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

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ClinicalTrials.gov Identifier: NCT01265030
Recruitment Status : Active, not recruiting
First Posted : December 22, 2010
Last Update Posted : April 23, 2021
Sponsor:
Collaborators:
Desmoid Tumor Research Foundation
Pfizer
Information provided by (Responsible Party):
Aaron Weiss, MaineHealth

Tracking Information
First Submitted Date  ICMJE December 6, 2010
First Posted Date  ICMJE December 22, 2010
Last Update Posted Date April 23, 2021
Study Start Date  ICMJE February 2014
Actual Primary Completion Date May 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 21, 2010)
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 ]
To determine whether mTor pathway activation decreases in patients with surgically-resectable desmoid tumor that is removed following pre-operative treatment with sirolimus
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2010)
  • Assess whether sirolimus improves pain [ Time Frame: 6 months after the last subject has been enrolled ]
    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 ]
    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 ]
    To assess the safety and tolerability of pre-operative sirolimus in patients with desmoid tumor.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pilot Study Evaluating the Use of mTor Inhibitor Sirolimus in Children and Young Adults With Desmoid-Type Fibromatosis
Official Title  ICMJE A Pilot Study Evaluating the Use of mTor Inhibitor Sirolimus in Children and Young Adults With Desmoid-Type Fibromatosis
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Desmoid Tumor
Intervention  ICMJE 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:
  • Rapamune®
  • Rapamycin
Study Arms  ICMJE 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
Intervention: Drug: Sirolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 29, 2019)
9
Original Estimated Enrollment  ICMJE
 (submitted: December 21, 2010)
15
Estimated Study Completion Date  ICMJE July 2021
Actual Primary Completion Date May 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 29 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01265030
Other Study ID Numbers  ICMJE 10-491-B
44574 ( Other Grant/Funding Number: Desmoid Tumor Research Foundation )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Aaron Weiss, MaineHealth
Study Sponsor  ICMJE MaineHealth
Collaborators  ICMJE
  • Desmoid Tumor Research Foundation
  • Pfizer
Investigators  ICMJE
Principal Investigator: Aaron R Weiss, DO MaineHealth
PRS Account MaineHealth
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP