Conditions: Desmoid Tumor
Keywords: Desmoid Tumor Sirolimus Surgically-Resectable Desmoid Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
Desmoid-type fibromatosis (or desmoid tumor) represents an intermediate grade neoplasm with a striking predilection for locally invasive growth and recurrence following resection. It occurs in children as well as young adults. As a typically localized disease, the historical standard of care for treatment has been surgical resection, with or without ionizing radiation. In some cases where surgical resection or radiation is not feasible, chemotherapy has been used. Two clinical trials conducted in the Pediatric Oncology Group (POG) and the Children's Oncology Group (COG) evaluated the role for either low intensity or non-cytotoxic chemotherapy for children with desmoid tumor that is not amenable to standard therapy. These were largely empirical treatment strategies or based on somewhat anecdotal observations. By better understanding desmoid tumor biology, even more effective therapy targeting a particular protein that is central to the disease can be developed.

Desmoid tumor is well-known to be associated with deregulation of the Adenomatous Polyposis Cell/beta-catenin (APC/β-catenin pathway). This is true of familial cases associated with Gardner's Syndrome and also in sporadic desmoid tumor, nearly all of which display histological or molecular evidence of Adenomatous Polyposis Cell/beta-catenin (APC β-catenin) pathway activation (Alman et al., 1997; Lips et al., 2009). Several new pieces of evidence support the concept that deregulation of the mammalian target of rapamycin (mTOR) cell proliferation/survival pathway may play an important role in tumor biology when the APC/β-catenin pathway is disrupted. Sirolimus, a drug that inhibits mammalian target of rapamycin (mTOR), is currently being evaluated as an anti-cancer agent in a variety of tumor types, but it has not been previously studied in desmoid tumor.

The investigators are conducting this pilot study to begin to explore whether mTOR inhibition may be beneficial for children and young adults with desmoid tumor.

Detailed description:
We propose a translational research project that will directly test the hypothesis that mTOR is active in desmoid tumor in children and young adults. Activity will be assessed by clinical and histological studies following a course of pre-operative chemotherapy using sirolimus. Clinical response will be measured using validated pain assessment scales because desmoid tumor size is unlikely to change during the course of pre-operative chemotherapy in this study. Histological response will be based on quantifying the phosphorylation of following mTOR targets: thr389p-p70S6K, p-4E-BP1, and ser473p-AKT.

Arms:
arm 1: Preoperative sirolimus:

* loading dose of 12 milligrams/meter2; Per Os (PO), by mouth day 1 (Max dose 12 milligram)
* starting 24 hours after the initial loading dose, subjects will receive a dose of 4 milligram/meters2 daily; Per Os (PO), by mouth days 2 through 28

Interventions: intervention 1: Sirolimus
Intervention descriptions: intervention 1: * Loading dose of 12 milligrams/meter2; Per Os (PO), by mouth day 1 (Max dose 12 milligrams)
* Starting 24 hours after the initial loading dose, patients will receive a dose of 4 milligrams/meter2 daily; Per Os (PO), by mouth days 2 through 28 (Max dose 4 milligram/day)

Protocol document:
Prot_SAP_000.pdf: 
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Amendment No. 9 
 
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A PILOT STUDY EVALUATING THE USE OF THE mTOR INHIBITOR SIROLIMUS IN 
CHILDREN AND YOUNG ADULTS WITH DESMOID-TYPE FIBROMATOSIS.  
 
Co-Principal Investigators: 
Aaron Weiss, DO 
Maine Children’s Cancer Program 
100 Campus Drive, Unit 107 
Scarborough, ME 04074 
Phone:207.396.7565   Fax: 207.396.7577 
Email : weissa2@mmc.org 
 
 
Noah Federman, MD 
David Geffen School of Medicine at UCLA 
Pediatric Hematology/Oncology, MDCC A2-410, 
10833 Le Conte Avenue, Los Angeles, CA     
90095 
Phone: 310.825.6708   Fax: 310.206.8089 
Email: nfederman@mednet.ucla.edu 
 
 
 
 
 
 
 
Research Coordinator: 
Kathleen M. Glick, CCRP 
Coordinator of Clinical Research 
Maine Children's Cancer Program 
100 Campus Drive 
Scarborough, ME 04074 
Phone: 207.396.7565     Fax: 207.396.7577 
Email: glickk@mmc.org 
  
 
 
 


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TABLE OF CONTENTS 
 
Overview 
 
 
 
 
 
 
 
 
 
 3  
Objectives 
 
 
 
 
 
 
 
 
 
 3 
Background 
 
 
 
 
 
 
 
 
 
 3 
Subject Recruitment  
 
 
 
 
 
 
 
 9 
Eligibility 
 
 
 
 
 
 
 
 
 
 9 
Registration Procedures 
 
 
 
 
 
 
 
11 
Required Observations 
 
 
 
 
 
 
 
11 
Treatment Plan 
 
 
 
 
 
 
 
 
14 
Drug Administration Guidelines 
 
 
 
 
 
 
14 
Dose Modifications for Toxicity 
 
 
 
 
 
 
15 
Agent Information 
 
 
 
 
 
 
 
 
15 
Criteria for Removal from Protocol Therapy and Off Study Criteria  
 
19 
Pathology Guidelines  
 
 
 
 
 
 
 
19 
Response Criteria 
 
 
 
 
 
 
 
 
21 
Risks and Benefits 
 
 
 
 
 
 
 
 
21 
Informed Consent Procedure  
 
 
 
 
 
 
22 
Subject Confidentiality 
 
 
 
 
 
 
 
22 
Adverse Event and Data Reporting  
 
 
 
 
 
22 
Statistical Analysis 
 
 
 
 
 
 
 
 
25 
References 
 
 
 
 
 
 
 
 
 
27 
Appendix 1 – Pain Scales 
 
 
 
 
 
 
 
31 
 
 
 
IND 116947 – Exempt IND for Sirolimus, Rapamycin and Rapamune 
Clinical Trials.gov Identifier:  NCT01265030 


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OVERVIEW 
 
Desmoid-type fibromatosis (or desmoid tumor) represents an intermediate grade neoplasm with 
a striking predilection for locally invasive growth and recurrence following resection.  It occurs in 
children as well as young adults.  As a typically localized disease, the historical standard of care 
for treatment has been surgical resection, with or without ionizing radiation.  In some cases 
where surgical resection or radiation is not feasible, chemotherapy has been used.  Two clinical 
trials conducted in the Pediatric Oncology Group (POG) and the Children’s Oncology Group 
(COG) evaluated the role for either low intensity or non-cytotoxic chemotherapy for children with 
desmoid tumor that is not amenable to standard therapy.  These were largely empirical 
treatment strategies or based on somewhat anecdotal observations.  By better understanding 
desmoid tumor biology, even more effective therapy targeting a particular protein that is central 
to the disease can be developed.   
 
Desmoid tumor is well-known to be associated with deregulation of the APC/β-catenin pathway. 
This is true of familial cases associated with Gardner’s Syndrome and also in sporadic desmoid 
tumor, nearly all of which display histological or molecular evidence of APC/β-catenin pathway 
activation (Alman et al., 1997; Lips et al., 2009).  Several new pieces of evidence support the 
concept that deregulation of the mTOR cell proliferation/survival pathway may play an important 
role in tumor biology when the APC/β-catenin pathway is disrupted.  Sirolimus, a drug that 
inhibits mTOR, is currently being evaluated as an anti-cancer agent in a variety of tumor types, 
but it has not been previously studied in desmoid tumor.   
 
We are conducting this pilot study to begin to explore whether mTOR inhibition may be 
beneficial for children and young adults with desmoid tumor.   
 
OBJECTIVES 
  
Primary  
 
1. To determine whether mTOR pathway activation decreases in patients with surgically-
resectable desmoid tumor that is removed following pre-operative treatment with 
sirolimus. 
 
