of vision 
Grade 5 
Not applicable 
 
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APPENDIX IV (continued) 
PARAMETERS FOR GRADING FUNCTIONAL IMPAIRMENTS 
Obstruction of airway: 
Obstruction of: (select one or more) 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
 
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 indicated 
Grade 3 
Interfering with ADL; stridor or endoscopic intervention indicated (e.g., stent, 
 
 
laser, surgical removal) 
Grade 4 
Life-threatening airway compromise; tracheotomy or intubation indicated 
Grade 5 
Death 
 
Hemorrhage/Bleeding From Coagulopathy of VM: 
Grade 0 
No hemorrhage/bleeding from coagulopathy of VM 
Grade 1 
Mild without transfusion  
Grade 2 
Moderate without transfusion 
Grade 3 
Transfusion indicated  
Grade 4 
Catastrophic bleeding, requiring major non-elective intervention 
Grade 5 
Death 
Thrombotic Event from Coagulopathy of VM: 
Grade 0 
No thrombotic event from coagulopathy of VM 
Grade 1 
Phleboliths present on clinical or radiographic exam but asymptomatic 
Grade 2 
Phleboliths present on clinical or radiographic exam and symptomatic 
Grade 3 
Deep/Large Venous Thrombosis without Acute decompensation 
Grade 4 
Life threatening Venous Thrombosis with Acute decompensation requiring 
 
 
intensive intervention 
Grade 5 
Death 
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  
Grade 4 
Life-threatening; disabling; operative intervention indicated to prevent or treat 
CNS necrosis 
Grade 5 
Death 
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APPENDIX IV (continued) 
PARAMETERS FOR GRADING FUNCTIONAL IMPAIRMENTS 
Liver dysfunction: 
Grade 0 
Normal 
Grade 1 
Asymptomatic  
Grade 2 
Jaundice 
Grade 3 
Asterixis  
Grade 4 
Encephalopathy  
Grade 5 
Death 
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 
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 
Grade 3 
Altered ADL secondary to symptoms: pain, fracture 
Grade 4 
Complete loss of function 
Grade 5 
Death 
Effusions caused by VA (pleural, cardiac): 
Grade 0 
No effusions caused by VA (pleural, cardiac) 
Grade 1 
Asymptomatic, radiologic findings only 
Grade 2 
Symptomatic, but not requiring immediate intervention 
Grade 3 
Requiring intervention, fluid removal,  
Grade 4 
Requiring ventilation or more aggressive surgical support 
Grade 5 
Death 
 
Lymphedema caused by VA: 
Grade 0 
No lymphedema caused by VA 
Grade 1 
Pitting with application of pressure, edema improvement with elevation 
Grade 2 
Increased circumference, no longer pits with pressure 
Grade 3 
Worsened swelling with skin changes 
Grade 4 
Skin breakdown with or without infection 
 
AVM Progression: 
Grade 0 
No AVM progression 
Grade 1 
Cutaneous blue stain, warm, shunting on Doppler 
Grade 2 
Enlargement, pulsation, thrill, bruit 
Grade 3 
Skin changes: ulceration, bleeding, pain 
Grade 4 
Cardiac failure 
Grade 5 
Death 
 
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APPENDIX IV (continued) 
PARAMETERS FOR GRADING FUNCTIONAL IMPAIRMENTS 
 
Grading System for Kaposiform Hemangioendotheliomas (KHE)/Tufted Angiomas (TA) 
and Kasabach Merritt Syndrome (KMP): 
Grade 0 
KHE/TA without KMP 
Grade 1 
KHE/TA with KMP without bleeding or blood product support 
Grade 2 
KHE/TA with KMP (thrombocytopenia, hypofibrinogenemia) with no active 
 
 
bleeding or DIC, but receiving blood product support 
Grade 3 
KHE/TA with KMP with DIC active bleeding 
Grade 4 
KHE/TA with KMP/DIC/bleeding requiring aggressive medical care 
(mechanical   
ventilation, pressor support) 
Grade 5 
Death 
 
Grading of Hematological Support of KHE/TA with KMP: 
Grade 0 
KHE/TA without KMP 
Grade 1 
No Blood product support 
Grade 2 
One of the following hematological supports: PRBC, platelets, fibrinogen 
(cryoprecipitate) 
Grade 3 
Two of the following hematological supports: PRBC, platelets, fibrinogen 
(cryoprecipitate) 
Grade 4 
All three of the following hematological supports: PRBC, platelets, fibrinogen 
(cryoprecipitate) 
Grade 5 
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 for KHE/TA with KMP: 
Grade 0 
KHE/TA with normal platelet count 
Grade 1 
plat > 40,000 above initial count 
Grade 2 
plat > 20,000 above initial count 
Grade 3 
Thrombocytopenia without bleeding 
Grade 4 
Thrombocytopenia with bleeding 
Grading of Fibrinogen for KHE/TA with KMP: 
Grade 0 
KHE/TA with normal fibrinogen 
Grade 1 
Fibrinogen > 40 above initial count 
Grade 2 
Fibrinogen > 20 above initial count 
Grade 3 
Hypofibrinogenemia without bleeding 
Grade 4 
Hypofibrinogenemia with bleeding 
 
