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Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Desmoid Tumor

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Nirogacestat

Gamma Secretase Inhibitors and Modulators

Enzyme Inhibitors

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

Patients will receive nirogacestat tablets to be taken orally.

Nirogacestat (Gamma Secretase Inhibitor)

SpringWorks Medical Information

This program is being offered on a patient by patient basis and will require company, Institutional Review Board/Independent Ethics Committee, and applicable competent authority approval.

Individual Patient Compassionate Use of Nirogacestat

SpringWorks Therapeutics, Inc.

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)
Individual Patient Compassionate Use of Nirogacestat	NCT05041036	Desmoid Tumor NOTCH Gene Muta...	Nirogacestat (G...	-	SpringWorks Therapeutics, Inc.
Individual Patient Compassionate Use of Nirogacestat	NCT05041036	Desmoid Tumor NOTCH Gene Muta...	Nirogacestat (G...	-	SpringWorks Therapeutics, Inc.

Spots Global Cancer Trial Database for aggressive fibromatosis