Secondary 
 
1. To assess whether sirolimus improves desmoid tumor-associated pain. 
2. To begin to explore whether pre-operative sirolimus decreases tumor recurrence 
following surgical removal of desmoid tumor felt to be at high-risk for recurrence 
because of size and/or anatomic site. 
3. To assess the safety and tolerability of pre-operative sirolimus in patients with desmoid 
tumor. 
 
BACKGROUND 
 
Past experience using chemotherapy for desmoid tumor 
 
Effective treatment of desmoid-type fibromatosis (desmoid tumor) poses two major clinical 
problems.  One major problem is how to best control disease that cannot be resected or treated 
with radiation, both of which represent the historical standards of care for adults with desmoid 
tumor.  Interestingly, though, radiation therapy may be less effective for children with this 


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disease (Merchant et al., 2000).    Further, the high doses of radiation that are required can 
make its use problematic for disease at certain anatomic sites and in children.    
 
A second problem relates to preventing disease recurrence in those patients with resectable 
disease.   Recurrence rates are highly variable and depend largely on whether the tumor has 
been completely excised.  For example, Faulkner and colleagues show a 75% recurrence rate 
in a series of 63 pediatric patients (Faulkner et al., 1995); however, recurrence-free survival 
after three years approximates 70% and 10% in patients with negative margins and positive 
margins, respectively.    Some pre-operative predictors of recurrence risk have been proposed.  
For example, two retrospective series indicate that chance of getting a complete resection is 
smaller in those with tumor > 5 cm (Rao et al., 1987; Meazza et al., 2010); however, tumor size 
alone was not predictive of outcome in other series (Faulkner et al., 1995; Merchant et al., 
1999). Ballo and colleagues found that, in addition to positive surgical margins, age < 30 years 
was associated with significantly more relapse (Ballo et al., 1999); recurrence tended to be 
greater in those with extremity desmoid tumor and those with more than one prior treatment, but 
this did not reach statistical significance. Post-operative radiation decreases the recurrence risk 
(Ballo et al., 1999) but, as noted above, its use may be constrained by certain anatomic sites, 
especially in children where skeletal and muscle growth and development are added concerns.   
 
Some effort has been devoted to attempting to use systemic chemotherapy to ameliorate these 
problems.  Much of what is known about chemotherapy in patients with desmoid-type 
fibromatosis stems from small, single institution, retrospective analyses.  Cytotoxic agents 
demonstrated to have some activity include vincristine/actinomycin/cyclophosphamide (Raney 
et al., 1987), liposomal doxorubicin (Wehl et al., 2004), continuous infusion doxorubicin/DTIC 
(with or without meloxicam) (Constantinidou et al., 2009; Gega et al., 2006), hydroxyurea 
(personal communication, R. Womer, U. Penn), and vinblastine/methotrexate (Skapek et al., 
2007; Azzarelli et al., 2001; Weiss and Lackman, 1989).  Response rates range from 36-80%.    
“Targeted drugs” such as imatinib (Heinrich et al., 2006; Mace et al., 2002) and sunitinib 
(Skubitz et al., 2009), have also been used in small series.  Lastly, “non-cytotoxic” agents with 
some activity include tamoxifen (with or without a variety of non-steroidal anti-inflammatory 
drugs) (Hansmann et al., 2003) and non-steroidal anti-inflammatory drugs as single 
agents(Klein et al., 1987) (Janinis et al., 2003).   
 
In an effort to better understand chemotherapy effectiveness for children with desmoid-type 
fibromatosis, two consecutive, prospective, multi-institutional clinical trials were completed in 
children with desmoid tumor that was either recurrent or not amenable to surgical resection or 
radiation.   The first, conducted within the Pediatric Oncology Group (POG Study 9650), 
investigated the efficacy and safety of vinblastine and methotrexate (Skapek et al., 2007).  
Benefit was evidenced by disease stabilization or regression in approximately two thirds of 
children enrolled on the study.  The 1 year progression-free survival was 58%.  Toxicity was 
significant with 66% of subjects experiencing grade 3 or 4 toxicity.  The second study, 
conducted within the Children’s Oncology Group (COG study ARST0321) tested the efficacy of 
high-dose tamoxifen and sulindac in a similar population.  This study completed accrual in May 
2009; a preliminary report from the COG Data Safety and Monitoring Committee indicates that 
the failure-free survival with tamoxifen and sulindac will not be better that that achieved with 
vinblastine and methotrexate (unpublished data from COG Statistics and Data Center).  
Toxicities, although different from POG9650, were not insignificant. 
 


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Given the less-than-ideal success of these chemotherapy approaches, there is a need to 
evaluate other drugs that may be more effective and better tolerated.  The current pilot study 
differs from these prior chemotherapy studies in children because it is focused on using pre-
operative chemotherapy.  This will offer a window to judge chemotherapy efficacy, based on 
improved symptoms of pain which commonly precede objective decreases in tumor size [for 
example, (Weiss and Lackman, 1989)].  Conceptually, 
pre-operative chemotherapy may decrease the chance 
for tumor recurrence following surgery and, if there is 
evidence for efficacy, it can be continued following 
surgery.  Beyond this potential benefit, the primary 
objective is to gain evidence of response to sirolimus 
by using well-described, histochemical studies that 
correlate with blockade of the mTOR pathway by 
sirolimus and similar drugs.  The strategy will provide 
concrete evidence as to whether the drug effectively 
“hits” its target in children and young adults with the 
disease following a relatively short treatment.   
 
mTOR as a potential therapeutic target 
 
Several independent lines of evidence suggest that the 
mTOR kinase may represent an important therapeutic 
target in this disease.  mTOR forms two separate 
complexes with additional proteins to influence a variety of cellular pathways (Ballou and Lin, 
2008).  First, it physically interacts with RAPTOR to form the mTORC1 complex, which fosters 
cell growth, proliferation, motility, and angiogenesis.  mTOR also interacts with RICTOR to form 
the mTORC2 complex; TORC2 phosphorylates AKT to control cytoskeleton organization (Figure 
1).    The mTORC1 complex appears to be the most critical pathway for tumorigenesis.  The 
mTOR kinase has been established to have a range of tumorigenic effects in human cancer 
(Bjornsti and Houghton, 2004).   
 
Support for the role that mTOR may play in desmoid tumor comes, in part, from pre-clinical 
studies in a mouse model of Gardner’s Syndrome/FAP (Fujishita et al., 2008).  This is 
potentially relevant because nearly all desmoid tumor specimens show evidence for APC gene 
mutation or deregulation of its down-stream effector, β-catenin (Alman et al., 1997; Lips et al., 
2009; Miyoshi et al., 1998).  Mice bearing a germ-line mutant Apc∆716 allele develop intestinal 
polyps (Oshima et al., 1995).  It was recently shown that mTOR expression and mTORC1 
activity are increased in these intestinal polyps (Fujishita et al., 2008).   The functional 
importance of mTORC1 comes from the finding that RAD001 (everolimus), an mTOR inhibitor, 
(a) suppresses mTORC1 expression,  (b) inhibits adenoma cell proliferation, (c) decreases the 
number and size of intestinal polyps, (d) impedes tumor angiogenesis, and (e) prolongs animal 
survival.  The treatment effects were limited to the polyps and vascular epithelial cells while 
sparing the adjacent normal intestinal mucosa.  Further, knockdown of β-catenin using siRNA 
similarly decreased mTOR expression (Fujishita et al., 2008).   
 
Figure 1: Schematic diagram depicting mTOR 
pathway.  Arrows denote proteins that will be 
evaluated as part of this study (see below). 


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Numerous studies have used immunohistochemical (IHC) staining 
to assess mTOR pathway activation with phospho-specific 
antibodies against AKT, S6K, and eIF4E-BP1 [for example, 
(Chung et al., 2009; Baba et al., 2009)]. To our knowledge, this 
has not been addressed in desmoid tumor.   We have explored 
this using a single archived desmoid tumor specimen, and 
showed that both AKT and S6 kinase are phosphorylated in the 
tumor cells (Figure 2).   
 
