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Neoplasms, Fibrous Tissue

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Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Desmoid Tumor

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Nirogacestat

Gamma Secretase Inhibitors and Modulators

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PF-03084014 will be administered orally at 150 mg twice a day in 21-day cycles

Treatment with the selective small-molecule \>=-secretase inhibitor PF- 3084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early-phase clinical trial.

PF-03084014

Geraldine H O'Sullivan Coyne, M.D.

Background:

* Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.
* Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.
* The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.

Objectives:

* Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis
* Secondary: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration

Eligibility:

* Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function
* Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies

Study Design:

* This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cycles
* Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)
* Restaging scans (magnetic resonance imaging (MRI) with diffusion weighting) will be performed at baseline, at the end of cycles 1 and 6, and then every 6 cycles
* Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at each Clinical Center visit

Background:

* Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.
* Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.
* The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.

Objectives:

* Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis
* Exploratory: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration

Eligibility:

* Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function
* Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies

Study Design:

* This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cycles
* Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)
* Restaging scans (computed tomography (CT) scan of the known site of disease) will be performed at baseline and then every 6 cycles (+/- one cycle)
* Optional magnetic resonance imaging (MRI) scans may be performed prior to start of study treatment, end of cycle 1, and every 6 cycles (at the same times as the CT scans)
* Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at restaging

Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Complete Response + Partial Response was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Tumor and blood samples were obtained from participants and genotyped for somatic and germline mutations.

The MD Anderson Symptoms Inventory (MDSAI) questionnaire includes questions regarding 13 symptoms commonly experienced by patients with cancer and 6 additional items that assess the extent to which these symptoms interfered with how patients felt and were able to function. The 0-10 scale (0=none, 1-4=mild, 5-6=moderate, and 7-10=severe) assesses how patients felt and were able to function over the previous 24 hours. A component score representing symptom severity is obtained by taking the average of the 13 symptom items (e.g., pain, fatigue, etc.) together. A component score representing symptom distress is obtaining by averaging the 6 symptom interference items (e.g., general activity, mood, etc.).

National Cancer Institute (NCI)

Associate Investigator

PF-03084014 will be administered orally at 150 mg twice a day in 21-day cycles

PF-03084014: Treatment with the selective small-molecule \>=-secretase inhibitor PF- 3084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early-phase clinical trial.

PF-03084014 in Desmoid Tumors/Aggressive Fibromatosis

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Symptom Severity Score

Symptom Interference Score

The MD Anderson Symptoms Inventory (MDSAI) questionnaire evaluates 13 symptoms commonly experienced by patients with cancer with 6 additional items assessing the extent to which symptoms interfered with how patients feel and function. Scale is 0 (none), 1-4 (mild), 5-6 (moderate), and 7-10 (severe). A component score representing symptom severity is obtained by averaging the 13 symptom items (e.g., pain, fatigue, etc.) together. A component score representing symptom distress is obtaining by averaging the 6 symptom interference items (e.g., general activity, mood, etc.).

Mean MD Anderson Symptom Inventory Scores at Baseline

Dr. Geraldine H O'Sullivan Coyne

Complete Response

Partial Response

Not Evaluable

Stable Disease

Progressive Disease

Number of Participants With a Complete Response (CR) + Partial Response (PR)

Number of Participants With Serious and Non-serious Adverse Events

Number of Participants With Somatic or Germline Mutations Identified in Adenomatous Polyposis Coli Gene (APC) or Catenin Beta-1 (CTNNB1) Genes

Mean MD Anderson Symptom Inventory Scores After Treatment

Overall Study

Pierre AULOGE, MD

Afshin GANGI, MD, PhD

Roberto Luigi CAZZATO, MD

Julien GARNON, MD

François SEVERAC, Statistician

Desmoid tumors, also called aggressive fibromatosis, are rare, locally invasive tumors with no potential for metastasis. The incidence is approximately 2 to 4 per million per year in the general population. The "watch and wait" policy is the standard of care for newly diagnosed patients in Europe. Patients who progress have first-line medical treatment, surgery is no longer the treatment because there is a high rate of recurrence (\> 60%) and radiotherapy is not very suitable because the patients are often young and the tumors are large. Cryoablation seems to be an effective therapeutic option that should be evaluated.

Cryoablation for Advanced and Refractory Desmoid Tumors

University Hospital, Strasbourg, France

patients undergo cryoablation procedure for desmoid tumor

Patient undergo percutaneous cryoablation of desmoid tumor, with cryoprobes

"cryoprobes"

Afshin GANGI, MD

Desmoid tumors (DT) are rare tumors (2-4 cases/million/year) that originate from musculoaponeurotic structures. Although they are benign tumors with no metastatic potential, DT are considered as locally aggressive tumors, with local invasiveness and tissue destruction, leading to pain, and disability. Surgery remains the keystone of therapy, but is limited by the anatomical situation of extra-abdominal desmoid (EAD) tumors (chest wall, root members). In patients where surgery is considered, negative-margin resection (R0) is recommended, but this frequently results in cosmetic/functional impairment. Moreover, prognostic impact of R0 resections remains controversial. The outcome after initial surgery depends upon several factors such as age, tumor site, and tumor size as demonstrated by recent data from the French Sarcoma Group.