 
ADL = Activities of Daily Life 
KMP = Kasabach-Merritt Phenomenon 
VA = Vascular Anomalies (vascular tumors and vascular malformations) 
VM = Vascular Malformations 
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APPENDIX V: QOL INSTRUMENTS 
 
Pediatric QOL Measures 
Pediatric Quality of Life Inventory (PedsQL; Varni, 2001), 0-18 years:  The PedsQL 4.0 
Generic Core Scales are multidimensional child self-report and parent proxy-report scales to 
assess health-related quality of life (QOL) in children and adolescents ages 2 – 18 years. It is 
brief standardized pediatric QOL scale with good reliability and validity, which includes both 
generic and disease specific modules. It takes approximately 5 - 10 minutes to complete and 
consists of a 23-item core measure of global QOL that has four subscales:  physical functioning, 
emotional functioning, social functioning, and school functioning. There are different forms for 
parents of children ages 0 – 18 years (infant 0 - 12 months; infant 13 - 24 months; toddler: 2 – 
4; young child: 5 – 7; child: 8 – 12; adolescent:  13 – 18) and parallel self-report forms for ages 
5 – 18 years (young child: 5 – 7; child: 8 – 12; adolescent: 13 – 18).   
 
Adult QOL Measures 
Functional Assessment of Chronic Illness Therapy (FACIT; Cella et al., 2002, 19-31 years):  
Adult self-report generic and disease-specific health-related QOL scales that consist of an 
assessment of general health status, the Functional Assessment of Cancer Therapy-General 
(FACT-G), and different subscales to assess disease specific issues of both cancer and non-
cancer illnesses as well as specific symptoms. The 4 generic core subscales of the 27-item 
FACT-G are 1) physical well-being, 2) emotional well-being, 3) social well-being, and 4) 
functional well-being. The FACT-G is a brief, reliable, and valid QOL measure, which is 
sensitive to clinical change (Cella et al, 1993) and has been used with patients with cancer and a 
variety of other chronic illnesses (Cella et al, 2001). The response format is a 5-point likert 
scale. It will be administered to individuals 18 years and older and takes about 5 – 10 minutes to 
complete.  
 
Pediatric Pain Measure 
Peds QL Pediatric Pain Questionnaire (Varni et al., 1987):  A pediatric pain scale designed so 
that parents and children from 5 – 18 years of age can independently assess the intensity of 
children’s present pain and their worst pain in the past week. It consists of a visual analogue 
scale (VAS) with a happy face on one end of the line and a sad face on the other end. The child 
(or parent) is instructed to put a mark on the line that indicates how much pain the child is 
feeling. In addition, there is a drawing of a child and the child is asked to color where on the 
body the pain is. The VAS measure has been shown to be reliable and valid of pain perception 
in pediatrics. Higher scores indicate greater pain intensity. This scale takes approximately 5–10 
minutes to complete.   
 
Adult Pain Measure 
The short-form McGill Pain - 2 Questionnaire (SF-MPQ-2) (Dworkin, RH, 2009):  A revised 
self-report form of the original short form McGill Pain Questionnaire (SF-MPQ) that consists of 
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22 descriptors divided into 4 subscales.  Three of these subscales consist of sensory descriptors 
and one consists of the original four SF-MPQ affective descriptors, as follows: (1) continuous 
pain descriptors (6 items): “throbbing pain”, “cramping pain”, “gnawing pain”, “aching pain”, 
“heavy pain”, and “tender”; (2) intermittent pain descriptors (6 items): ‘‘shooting pain”, 
‘‘stabbing pain”, ‘‘sharp pain”, ‘‘splitting pain,” ‘‘electric-shock pain”, and ‘‘piercing”; 
(3)predominantly neuropathic pain descriptors (6 items): ‘‘hot-burning pain”, ‘‘cold-freezing 
pain”, ‘‘pain caused by light touch”, ‘‘itching”, ‘‘tingling or ‘pins and needles,’”, and 
‘‘numbness”; and (4) affective descriptors (4 items): ‘‘tiring-exhausting”, ‘‘sickening”, 
‘‘fearful”, and ‘‘punishing-cruel” 
 
The FLACC will also be used for subjects unable to complete the age appropriate pain 
questionnaire. 
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APPENDIX VI 
 INVESTIGATOR’S SIGNATURE 
Study Title:  
A Randomized Phase 2 Study of Vincristine versus Sirolimus 
to treat High Risk Kaposiform Hemangioendothelioma 
(KHE) 
Study Number:  
SIR-DA-1202 
Protocol Version:  
Version 6: 01/31/2018 
 
 
I have read the protocol and agree that it contains all the details necessary for carrying out this 
study, and I will conduct the study as described herein.  
 
 
Investigator’s Signature:   
 
 
 
 
 
 
 
 
    
 
Investigator (Printed name):    
 
 
 
 
 
 
  
 
Date:    
 
 
 
 
 
 
 
 
 
 
  
 
Institution:   
 
 
 
 
 
 
 
 
 
 
  
 
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