Lastly, a recent case report provides what appears to be the first 
published evidence of mTOR inhibition in desmoid tumor.  In this 
case, a 7 year old male with tuberous sclerosis and a recurrent 
chest wall desmoid tumor was treated using sirolimus (Pressey et 
al., 2010).  The tumor size decreased from 5.63 to 4.05 cm and 
developed septations suggestive of tumor necrosis.  The 
response was maintained for 22 months.   
 
These preliminary pre-clinical, translational, and clinical findings 
support the notion that mTOR may control tumorigenic aspects of 
desmoid tumor and represent a rational target.  
 
Previous clinical experience with sirolimus and related drugs in 
cancer 
 
Three mTOR inhibitors are available for use in the clinic: sirolimus (Rapamune®, Rapamycin), 
temsirolimus (Torisel®, CCI-779), and everolimus (Afinitor®, RAD001).  mTOR inhibition in 
cancer has included a number of phase I and phase II studies.  Anti-tumor activity of mTOR 
inhibitors has been observed in adult patients in a range of cancers [for example, (Witzig et al., 
2005; Amato et al., 2008; Mita et al., 2008)].  Pre-clinical findings and results emerging from 
clinical trials supports the use of mTOR inhibitors in  sarcoma as well (Wan and Helman, 2007).  
This may be particularly relevant because desmoid tumors are of mesenchymal origin and 
share biological properties with sarcoma subtypes.   
 
For the most part, mTOR inhibitors have tolerable side effects:  The sarcoma study by Chawla 
and colleagues revealed minimal Grade 3 or 4 adverse drug reactions.  The most common 
toxicities were Grade 1 and 2 toxicities: mucositis, rash, hypertriglyceridemia, and fatigue.  
Everolimus was studied in a group of 92 patients with advanced solid tumors (O'Donnell et al., 
2008).  Partial responses were seen in 4 patients while 12 patients experienced prolonged 
disease stabilization.  The most common non-hematologic adverse drug events involved 
mucositis, rash, and fatigue.  Grade 3 and 4 toxicities were infrequent.    
 
Because mTOR inhibitors are thought to act, in part, by interfering with angiogenesis, there is a 
theoretical concern that they may also interfere with surgical wound healing.  While there are no 
published data about the use of sirolimus in this specific setting, there are limited publications 
discussing the risk of sirolimus in the peri-operative time frame in other disease types 
(Kuppahally et al., 2006; Tiong et al., 2009; Goldberg et al., 2014; Schwarz et al., 2014; Heble 
et al., 2018).  In most of these studies sirolimus was used de novo following surgery.  Although 
the incidence of surgical wound complications was low in the few studies reviewing the risk 
when sirolimus was used pre-operatively (Schwarz et al., 2014; Heble et al., 2018), as in this 
study,  we will carefully monitor surgical complications and wound healing and terminate the 
study, should a significant number of surgical complications be observed.   
 
Figure 2: Representative IHC 
staining for indicated proteins in a 
desmoid tumor. No staining 
observed in negative control done in 
parallel (negative data not shown).   


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Preclinical use of sirolimus in pediatric cancer  
Initial testing of sirolimus by the Pediatric Preclinical Testing Program demonstrated broad 
antitumor activity.  Sirolimus induced 50% or greater growth inhibition in 10 of 23 cell lines 
(Houghton et al., 2008).  Against in vivo panels, sirolimus induced significant differences in 
event free survival in 27 of 36 (75%) solid tumor xenografts when compared to controls.  Tumor 
regression was observed in several solid tumor models, most notably, rhabdoid tumor, 
rhabdomyosarcoma, and osteosarcoma.   
 
mTOR inhibitor use in children 
 
Each of the above-mentioned mTOR inhibitors has completed Phase I testing in children.   
 
A Phase I study of everolimus in pediatric patients with refractory solid tumors demonstrated 
prolonged disease stabilization in patients with osteosarcoma and peripheral PNET (Fouladi et 
al., 2007).   Everolimus was found to be well tolerated in children with dose limiting toxicity 
associated with diarrhea (n=1), mucositis (n=1), and elevation in ALT (n=1).  
 
Sirolimus has been routinely used as an immunosuppressive drug after solid organ transplant 
and to control graft-versus-host disease following hematopoietic stem cell transplant in children 
(Campistol et al., 2009; Buhaescu et al., 2006).  In these contexts, doses range from 2 to 5 
mg/m2/day, which result in trough levels from 5 to 20 mg/mL.   
 
The standard sirolimus dose in adults is a 12 mg PO loading dose and 4 mg PO daily.  
Sirolimus has also been used in a Phase I study conducted at The Children’s Hospital of 
Philadelphia in pediatric patients with acute leukemia in the second or subsequent relapse 
(personal communication: S. Rheingold, Children’s Hospital of Philadelphia and 2007 American 
Society of Hematology abstract).   No dose-limiting toxicities were observed at the first two dose 
levels (loading dose: 9 mg/m2, subsequent daily dose: 3 mg/m2; and loading dose: 12 mg/m2, 
subsequent daily dose: 4 mg/m2).  Trough levels ranged from 7 to 9 and 10 to 11 ng/ml at the 
first and second dose level, respectively. 
 
Because obvious differences in efficacy of the three available mTOR inhibitors do not exist 
(Wan and Helman, 2007), sirolimus will be used in this study. 
 
Pain as a Surrogate Marker of Response in Desmoid Tumor 
 
Desmoid tumor represents a heterogeneous disease and can have an unpredictable clinical 
course, particular related to growth rate (De, I et al., 2000; de et al., 2009).  Often, the slow 
growth and slow response of desmoid tumor precludes the use of previously established 
standardized radiographic measurements of response, such as the Response Evaluation 
Criteria in Solid Tumors (RECIST).  This is particularly true in shorter treatment schedules such 
as the one proposed in this pilot study.   Therefore, other surrogate markers of response are 
needed.          
 
Burris and colleagues were one of the first groups to look at pain as a measure of ‘clinical 
benefit’ within the context of a therapeutic cancer study (Burris, III et al., 1997).  Clinical benefit 
was a composite assessment of pain, performance status, and weight.  Clinical benefit was 
measured prospectively as a primary endpoint of the study.  Patients with advanced pancreatic 
cancer were randomized to receive gemcitabine or 5-fluorouracil (5-FU).  The designation for 
pain integrated both the subjective report of pain intensity as well as analgesic consumption.  


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Pain intensity was measured daily on the Memorial Pain Assessment Card (MPAC) 0-100 visual 
analog scale, and a positive response was associated with an improvement of ≥ 50% from 
baseline sustained for ≥ 4 weeks. Analgesic consumption was measured weekly in morphine-
equivalent milligrams, and a positive response was indicated by a decrease of ≥ 50% from 
baseline, sustained for ≥ 4 weeks).  Clinical benefit was experienced by 24% of gemcitabine-
treated patients compared with 5% of 5-FU treated patients.   
  
Recently, Ohorodnyk and co-authors performed a literature search for reports of all clinical trials 
(phase I, II, and III) published in the Journal of Clinical Oncology from 1997-2008 citing ‘clinical 
benefit’ (Ohorodnyk et al., 2009).  Eligible trials were those reporting clinical benefit as an 
endpoint.  Clinical benefit was classified as patient-centered if it referred to improvement in the 
clinical parameters used by Burris and colleagues or in other disease-related symptoms.  71 
trials reporting clinical benefit were identified: 37 in breast, 8 in pancreas and 26 in other 
cancers.  Among the 71 trials reporting clinical benefit, 31 (44%) trials had that endpoint defined 
as a primary or secondary study objective.  Of note, the authors found a steady increase in the 
number of trials using clinical benefit as an endpoint; in the second half of the study period the 
number of trials increased from 17 to 54.  
 
