Desmoid TumorPhase 1/2NCT01265030
A Pilot Study Evaluating the Use of mTor Inhibitor Sirolimus in Children and Young Adults With Desmoid-Type Fibromatosis
A Phase 1/2 study testing Sirolimus in people with Desmoid Tumor, run by MaineHealth at 8 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 29 years
- Conditions the study is for
- Desmoid Tumor
- What is being tested?
- Sirolimus
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 8 sitesUnited States
- Study dates
- Feb 2014to 22 Dec 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 29 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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)
Show all 31Show fewer
- 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
Who cannot join
- 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
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
United States8 sites
University of Florida College of Medicine
Gainesville, Florida, 32611
Children's Mercy Hospital
Kansas City, Missouri, 64108
UCLA Medical Center
Los Angeles, California, 90095
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
University of Minnesota
Minneapolis, Minnesota, 55455
Maine Medical Center
Portland, Maine, 04102
Rady Children's Hospital
San Diego, California, 92123
Seattle Children's Hospital
Seattle, Washington, 98101
About this study
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.
Read the 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.
- Conditions
- Desmoid Tumor
- Being tested
- Sirolimus
- Keywords
- Desmoid Tumor, Sirolimus, Surgically-Resectable Desmoid Tumor
- Medical subject headings
- Desmoid Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
Also called Rapamune®, Rapamycin
- 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)
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: Sirolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 4 weeks
Secondary outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Dec 2010 (estimated)
- Study startFeb 2014
- Primary completion22 Dec 2021
- Study completion22 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Desmoid TumorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- MaineHealth
- Sponsor type
- University, hospital or other
- Collaborators
- Desmoid Tumor Research Foundation, Pfizer
- Responsible party
- Principal investigator, Aaron Weiss, MaineHealth
- Investigators
- Aaron R Weiss, DO, Principal investigator, MaineHealth
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01265030
- Sponsor's protocol ID
- 10-491-B
- Other IDs
- 44574
- Status last verified
- Jun 2023
- First submitted
- 6 Dec 2010
- Last updated
- 26 Jun 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 26 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study Evaluating the Use of mTor Inhibitor Sirolimus in Children and Young Adults With Desmoid-Type Fibromatosis
- ClinicalTrials.gov ID
- NCT01265030
- Acronym / sponsor ID
- 10-491-B
- Conditions
- Desmoid Tumor
- Keywords
- Desmoid Tumor, Sirolimus, Surgically-Resectable Desmoid Tumor
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- MaineHealthUniversity, hospital or other
- Collaborators
- Desmoid Tumor Research Foundation, Pfizer
- Study start
- Feb 2014 (actual)
- Primary completion
- 22 Dec 2021 (actual)
- Study completion
- 22 Dec 2021 (actual)
- First posted
- 22 Dec 2010 (estimated)
- Results
- Posted 26 Jun 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Sirolimus | Experimental | Drug: SirolimusPreoperative 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 |
Who may qualify
- Ages
- Up to 29 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (31 listed)
- 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:
- 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
Key exclusion criteria (6 listed)
- Patients with other fibroblastic lesions or other fibromatoses are NOT eligible.
- Concomitant medication restrictions
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SirolimusAlso: Rapamune®, Rapamycin* 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) | Drug | Sirolimus |
Primary outcome
Immunohistochemical Immunoreactive Score Results After 4 Weeks of Sirolimus Compared to Control Specimens
Time frame: 4 weeks
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.
3 secondary outcomes
Pain Levels After 4 Weeks of Sirolimus
Time frame: 4 weeks
Number of Participants Without Tumor Recurrence
Time frame: 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
Time frame: 4 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jun 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Desmoid Tumor
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Nirogacestat in Premenopausal Females With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)
Desmoid Tumor, Aggressive Fibromatosis
RecruitingPhase 1/2
FOG-001 in Locally Advanced or Metastatic Solid Tumors
Cancer, Colorectal Cancer
Active, not recruitingPhase 2
A Study of a New Drug, Nirogacestat, for Treating Desmoid Tumors That Cannot be Removed by Surgery
Desmoid Fibromatosis, Recurrent Desmoid Fibromatosis
Enrolling by invitationObservational study
Patient-reported Outcomes Following Percutaneous Ablation of Desmoid Tumors
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Aaron R Weiss, DO principal investigator
MaineHealth
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Sirolimus in people with Desmoid Tumor, run by MaineHealth at 8 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 31 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jun 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Immunohistochemical Immunoreactive Score Results After 4 Weeks of Sirolimus Compared to Control Specimens (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jun 2023.