Alternative therapies to DT surgery for front-line or recurrence include NSAID's, anti-estrogens alone or in combination, -interferon, chemotherapy, targeted therapies or radiation therapy. All of these medical approaches however may fail to achieve long-term disease control and a number of patients suffer from irreducible pain, and disability from tumor volume.

Cryoablation is a promising technique that is suitable for patients experiencing extra-abdominal DT. The procedure is based on repeated cycles of freezing/passive thawing of the tumor, leading to cell death. The technique has many advantages, among which: the accurate control of iceball under real-time MRI or CT-scan monitoring (that is not possible with other techniques such as radiofrequency), the lack of mutilation, the possibility of repeating the procedure. The cryoablation procedure has proven to be beneficial for the treatment of various tumors (liver metastases, breast, kidney). Recently, percutaneous cryotherapy has been reported in the treatment of EAD tumors poorly suited to surgery, with promising results.

In the light of these encouraging data, it is believed that patients with extra-abdominal DT not amenable to surgery unless unacceptable surgical sequel and progressing after at least two lines of adequate medical therapy (tamoxifen, NSAID or chemotherapy), could benefit from the cryoablation procedure. Tumor cryotherapy-induced regression should allow symptoms relief, prolonged progression-free survival and a better quality of life.

Evaluation of the Cryodestruction of Non Abdominopelvic Desmoid Tumors in Patients Progressing Despite Medical Treatment

Evaluation of the Cryodestruction of Non Abdominopelvic Desmoid Tumors in Patients Progressing Despite Medical

The success of cryoablation, i.e. non-progression of non-abdominopelvic desmoid tumor, will be declared if the MRI control at 1 year after the last procedure shows:

* no suspicious contrast enhancement (the suspicious character is defined by heterogeneous or nodular or crescent-shape contrast enhancement) in the treated zone,
* and if the cryolesion (ablation zone) is not increasing in size compared to early post-ablation control (M1)

Antineoplastic Agents

Antisickling Agents

Hydroxyurea

Patients will take oral hydroxyurea with a starting dose of 20 mg/kg daily. Patients will remain on hydroxyurea as long as there is a response or stability in tumor size and associated toxicities are manageable. Maximum treatment duration will be one year.

Richard B Womer, M.D.

The purpose of this study is to examine the response rate of desmoid tumors to hydroxyurea. The investigators hypothesize that hydroxyurea will be a safe, non-toxic alternative to aggressive surgery or chemotherapy for this difficult to treat tumor.

The treatment of desmoid tumors is complicated by benign histology and potentially aggressive and recurrent behavior. Invasive or intensive treatments with surgery or radiation therapy can lead to good tumor control, but at the expense of significant side effects along with a high risk of local recurrence after surgical excision. Low dose regimens of standard chemotherapy drugs have been favored as a conservative first-line treatment; however, refractory and recurrent tumors are not uncommon. The purpose of this study is to investigate the efficacy and safety of using hydroxyurea, an anti-neoplastic agent with relatively few side-effects, as a novel treatment for primary, unresectable desmoid tumors, desmoid tumors that have had an incomplete primary resection, or desmoid tumors that have recurred after other therapy.

Patients presenting to our oncology center with a new diagnosis of desmoid tumor, or a recurrent desmoid tumor, will be eligible for this study. After informed consent, physical examination, and baseline imaging studies (CT/MRI), patients will receive oral hydroxyurea at a starting dose of 20 mg/kg daily. Laboratory tests will be performed at set intervals to maintain the appropriate dose and monitor for cytopenias. Clinical evaluations, physical examinations, and/or imaging studies will be conducted every three months to assess for changes in tumor size. Patients will remain on hydroxyurea as long as there is a response or stability in tumor size and associated toxicities are manageable. Data will be collected regarding the response to the drug, the duration of the response, and the occurrence of adverse events. The goal of the analysis will be to determine the efficacy of hydroxyurea as a treatment modality for desmoid tumors.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis	NCT01981551	Desmoid Tumors Aggressive Fibr...	PF-03084014	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis	NCT01981551	Desmoid Tumors Aggressive Fibr...	PF-03084014	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Cryoablation for Advanced and Refractory Desmoid Tumors	NCT06113094	Desmoid Tumors		18 Years -	University Hospital, Strasbourg, France
Evaluation of the Cryodestruction of Non Abdominopelvic Desmoid Tumors in Patients Progressing Despite Medical Treatment	NCT02476305	Desmoid Tumors	"cryoprobes"	18 Years -	University Hospital, Strasbourg, France
Effect of Hydroxyurea as Treatment for Primary Desmoid Tumors	NCT00978146	Desmoid Tumors Fibromatosis	Hydroxyurea	- 21 Years	Children's Hospital of Philadelphia

Spots Global Cancer Trial Database for desmoid tumors