The locally invasive nature of desmoid tumor frequently results in significant pain (Hosalkar et 
al., 2006).   Improvement in pain for patients undergoing treatment for desmoid tumor has been 
described in a few previous studies.  Constantinidou et al demonstrated improvement in pain 
with the use of pegylated liposome doxorubicin (PLD) (Constantinidou et al., 2009).  Eleven of 
12 patients with desmoid tumor treated with PLD had clinical benefit in terms of pain relief or 
improved mobility and cosmesis.  Skubitz and colleagues noted improved pain in a sunitinib-
treated patient with recurrent desmoid tumor (Skubitz et al., 2009).  The pain improved and 
resolved by 28 days of treatment.  A reduction in tumor size was noted after 5 months of 
therapy.  Neither study mentioned the specific pain assessment tool utilized. 
 
To our knowledge, no pediatric study has used pain as a primary or secondary endpoint in 
cancer treatment.  Because of pain often associated with desmoid tumor and the slow changes 
in tumor size, we will use pain assessment as a surrogate marker of response in this study.  
Validated pain assessment scales, depending on the age of the patient, have been established 
for our patient population (Bijur et al., 2003; Hain, 1997; von Baeyer, 2006).  For this pilot study, 
the Wong-Baker FACES scale will be used for patients ≥ 3 and < 10 years of age and the 
numeric scale will be used for patients who are 10 years of age or older.  
 
Summary of trial design 
   
Our overall goal is to conduct a pilot study to begin to assess whether a four week course of 
sirolimus, given prior to planned surgery, can decrease evidence of mTOR activity, decrease 
tumor associated pain, and decrease tumor recurrence.   The target patient population will be 
patients < age 30 years at the time of original diagnosis in whom surgery is planned to remove 
the desmoid tumor and either (a) the desmoid tumor has already recurred after a prior surgery 
or (b) the newly diagnosed and/or previously unresected disease is judged to be at high risk for 
recurrence due to its size (> 5cm) or location at an anatomic site making it unlikely to be 
resected with negative margins (e.g., adjacent to neurovascular structures).   
 
A total of 15 subjects will be enrolled in the trial.  The primary endpoint will be achieved by 
performing immunohistochemical studies for mTOR pathway activation on the resected tumor 
samples.   Immunostaining results will be compared to a cohort of previously untreated, 


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archived specimens (n=50), and also by paired comparison with pre-treatment tumor or biopsy 
specimens if available. 
 
The secondary endpoints will be accomplished using validated pain assessment scales at 
weekly intervals and routine, post-operative surveillance imaging.   
This clinical trial is an IND exempt study. Maine Medical Center (MMC)/Maine Children’s Cancer 
Program (MCCP) will be the coordinating center for this multi-site trial.  As the coordinating 
center we will ensure that IRB documentation is in place at each of the participating sites.  
Participating sites will submit to Dr. Weiss at MMC/MCCP local reportable adverse events, 
protocol deviations, and any reportable new information as well as require each local site to 
submit this to their IRB per local policy 
  
 
SUBJECT RECRUITMENT 
 
Subjects will be identified upon diagnosis by attending orthopedic surgeons, general surgeons 
or oncology physicians at the participating enrolling institution. Disease evaluation and routine 
tests will take place at these sites.  In some instances, laboratory tests may be collected either 
by local clinics and results will be faxed to the attending physician.  Subjects will not be paid for 
participation on this protocol.  In addition, all tests and study drugs that are considered standard 
of care will be charged to the patient or their insurer.   
 
ELIGIBILITY 
 
Inclusion criteria 
 
Must be less than 30 years of age at the time of original diagnosis. 
 
Must have biopsy-proven desmoid tumor (or aggressive fibromatosis).  For patients with 
recurrent disease, a biopsy is not required at the time of recurrence.   
 
Patients known to have germ-line APC mutations or clinical manifestations of FAP/Gardner’s 
syndrome can be included. 
 
Patients must have surgery planned to remove the desmoid tumor and either: 
a) The desmoid tumor has already recurred after a prior surgery or 
b) The newly diagnosed and/or previously unresected disease is judged 
to be at high risk for recurrence due to its size (> 5 cm) or location at 
an anatomic site making it unlikely to be resected with negative 
margins (e.g., adjacent to neurovascular structures) 
 
There must be a commitment by the surgical team to resect the primary tumor within 3 days 
following the 4 weeks of sirolimus unless the clinical situation at the time of resection 
suggests that these interventions are not in the patient’s best interest. 
 
Concomitant medication restrictions: 
a) Patients may have received prior chemotherapy (excluding prior 
mTOR inhibitors). 
b) Use of steroids for non-tumor indications (e.g., asthma or severe 
allergic reaction) is permitted. 
 
Patients must have a Karnofsky performance status ≥ 50 for patients > 16 years of age or 
Lansky performance status ≥ 50 for patients 16 years of age. 
 
Patients must have a life expectancy ≥ 8 weeks. 
 
Patients must have recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study. 
a) Myelosuppressive chemotherapy: Must not have received within 2 
weeks of entry onto this study (4 weeks if prior nitrosourea). 


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b) Biologic (anti-neoplastic agent): At least 7 days since the completion 
of therapy with a biological agent. 
c) Stem Cell Transplant (SCT):  No evidence of active graft vs. host 
disease.  For allogeneic SCT, ≥ 6 months must have elapsed. 
 
Patients must be able to consume oral medication in the form of tablets or solution. 
 
Patients must have normal laboratory values as defined below:  
 
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2 or 
 
- A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum Creatinine (mg/dL) 
 
        Male                    Female 
1 month to < 6 months 
          0.4                          0.4 
6 months to < 1 year 
          0.5                          0.5 
1 to < 2 years 
          0.6                          0.6 
2 to < 6 years 
          0.8                          0.8 
6 to < 10 years 
          1                             1 
10 to < 13 years 
         1.2                          1.2 
13 to < 16 years 
         1.5                          1.4 
≥ 16 years 
         1.7                          1.4 
 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data 
published by the CDC. 
 
 
Hepatic 
 
Adequate liver function defined as: 
- 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and 
- 
SGPT (ALT) ≤ 2.5 x upper limit of normal (ULN) for age. 
 
 
Hematologic function 
 
Adequate bone marrow function defined as: 
- 
ANC ≥ 1 × 109/L 
- 
Hemoglobin  ≥ 10g/dL 
- 
Platelet count ≥ 100 × 109/L 
 
 
Female patients must have a negative pregnancy test. 
 
Female patients who are lactating must agree to stop breast-feeding. 
 
Sexually active patients of childbearing potential must agree to use effective contraception. 
 
Patients must be able to cooperate fully with all planned protocol therapy. 
 
Signed informed consent MUST be obtained from patient or parent/legal guardian (if patient 
is <18 yrs of age).  Consent must be obtained prior to any study procedures and study entry. 
 
Exclusion criteria 
 
Patients with other fibroblastic lesions or other fibromatoses are NOT eligible. 
 
Concomitant medications restrictions: 
a) Patients may NOT have received prior mTOR inhibitors. 
b) Growth factor(s): Must not have received within 1 week of entry onto this 
study. 


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 
Patients must not be known to be HIV positive. Testing for HIV is not mandatory. 
 
Patients must not be taking medicines known to influence sirolimus metabolism (see Table 
on Page 15). 
 
 
Regulatory 
 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
As the coordinating center MMC/MCCP will obtain a copy of each local sites IRB approval 
and IRB approved informed consent documents and all subsequent IRB reportable 
changes.   
 
REGISTRATION PROCEDURES 
 
All eligible subjects that provide consent to this study will be registered at MMC/MCCP.  
Eligibility will be verified with the Investigator or treating physician prior to registering the subject 
to study. 
 
REQUIRED OBSERVATIONS 
 
Tumor evaluation must be completed within 21 days prior to study entry.  In addition, labs and 
physical exam must be completed within 7 days prior to study entry.  Therapy must begin within 
21 days following signing informed consent document.   
 
