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

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.

Study Overview

• Status: Completed
• Conditions: Desmoid Tumor
• Intervention / Treatment: Drug: Sirolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida College of Medicine
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 27 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 age/gender

• Hepatic: Adequate liver function is defined as:

  • Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)for age, and
  • 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 ninth/Liter
  • 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 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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sirolimus; 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	Drug: Sirolimus; 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); Other Names: Rapamycin; Rapamune®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunohistochemical Immunoreactive Score Results After 4 Weeks of Sirolimus Compared to Control Specimens	Changes to the mTOR pathway were determined using an immunohistochemical immunoreactive score (IRS). The components of the IRS for each phosphoprotein (p4EPB and pS706K) are as follows: the percentage of positive cells were scored as: 0 (0%); 1 (<10%); 2 (11-50%); 3 (51-80%); 4(>80%). The staining intensity were scored as: 0 (negative), 1 (weak), 2 (moderate), and 3 (strong). To derive the IRS, the percentage of positive cells and staining intensity were multiplied together, resulting in a value from 0 to 12. The score for patients after 4 weeks of sirolimus was compared to a group of control desmoid tumor samples from the UCLA tumor bank (n=68). Lower scores for patients following 4 weeks of sirolimus compared to control sample scores indicate a better outcome.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Levels After 4 Weeks of Sirolimus	Pain assessments were performed using the validated numeric (age ≥ 10 years) and Wong-Baker FACES (≥3 and < 10 years) pain rating scales at specified study time points including baseline, at week 1 and after 4 weeks of treatment (just prior to surgery). Both pain scales range from a value of 0 to 10 with 0 being equal to no pain and 10 being equal to the worst pain. The median pain score and pain score range for study participants at Week 1 and Prior to Surgery (Week 4) timepoints are provided. Lower pain scale values (median and upper limit of the range) at the Prior to Surrgery timepoint are considered a better outcome.	4 weeks
Number of Participants Without Tumor Recurrence	We evaluated the number of study participants whose tumor did not recur by 3 years from the date of surgery.	3 years from the end of therapy, a total duration of 3 years and 4 weeks
Number of Participants With Grade 3 or Higher Toxicity Per CTCAE Definitions	The safety and tolerability of patients receiving sirolimus was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading criteria. All reported grades of toxicity (1-5) were collected.	4 weeks

Collaborators and Investigators

• Sponsor: MaineHealth
• Collaborators: Pfizer; Desmoid Tumor Research Foundation
• Investigators: Principal Investigator: Aaron R Weiss, DO, MaineHealth

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2014
• Primary Completion (Actual): December 22, 2021
• Study Completion (Actual): December 22, 2021

Study Registration Dates

• First Submitted: December 6, 2010
• First Submitted That Met QC Criteria: December 21, 2010
• First Posted (Estimated): December 22, 2010

Study Record Updates

• Last Update Posted (Actual): June 26, 2023
• Last Update Submitted That Met QC Criteria: June 1, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Sirolimus; Desmoid Tumor; Surgically-Resectable Desmoid Tumor
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Fibrous Tissue; Fibromatosis, Aggressive; Fibroma; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 10-491-B; 44574 (Other Grant/Funding Number: Desmoid Tumor Research Foundation)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• product manufactured in and exported from the U.S.: Yes