A Pilot Study Evaluating the Use of mTor Inhibitor Sirolimus in Children and Young Adults With Desmoid-Type Fibromatosis

Therapuetic Areas:Oncology
Age Range:Any - 29
Start Date:February 2014
End Date:December 2019
Contact:Aaron R Weiss, DO

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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.

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.

Inclusion Criteria:

- Must be less than 30 years of age at 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 adenomatous polyposis coli (APC) mutations or
clinical manifestations of Familial Adenomatous Polyposis(FAP)/Gardner's syndrome can
be included

- Patients must have surgery planned to remove the desmoid tumor and either:

- the desmoid tumor has already recurred after a prior surgery or

- the newly diagnosed and/or previously unresected disease is judged to be at high
risk for recurrence due to its size (>5 centimeters) or location at an anatomic
site making it unlikely to be resected with negative margins (eg. 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:

- Patients may have received prior chemotherapy (excluding prior mTOR inhibitors)

- Use of steroids for non-tumor indications (for example: asthma or severe allergic
reaction) is permitted

- Patients must have a Karnofsky performance status of greater than or equal to 50 for
patients older than 16 years of age or Lansky performance status of greater than or
equal to 50 for patients less than or equal to 16 years of age.

- Patients must have a life expectancy of greater than or equal to 8 weeks.

- Patients must have recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study

- Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry
onto this study (4 weeks if prior nitrosourea)

- Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy
with a biological agent

- Stem Cell Transplant (SCT): No evidence of active graft versus host disease. For
allogeneic SCT, greater than or equal to 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 Glomerular Filtration Rate ≥
70millileters/minute/1.73 meters2 or a normal serum creatinine based on

- Hepatic: Adequate liver function is defined as:

- Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)for age,

- Serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 x upper
limit normal (ULN) for age

- Hematologic function: Adequate bone marrow function is defined as:

- Absolute Neutrophil Count (ANC) greater than or equal to 1 x 10 to the

- Hemoglobin greater than or equal to 10 gram/deciliter

- Platelet count greater than or equal to 100 x 10 to the ninth/Liter

- 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

- 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 less than 18 years of age). Consent must be signed prior to any study
procedures and study entry

Exclusion Criteria:

- Patients with other fibroblastic lesions or other fibromatoses are NOT eligible.

- Concomitant medication restrictions

- Patients may NOT have received prior mTor inhibitors

- Growth factor(s): Must not have received within 1 week of entry onto this study.

- Patients must not be known to be Human Immunodeficiency Virus positive. Testing for
Human Immunodeficiency Virus is not mandatory.

- Patients must not be taking medicines known to influence sirolimus metabolism
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