Other recommended and required observations are detailed in the following Tables: 
 
 
 
 
 
 


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Evaluations 
Prior to Study Entry* 
During Course 1** 
Prior to Surgery* 
 
History 
 
X 
Weekly 
 
 
Physical Exam ( HT, WT, BSA, VS) 
 
X 
Weekly 
 
X 
 
Performance Status 
 
X 
 
 
 
Pain Scale1 
 
X 
Weekly (required) 
 
X 
 
CBC, differential, platelets 
 
X 
Weekly 
 
X 
 
Serum electrolytes including Ca++, PO4, Mg++ 
 
X 
Weekly 
 
X 
Creatinine, SGPT, bilirubin 
                   X 
Weekly 
                  X 
 
Fasting Glucose/Cholesterol/Triglyceride  
 
X 
Prior to week 3 
 
X 
 
Urine Pregancy Test2 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
Trough Sirolimus Level 
 
 
Weekly 
 
 
MRI of Primary3 
 
X 
 
 
X4 
* All evaluations required except where noted. 
** Course 1 represents the first 4 weeks of sirolimus; all evaluations strongly recommended except where otherwise noted.    1 
Patients ≥3 and < 10 years of age will use the Wong-Baker FACES scale; patients who are ≥ 10 years of age will use the numeric 
scale.  See Appendix 1. 
2 Patients of childbearing potential require a negative pregnancy test prior to starting treatment.   
3 MRI should include images in at least two planes with (a) pre-contrast images with the following pulse sequences (1) T-1 weighted, 
(2) fast spin echo T-2 weighted with fat saturation OR a short tau inversion recovery (STIR); and (b) post-contrast images with T-1 
weighted pulse sequence with fat suppression. 
4Optional but strongly recommended.  If performed, attempt to obtain as close to planned surgery as possible. 


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Post-surgery follow-up evaluation – months post therapy 
 
           
* All evaluations strongly recommended except where otherwise noted. 
1See Case Report Forms
 
Evaluations post-Surgery* 
 
 
3 
 
6 
 
9 
 
12 
 
18 
 
24 
 
36 
 
History 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Physical Exam ( HT, WT, BSA, VS) 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
MRI of Primary 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Data Collection Forms1 (required) 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Operative Report (required) 
 
x 
 
 
 
 
 
 


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TREATMENT PLAN 
 
Preoperative Chemotherapy for all patients 
 
 
Sirolimus: 
 
Loading dose of 12 mg/m2; PO day 1 (MAX dose 12 mg) 
 
Starting 24 hours after the initial loading dose, patients will receive a dose 
of 4 mg/m2 daily; PO days 2 through 28 (MAX dose 4 mg/day) 
 
If the patient suffers any Grade 3 or 4 toxicity that the treating physician feels may delay 
surgery, the patient will come off study. 
 
Surgical Resection for all patients 
 
 
Sirolimus will be discontinued following 28 days of therapy.  Surgical resection 
should be accomplished within 3 days of completing therapy.  The tumor will be 
processed for routine histology as well as for study specific tests. 
 
Anticipated or unanticipated surgical delay beyond 3 days should be discussed with 
the study PI to determine if a patient should be removed from protocol therapy. 
 
 
Note about Postoperative Chemotherapy  
 
 
The pilot study is complete following tumor resection.  If the treating physician chooses 
to continue sirolimus following resection, for example, based on symptomatic 
improvement, it will be independent of this clinical trial. 
 
 
DRUG ADMINISTRATION GUIDELINES:  
 
 
Sirolimus 
 
Prior to beginning and each week, the following laboratory criteria must be 
met before beginning or continuing Sirolimus: 
o ANC > 0.75 x 109/L 
o Platelets > 75 x 109/L 
o Serum creatinine < 2 x baseline or GFR > 70 mL/min/1.73 m2 
o Total bilirubin 0 – 21 μmol/L (0 -1.24 mg/dL) 
 
Sirolimus is to be administered daily by mouth. 
 
The drug may be given without regard to food, but should be consistently 
administered the same way (with or without food).  
 
The oral solution may be diluted in 2 ounces of water or orange juice 
immediately prior to administration.  The glass should be rinsed with an 
additional 4 ounces of the same fluid and administered to the patient. 
 
Dose adjustments will not be made based on trough levels. 
 
 


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DRUG MODIFICATIONS FOR TOXICITY 
 
If the patient suffers any Grade 3 or 4 toxicity that the treating physician feels may delay 
surgery, the patient will come off study. 
 
Dose Modifications for Sirolimus 
Toxicity 
Criteria/Grade 
Action 
Myelosuppression 
ANC < 0.75 x 109/L 
Plts < 75 x 109/L 
Withhold sirolimus, and repeat within 3-4 days 
until neutropenia or thrombocytopenia are 
resolved. 
If no previous delay, resume at full dose. 
If previous delay, reduce dose by 25%. 
Mucositis, Severe 
Abdominal Pain, 
Diarrhea 
Grade 4 mucositis or 
repeated Grade 3 
mucositis 
Delay until resolved and decrease subsequent 
sirolimus dose by 25%. 
Renal Toxicity 
Serum creatinine > 2 x 
baseline or 
GFR < 70 mL/min/1.73 
m2 
Delay for one week and decrease subsequent 
sirolimus dose by 25%. 
If renal function does not improve, discontinue 
sirolimus. 
Hepatic Toxicity 
Raised Total Bilirubin 
Reduce sirolimus as follows: 
Bilirubin Concentration                         % Dose 
0 – 21 μmol/L (0 -1.24 mg/dL)                   100% 
22 – 35 μmol/L (1.25-2.09 mg/dL)                75% 
36 – 52 μmol/L (2.1 -3.05 mg/dL)                50% 
53 – 86 μmol/L (3.06-5.0 mg/dL)                 25% 
> 87 μmol/L ( > 5.0 mg/dL)                             0% 
 
 
Other Toxicity: 
Any other persistent grade 3 or 4 toxicity should be discussed with the Study co-PIs and 
decided on a case by case basis.  Common Terminology Criteria for Adverse Events (CTCAE) 
version 4 will be used for toxicity assessment.  Please see Adverse Event and Data Reporting 
for guidelines for submitting AdEERs forms to the NCI for other grade 4 toxicities.   
 
 
AGENT INFORMATION 
 
Sirolimus (Rapamune®, Rapamycin) 
 
Supplier: 
 
Commercially available as Rapamune® oral solution 1mg/mL and 0.5mg, 1mg, and 2mg tablets. 
 
Pharmacology: 
 
Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic 
and cytokine (Interleukin (IL)-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from 
that of other immunosuppressants.  Sirolimus also inhibits antibody production.  Sirolimus binds 
to the immunophilin, FK binding protein-12 (FKBP-12).  Sirolimus suppresses cytokine driven T-
cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. 


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Formulation: 
 
The 1 mg/mL oral solution must be refrigerated and protected from light.  0.5mg, 1mg, and 2mg 
tablets. 
 
Stability: 
 
Once the bottle is opened, the solution is stable for 30 days.  The individual oral solution 
pouches are stable at room temperature for 24 hours.  The bottles of oral solution are stable at 
room temperature for 15 days. 
 
Guidelines for Administration: 
 
Sirolimus is to be taken by mouth.  Doses should be given every 24 hours +/- 2 hours.  The drug 
may be given without regard to food, but should be consistently administered the same way 
(with or without food).  The oral solution may be diluted in 2 ounces of water or orange juice 
immediately prior to administration.  The glass used should be rinsed with an additional 4 
ounces of the same fluid and administered to the patient. 
 
