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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Maine Medical Center
Sponsor:
Collaborator:
Desmoid Tumor Research Foundation
Information provided by (Responsible Party):
Aaron Weiss, Maine Medical Center
ClinicalTrials.gov Identifier:
NCT01265030
First received: December 6, 2010
Last updated: February 13, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Desmoid Tumor
Drug: Sirolimus
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study Evaluating the Use of mTor Inhibitor Sirolimus in Children and Young Adults With Desmoid-Type Fibromatosis

Resource links provided by NLM:


Further study details as provided by Maine Medical Center:

Primary Outcome Measures:
  • Determine if mTor pathway activation decreases in patients with surgically-resectable desmoid tumor removed following pre-operative treatment with sirolimus [ Time Frame: 6 months after the last subject has been enrolled ] [ Designated as safety issue: No ]
    To determine whether mTor pathway activation decreases in patients with surgically-resectable desmoid tumor that is removed following pre-operative treatment with sirolimus


Secondary Outcome Measures:
  • Assess whether sirolimus improves pain [ Time Frame: 6 months after the last subject has been enrolled ] [ Designated as safety issue: No ]
    To assess whether sirolimus improves desmoid tumor-associated pain.

  • Explore whether pre-operative sirolimus decreases tumor recurrence following resection of high-risk tumor [ Time Frame: 6 months after last subject has been enrolled ] [ Designated as safety issue: No ]
    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 anatomical site.

  • Assess safety and tolerability of pre-operative sirolimus in patients with desmoid [ Time Frame: 6 months after last subject is enrolled ] [ Designated as safety issue: Yes ]
    To assess the safety and tolerability of pre-operative sirolimus in patients with desmoid tumor.


Estimated Enrollment: 15
Study Start Date: February 2014
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Rapamune®, Rapamycin

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.

  Eligibility

Ages Eligible for Study:   up to 29 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must be less than 30 years of age at time of 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 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 1 week 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 not 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01265030

Contacts
Contact: Aaron R Weiss, DO 207-396-7565 weissa2@mmc.org
Contact: Noah Federman, MD 310-825-6708 nfederman@mednet.ucla.edu

Locations
United States, California
UCLA Medical Center Recruiting
Los Angeles, California, United States, 90095
Contact: Noah Federman, MD    310-825-6708    nfederman@mednet.ucla.edu   
Principal Investigator: Noah Federman, MD         
Sub-Investigator: Sarah Dry, MD         
United States, Maine
Maine Medical Center Recruiting
Portland, Maine, United States, 04102
Contact: Aaron R Weiss, DO    207-396-7565    weissa2@mmc.org   
Principal Investigator: Aaron R Weiss, DO         
United States, New Jersey
The Cancer Institute of New Jersey Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Archana Sharma, DO    732-235-8864    sharmaar@cinj.rutgers.edu   
Principal Investigator: Archana Sharma, DO         
Sponsors and Collaborators
Maine Medical Center
Desmoid Tumor Research Foundation
Investigators
Principal Investigator: Aaron R Weiss, DO Maine Medical Center
  More Information

No publications provided

Responsible Party: Aaron Weiss, Principal Investigator, Maine Medical Center
ClinicalTrials.gov Identifier: NCT01265030     History of Changes
Other Study ID Numbers: 10-491-B, 44574
Study First Received: December 6, 2010
Last Updated: February 13, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Maine Medical Center:
Desmoid Tumor
Sirolimus
Surgically-Resectable Desmoid Tumor

Additional relevant MeSH terms:
Fibromatosis, Aggressive
Fibroma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Neoplasms, Connective Tissue
Neoplasms, Fibrous Tissue
Everolimus
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014