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

NCT01265030 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 10-491-B44574
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 8

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.

Conditions

Desmoid Tumor

Keywords

Desmoid Tumor; Sirolimus; Surgically-Resectable Desmoid Tumor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Pain Levels After 4 Weeks of Sirolimus

  4 weeks

• Number of Participants Without Tumor Recurrence

  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

  4 weeks

Study Arms (1)

Sirolimus

EXPERIMENTAL

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

Interventions

Sirolimus DRUG

* 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)

Also known as: Rapamune®, Rapamycin

Sirolimus

Eligibility Criteria

• Age: Up to 29 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• MaineHealth: lead
• Desmoid Tumor Research Foundation: collaborator
• Pfizer: collaborator

Study Sites (8)

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Rady Children's Hospital

San Diego, California, 92123, United States

Location

University of Florida College of Medicine

Gainesville, Florida, 32611, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98101, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Desmoid Tumors

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Fibroma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Aaron Weiss, Principal Investigator
• Organization: Maine Medical Center

Aaron.Weiss@mainehealth.org

2073967565

Study Officials

• Aaron R Weiss, DO

  MaineHealth

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 6, 2010
• First Posted: December 22, 2010
• Study Start: February 1, 2014
• Primary Completion: December 22, 2021
• Study Completion: December 22, 2021
• Last Updated: June 26, 2023
• Results First Posted: June 26, 2023

Record last verified: 2023-06

Locations

US (8)