Potential toxicities: 
 
 
Common (21-100% 
Frequency) 
Occasional (5-20% 
Frequency) 
Rare (<5% 
Frequency) 
Immediate: Within 
1-2 days of 
recovery drug 
Nausea, Vomiting 
Rash 
Angioedema 
Prompt: Within 2-
3 weeks, prior to 
next course. 
Diarrhea 
Hypertension 
Increased Creatinine 
Infections (e.g. 
nasopharyngitis); 
Edema; Weight Gain, 
Arthralgia; Tremor; 
Acne; 
Myelosuppression; 
Abdominal Pain; 
Fatigue; Myalgia; 
Chest Pain; 
Dizziness; 
Hypokalemia; 
Hypophosphatemia; 
Hyperglycemia 
(diabetes mellitus) 
Hepatotoxicity 
Delayed:  Anytime 
after above. 
Hypercholesteremia, 
Hypertriglyceridemia 
Stomatitis, 
Wound 
Complications 
Hirsutism, Secondary 
Lymphoma, Pulmonary 
Hemorrhage 
Interstitial Lung 
Disease 
Late:  Anytime 
after completion of 
treatment 
 
 
 
 
 


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TABLE OF CLINICALLY RELEVANT DRUG INTERACTIONS FOR CYP3A4, 5, 0r 7 
 
SUBSTRATES 
INHIBITORS 
INDUCERS 
Macrolide antibiotics: 
clarithromycin 
erythromucin 
NOT azithromycin 
Telithromycin 
 
Anti-arrhuythmics: 
alprazolam 
diazepam 
midazolam 
triazolam 
 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
HIV Protease Inhibitors: 
indinavir 
ritonavir 
saquinavir 
 
Antihistamines: 
astemizole 
chlorapheniramine 
 
Calcium Channel 
Blockers: 
amlodipine, diltiazem, 
felodipine, nifedipine, 
nisoldipine, nitrendipine, 
verapamil 
 
HMG CoA Reductase 
Inhibitors: 
Atorvastatin, cerivastatin, 
lovastatin, NOT pravastatin, 
simvastatin 
 
Other: 
aripiprazole 
buspirone 
cisapride 
imatinib 
haloperidol (in part) 
methadone 
pimozide 
quinine 
NOT rosuvastatin 
HIV Antivirals: 
delaviridine 
indinavir 
nelfinavir 
ritonavir 
 
Other: 
amiodarone 
aprepitant 
NOT azithromycin 
chloramphenicol 
cimetidine 
clarithromycin 
diethyl-dithiocarbamate 
diltiazem 
erythromycin 
fluconazole 
fluvoxamine 
gestodene 
grapefruit juice 
itraconazole 
ketoconazole 
mifepristone 
nefazodone 
norfloxacin 
norfluoxetine 
mibefradil 
star fruit 
verapamil 
voriconazole 
HIV Antivirals: 
efavirenz 
nevirapine 
 
Other: 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
phenobarbital 
phenytoin 
rifampin 
St. John’s wort 
troglitazone 
oxcarbazepine 
pioglitazone 
rifabutin 


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SUBSTRATES 
INHIBITORS 
INDUCERS 
sirolimus 
sildenafil 
tamoxifen 
trazodone 
vincristine 
Adapted from a table prepared by Division of Pharmacology School of Medicine at Indiana 
University.  New drug interactions may be identified after this table was printed; please check 
periodically for updates at http://medicine.iupui.edu/flockhart/ 
 
 
TABLE OF P-GLYOPROTEIN SUBSTRATES, INDUCERS, AND INHIBITORS 
SUBSTRATES 
INHIBITORS 
INDUCERS 
amiodarone 
amprenavir, (also indinavir, 
fosamprenavir, ritonavir, 
saquinavir, nelfinavir) 
atorvastatin, lovastatin 
celiprolol 
cetrizine 
cimetidine 
ciprofloxacin 
colchicines 
cyclosporine 
daunorubicin (also 
doxorubicin, idarubicin) 
desloratidine, loratadine 
dexamethasone 
digitoxin, figoxin 
diltiazem 
docetaxel 
erythromycin 
estradiol 
etoposide, teniposide 
fexofenadine 
hydrocortisone 
imatinib 
irinotecan 
ivermectin 
lidocaine 
loperamide 
methotrexate 
mitomycin 
amiodarone 
amitriptylinie, (also 
desipramine, imipramine, 
trimipramine) 
atorvastatin, (also lovastatin, 
simvastatin) 
azelastine 
carvedilol, propanolol 
chlorpromazine 
prochlorperazine 
cimetidine, ranitidine 
clarithromycin, erythromycin 
cyclosporine 
dexrazoxane 
diltiazem, felodipine (also 
nicardipine, nifedipine, 
nitredipine, verapamil) 
dipyridamole 
disulfiram 
doxepin 
esomeprazole (also 
lansoprazole, omperazole) 
fluphenazine 
grapefruit juice 
haloperidol 
hydrocortisone 
hydrozyzine 
imatinib 
itraconazole, ketoconazole 
ivermectin 
Aspirin 
dexamethasone 
doxorubicin 
nefazodone 
prazosin 
rifampin 
St. John’s wort 
Trazodone 
vinblastine 


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SUBSTRATES 
INHIBITORS 
INDUCERS 
nadolol 
nicardipine 
ondansetron 
paclitaxel 
pravastatin 
quinidine 
ranitidine 
rifampin 
sirolimus 
tacrolimus 
verapamil 
vinblastine, vincristine 
lidocaine 
marprotilinie 
mefloquine 
midazolam 
mifepristone 
mitomycin 
nefazodone 
nelfinavir (also ritonavir, 
saquinavir) 
ofloxacin 
probenicid 
progesterone 
propafenone 
quinidine, quinine 
reserpine 
rifampin 
tacrolimus 
tamoxifen 
testosterone 
vinblastine 
 
Note: Predictions of drug interactions due to an effect on PGP transport is limited by the fact 
that drugs may be metabolized by multiple pathways, offering an alternative elimination route; 
the sum of the multiple drug effects on PGP is unknown; and PGP activity is influenced by non-
drug entities such as: inflammation, irradiation, etc. 
Adapted from Lexi-Comp’s Drug Interaction Handbook 2nd edition 2004 
 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
 
Criteria For Removal From Protocol Therapy 
 
Progressive disease 
 
Dose-limiting toxicity 
 
Patient withdrawal from protocol 
 
A delay in surgery > 7 days from the completion of sirolimus 
 
Patient missed >25% of sirolimus doses 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for off study 
(see below).  Follow-up data will be required. 
 
Off Study Criteria 
 
Death 
 
Lost to follow-up 
 
Patient withdrawal of consent for study follow-up 
 
PATHOLOGY GUIDELINES 
 
Pre-study pathology:  
Pre-Study tumor or biopsy sample will be analyzed for confirmation of diagnosis and for 
immunohistochemical analysis for mTOR pathway activation.   


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To accomplish this, representative H and E-stained sections and six (6) unstained, 5 micron 
sections on positive-charged slides, cut from the same block will be submitted.  If slides cannot 
be sent, blocks would be acceptable. 
 
Pathology of the specimen after neo-adjuvant chemotherapy: 
Immunohistochemical studies for mTOR pathway activation will be performed on the resected 
tumor samples.   Immunostaining results will be compared to a cohort of previously untreated, 
archived specimens, and also paired pre-treatment tumor or biopsy specimens if available.  
(See more below in Statistical Analysis.)  
 
To accomplish this, representative H and E-stained sections and ten (10) unstained, 5 micron 
sections on positive-charged slides, cut from the same block will be submitted. If slides cannot 
be sent, blocks would be acceptable. 
 
Pathology specimens should be sent within 3 weeks of enrollment to: 
 
Sarah Dry, MD 
UCLA Department of Pathology  
Bone, Soft Tissue and GI Pathology  
Director, Translational Pathology Core Laboratory, 13-145 CHS  
10833 Le Conte Ave, Los Angeles, CA 90095 
Phone: 310.794.9311    
Fax: 310.267.2104 
 
Histological Assessment 
 
H and E staining will be used to verify that the arrayed tissue/slides contain desmoid-type 
fibromatosis.  To assess mTOR pathway activation, immunohistochemical staining will be 
conducted for the following proteins and phosphoproteins: p-p70S6K, p-4E-BP1, both of which 
represent targets of mTOR; and p-AKT as this pathway could be activated as a drug resistance 
mechanism (see Figure 1).  Staining will be performed on the (a) post-treatment specimens, (b) 
paired, pre-treatment, archived specimens (if available), and (c) archived non-chemotherapy-
treated specimens from the UCLA tumor bank (approximately 50 are available).  All samples will 
be anonymized using an alpha-numeric code, with the key maintained in a HIPAA-compliant, 
secure database or locked file on the UCLA Server.  
 
Routine histology protocols (including positive and negative controls) will be used.  Quantitative 
analysis will be accomplished utilizing an Immuno-Reactive Score (IRS) as previously described 
(Noske et al., 2008; Chen et al., 2009; Lin et al., 2006).   Specifically, the percentage of positive 
cells will be scored as: 0 (0%); 1 (<10%); 2 (11-50%); 3 (51-80%); 4(>80%).  The staining 
intensity will be scored as:  0 (negative), 1 (weak), 2 (moderate), and 3 (strong).  To derive the 
IRS, the percentage of positive cells and staining intensity will be multiplied together, resulting in 
a value from 0 to 12.  IRS values 0 to 3 will be considered negative and values of 4 to 12 will be 
considered positive.  Of note, samples will be scored by an experienced pathologist, blinded to 
whether the samples represent pre- or post-treatment or archived non-chemotherapy treated 
specimens. 
 


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Pain Assessment 
 
Validated pain assessment measures, using the numeric and Wong-Baker FACES scales, will 
be collected at specific study time points.  Patients ≥3 and < 10 years of age will use the Wong-
Baker FACES scale and patients who are ≥ 10 years of age will use the numeric scale.  A 
positive response will be associated with an improvement of ≥ 50% from baseline after 4 weeks.  
A negative response will be associated with any worsening from baseline after 4 weeks.  A 
stable response will be any other result. 
 
Radiographic Assessment 
 
Anatomical imaging will be performed before therapy, prior to surgery (optional but strongly 
recommended), and at designated post-surgery surveillance intervals.  Although tumor size will 
be recorded at all imaging time points and compared, the main purpose of imaging will be to 
detect recurrence following treatment.  The slow growing nature of desmoid tumor precludes the 
use of previously established standardized radiographic measurements of response, such as 
the RECIST, for patients participating in this pilot study. 
 
RESPONSE CRITERIA 
 
Disease Response 
 
Disease response is defined as follows: 
 
Complete Response (CR) 
No clinical or radiographic evidence of disease 
 
Partial Response (PR) 
Reduction in the greatest product of 2 perpendicular diameters by >50%, no new lesions. 
 
Minor Response (MR) 
Reduction in the greatest product of 2 perpendicular diameters by >25%, but <50%, no new 
lesions. 
 
Stable Disease (SD) 
Change in the greatest product of 2 perpendicular diameters by <25%, no new lesions. 
 
Progressive Disease (PD) 
Increase in the greatest product of 2 perpendicular diameters by >25% or new biopsy-proven 
lesions. 
 
RISKS AND BENEFITS 
 
Specific drug risks have been included in the Agent Information section of the protocol. 
 
Blood drawing may cause pain, bruising, bleeding, or infection at the site of the needle stick. 
Care will be taken to avoid these complications.  There should be no added risks to subjects 
from the blood drawing or surgical procedures as a result of participating in this study. 
 
Another risk to subjects is the release of information from health records. Sometimes, health 
records have been used against subjects and their families. For example, insurance companies 


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Amendment No. 9 
 
22 
 
may deny a patient insurance or employers may not hire someone with a certain illness (such 
as AIDS or cancer). We will protect subjects' health records so that their name, address, and 
phone number will be kept private. The chance that this information will be given to someone 
else is very small. 
 
The protocol therapy may or may not provide benefit to participating subjects.  We hope that 
information learned from this clinical trial will benefit future desmoid tumor patients. 
 
INFORMED CONSENT PROCEDURE 
 
The subject or subject's guardians are first presented with the opportunity to join the trial in the 
Hematology/Oncology clinic at the respective institution when it is determined that the subject 
meets all protocol eligibility criteria.  The aim of the study will be explained to the subject or the 
subject's guardians in non-technical language by the principal investigator or by any of the 
members of the pediatric oncology team listed in supplemental form A.  Once the subjects 
consent to the study they are told that they may contact Dr. Weiss, Dr. Federman, Dr. Sharma 
or other collaborating physicians and nurses involved with the study to ask any additional 
questions or concerns that they may have.  Also, if the subject consents to the study, throughout 
the course of the study, the treating physician and nurses will continue to explain the nature of 
the study in non-technical language.  Assent will be sought from pediatric patients who are of an 
appropriate age and cognitive status.    
 
 
SUBJECT CONFIDENTIALITY 
 
The Private Health Information (PHI) for pre-screening case selection includes: subjects’ name, 
medical record number and surgical pathology report.  There will be potential risk resulting from 
breach of confidentiality.  After clinical information is abstracted on each case, all clinical 
information and material for analysis will be de-identified and given a unique case number.  
Data will be abstracted onto a secure database.  The link between the study code and the 
subject identifiers will be retained separately from the study documents in a secured password 
protected database only accessible to the research staff. 
 
All patient records used for this study will be kept confidential.  Patients will not be identified by 
name in any publications describing the results of this study.  Access to the patient records will 
contain identifiers that will be made available to the Principle Investigator and Clinical Research 
Associate. 
 
A database will be maintained by the principal investigator at the primary clinical trial site 
(MMC/MCCP).  The computer as well as the database will be password protected. 
 
ADVERSE EVENT AND DATA REPORTING 
 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment. An adverse event can be 
an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
syndrome or disease deemed to be possibly related to or occurring during the use of an 
investigational product. 
 
Serious adverse events (SAE) are adverse events occurring at any dose which meet one or 
more of the following serious criteria: 


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Amendment No. 9 
 
23 
 
 Results in death (i.e. the AE caused or lead to death) 
 Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it does not apply 
to an AE which hypothetically might have caused the death if it were more severe) 
 Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion) 
 Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability to carry out 
normal life functions) 
 Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a subject 
exposed to the study drug prior to conception or during pregnancy) 
 It does not meet any of the above serious criteria but may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 
When assessing causality, the investigator should determine the association and consider if 
there is a clinically plausible time sequence between onset of the AE and the associate drug 
administration; and/or there is a biologically plausible mechanism for the drug causing or 
contributing to the AE; and the AE cannot be attributed solely to concurrent/underlying illness, 
other drugs, or procedures. 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert. Unexpected adverse events are those not listed in the Package Insert or not 
identified. This includes adverse events for which the specificity or severity is not consistent with 
the description in the Package Insert.  
 
Unexpected adverse events grade 3, 4 and 5 as well as any medical event equivalent to CTC 
Grade 3, 4 or 5, which precipitated hospitalization (or prolongation of existing hospitalization) 
will be reported regardless of designation as expected or unexpected, along with attribution, to 
Dr. Aaron Weiss’s pager at 207-741-6679 within 24 hours.  These reportable adverse events 
will also be documented on a Medwatch 3500A form supplied by the coordinating center.  The 
Medwatch 3500A form will be submitted to Dr. Aaron Weiss within the time frame specified 
under AE Reporting Guidelines (on page 24) via fax to 207-396-7577 – use a FAX cover page.   
 
Expected adverse events grade 4 and 5 will be reported on a study supplied Medwatch 3500A 
form within 5 working days or 10 calendar days, whichever is sooner. (use study supplied 
Medwatch 3500A form). 
 
Dr. Aaron Weiss, who will discuss the adverse event with the local principal investigator (PI), will 
ensure that the Medwatch form has been obtained and the adverse event reported to the 
independent reviewer, Christian Thomas MD, who has been designated as independent data 
safety medical monitor. Christian Thomas, MD, Director of Research at Maine Center for 
Cancer Medicine will review incoming adverse event information and any data in real time.  The 
local principal investigator or treating physician along with Dr. Aaron Weiss, will determine if an 
AE is treatment related.  Dr. Thomas will review and evaluate all incoming events for causality 
and may discuss the events with all the PIs.  Dr. Thomas will review attribution and causality 
and may disagree with the previous determination.  Documentation of his review and any of the 
previous reviews will be forwarded to the bi-monthly Pediatric Solid Tumor Board.  Dr. Thomas 
has the authority to determine if an adverse event requires the study to be discontinued or be 
put on hold.  If this occurs, all participating sites will be notified immediately as well as the MMC 
IRB.  All sites are expected to inform their local IRB.   


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Amendment No. 9 
 
24 
 
 
In addition, patients enrolled to this study will be regularly discussed as a part of the bi-monthly 
Pediatric Solid Tumor Board. The discussion will include tumor response, toxicity and reported 
adverse events. A copy of all adverse event documentation and a summary of the discussion 
between Dr. Aaron Weiss and independent reviewer will be given to the Tumor board. The bi 
monthly Pediatric Solid Tumor Board Conference has the authority to determine if an adverse 
event requires the study to be discontinued or put on hold.  A Data and Safety Monitoring 
worksheet will be completed at this conference.  
 
The descriptions and grading scales found in the revised NCI Common Toxicity Criteria (CTC) 
version 4.0 (http://ctep.cancer.gov/reporting/ctc.html) will be utilized for adverse event reporting. 
All appropriate treatment areas should have access to a copy of the CTC version 4.0.  
 
A table showing the expected adverse events specific for each of the agents is found below. 
 
Expedited Adverse Event Reporting 
 
Expedited Reporting Guidelines – (including hospitalization defined in bullet 
1 below) 
 
 
Adverse Event Reporting Guidelines 
 
Unexpected Event 
Expected Event 
Grade 3, 4 and 5 
 
Report by phone to MMC/MCCP 
Coordinating Center  Dr. Aaron 
Weiss at 207-741-6679 within 24 
hrs. 
Written expedited Medwatch Form 
3500A report to be faxed to 207-
396-7677 within 48 hours. 
 
This includes all deaths within 30 
days of the last dose of sirolimus 
treatment regardless of attribution. 
 
Any 
late 
death 
attributed 
to 
sirolimus (possible, probable, or 
definite) should be reported within 
48 hours of site’s knowledge by 
phone and Medwatch form per 
above. 
 
Grade 3 
Grade 4 and 5 
Adverse Event Expedited 
Reporting NOT required. 
Written Medwatch 3500A 
report, within 5 working 
days or 10 calendar days, 
whichever is sooner. 
 
This includes all deaths 
within 30 days of the last 
dose of sirolimus treatment 
regardless of attribution. 
 
Any late death attributed to 
sirolimus (possible, 
probable, or definite) 
should be reported within 
48 hours of site’s 
knowledge by phone and 
Medwatch form per above. 
 
 
For Hospitalization only – Any medical event equivalent to CTC Grade 3, 4, or 5, which 
precipitated hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of designation as expected or unexpected and attribution.  
 


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Written reported procedures: 
• A completed MedWatch form will be utilized for collecting adverse event information. Complete 
in the timeframe specified in guidelines above and fax to 207-396-7577 to the attention of Dr. 
Aaron Weiss.  In addition each site must report adverse events per their local IRB policy.  
 
All delinquent reporting to the MMC/MCCP coordinating center must include documentation of 
reason for delinquency and may require implementation of an action plan. 
 
 
Records, Reporting, and Study Monitoring –  
Data Collection Forms: 
Forms should be completed at specified time points and sent to: 
 
Kathleen M. Glick, CCRP 
Coordinator of Clinical Research 
Maine Children's Cancer Program 
100 Campus Drive, Unit 107 
Scarborough, ME 04074 
Phone: 207.396.7565 
Fax: 207.396.7577 
Email- glickk@mmc.org 
 
 
Monitoring of Study Data: 
 
As the coordinating center MMC/MCCP will monitor and review all data for accuracy and 
completeness, and will collect data quarterly.  Queries will be generated to clarify unclear or 
missing data.  Records of this review will be maintained at MMC/MCCP.  Eligibility, deviations, 
adverse events and essential data elements will routinely be verified.  As the coordinating 
center MMC/MCCP will obtain a copy of each local sites IRB approval and IRB approved 
informed consent documents and all subsequent IRB reportable changes.  On an annual basis 
a random review of 20% of the data not previously reviewed will be performed. 
 
Unidentified patient SAE data will be shared w/ Pfizer.    
 
 
STATISTICAL ANALYSIS 
 
Primary Objective 
 
The primary scientific endpoint for patients enrolled on this pilot study is determine whether 
mTOR pathway activation decreases in patients with surgically-resectable desmoid tumor that is 
removed following pre-operative treatment with sirolimus.  We anticipate finding that 4 weeks of 
sirolimus 
will 
result 
in 
decreased 
mTOR 
pathway 
activation, 
assessed 
using 
immunohistochemical (IHC) studies outlined above.  IHC results after 4 weeks of sirolimus, 
scored on a scale of 0-12, from patients enrolled on the study will be compared with archived 
tumor samples from untreated patients using a two-sample t-test.  The sample size of n=15 trial 
patients and n=50 historical controls will provide 80% power to detect a true difference in means 
of 2.6 points on the 12-point scale.  While the t-test is fairly robust, if the data are highly non-
normally distributed a nonparametric, rank-sum test will be applied instead.  In addition, 
responses will be dichotomized as described above (negative <3, positive >4) and the 


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proportion positive compared between the two groups using Fisher’s exact test.  Finally, pre- 
and post-treatment values within patients enrolled on the trial will be compared using paired t or 
Wilcoxon, signed-rank tests. 
 
Secondary Objectives 
 
These scientific endpoints will be mostly exploratory, given the small numbers of patients 
enrolling in this pilot study.  Nonetheless, we anticipate finding that 4 weeks of sirolimus will 
result in decreased tumor-associated pain.  Pain assessments will be made using validated 
age-based pain assessment scales and compared pre- and post-treatment using a paired t test.  
Descriptively, the number of patients showing >50% improvement in their pain score, worsening 
pain, or between 0 and 50% improvement will be tabulated.  Having decreased pain in 
approximately 60% of patients without substantial toxicity will be viewed as a success.  
 
Patients will also be followed for recurrence post-surgery.  As a benchmark, in a similar cohort 
of patients treated on the Pediatric Oncology Group 9650 study with vinblastine and 
methotrexate, the progression-free survival rate at 1 year was 58%.  Vinblastine and 
methotrexate, which most would agree represents the current standard of care for desmoid 
tumor that is not amenable to surgery or radiation, is associated with significant toxicity: 18 of 27 
(66%) patients on that trial experienced NCI grade 3 or 4 toxicity.  Having histochemical 
evidence for decreased mTOR pathway activation with less toxicity will be viewed as a success, 
and lead the investigators to explore ways to test sirolimus in a randomized, phase II study in 
which the drug is used for patients with unresected disease and for patients in which the drug is 
continued following surgical resection of disease. 
 
An independent statistician has been recruited from Center for Outcomes Research and 
Evaluation (CORE) at Maine Medical Center Research Institute.  Lee Lucas, PhD, assisted in 
the original presentation of this project. There will be no interim analysis performed; analysis will 
be performed at study completion.  If Lee Lucas is not available, Christine Duarte, PhD. Senior 
Biostatistician at CORE, will be the lead statistician for this project.  Dr. Duarte will be assuming 
the analysis or consulting on this project as this is her area of expertise and her background is 
in translational research. 
 
 
Early Stopping Rules 
 
We anticipate surgical complications – such as excessive bleeding or wound dehiscence – to be 
rare, occurring in no more than 1 of the 15 patients enrolled.  If these or other significant and 
unexpected surgical complications are found in 3 patients, the study will be terminated. 
 
We feel that Grade 3 or 4 toxicity that will delay surgery will be rare, occurring in no more than 1 
of the 15 patients enrolled.  If this occurs in 3 patients, the study will be terminated. 
 


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APPENDIX 1 
 
 
Wong-Baker FACES Scale  
(to be used with patients >3 and <10 years of age) 
 
 
 
 
 
Numeric Pain Scale 
(To be used with patients >10 years of age)