Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)

Study Overview
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Brief Summary
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This study evaluates nirogacestat (PF-03084014) in the treatment of desmoid tumor/aggressive fibromatosis (DT/AF). In the double-blind phase, half of the participants will receive nirogacestat while the other half will receive placebo. Once participants are eligible to roll into the open-label phase, they will receive nirogacestat.

Detailed Description
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Desmoid tumors, also referred to as aggressive fibromatosis, are rare, locally invasive, slow growing soft tissue tumors. Although considered benign because of their inability to metastasize, desmoid tumors can cause significant morbidity and occasionally mortality in patients. Nirogacestat (PF-03084014) is a potent, small molecule, selective, reversible, noncompetitive inhibitor of γ-secretase (GS) with a potential antitumor activity. Nirogacestat is being investigated for the treatment of desmoid tumors due to its ability to bind to GS, blocking proteolytic activation of Notch receptors. Previous clinical study data have shown that Notch signaling plays an important role in cancer development. Hence, inhibition of Notch signaling is an important strategy for therapeutic treatment.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF)

Conditions
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Desmoid Tumor, Aggressive Fibromatosis

Intervention / Treatment
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* Drug: Nirogacestat oral tablet
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Double-Blind Key Inclusion Criteria: Participant has histologically confirmed DT/AF (by local pathologist prior to informed consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of the screening visit scan. Participant has: Treatment naïve, measurably progressing DT/AF that is deemed not amenable to surgery without the risk of significant morbidity; OR Recurrent, measurably progressing DT/AF following at least one line of therapy; OR Refractory, measurably progressing DT/AF following at least one line of therapy. Participant has a DT/AF tumor where continued progressive disease will not result in immediate significant risk to the participant. Participant agrees to provide archival or new tumor tissue for re-confirmation of disease. If participant is currently being treated with any therapy for the treatment of DT/AF, this must be completed at least 28 days (or 5 half-lives, whichever is longer) prior to first dose of study treatment. All toxicities from prior therapy must be resolved to ≤ Grade 1 or clinical baseline. Participants who are receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) as treatment for conditions other than DT/AF must be receiving them prior to the documented DT/AF progressive disease (inclusion criteria 2) and on a stable dose for at least 28 days prior to first dose of study treatment. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening. Participant has adequate organ and bone marrow function. Double-Blind Key Exclusion Criteria: Participant has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat. Participant has experienced any of the following within 6 months of signing informed consent: clinically significant cardiac disease (New York Heart Association Class III or IV), myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism. Participant has an abnormal QT interval at screening. Participant is using concomitant medications that are known to prolong the QT/QTcF interval including Class Ia and Class III antiarrhythmics at the time of informed consent. Non-antiarrhythmic medications which may prolong the QT/QTcF interval are allowed provided the participant does not have additional risk factors for Torsades de Pointes (TdP) Participant has congenital long QT syndrome. Participant has a history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). Participant has had lymphoma, leukemia, or any malignancy within the past 5 years at the time of informed consent, except for any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast), with no evidence of metastatic disease for 3 years at the time of informed consent. Participant has current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones). Participant previously received or is currently receiving therapy with GS inhibitors or anti-Notch antibody therapy. Participant is currently using any treatment for DT/AF including tyrosine kinase inhibitors (TKIs), NSAIDs (chronic daily use) or any investigational treatment 28 days (or 5 half-lives, whichever is longer) prior to the first dose of study treatment. OR Participant has started any treatment for DT/AF after the documented DT/AF progressive disease. Participant is currently using or anticipates using food or drugs that are known strong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or strong CYP3A inducers within 14 days prior to the first dose of study treatment. Participant has a positive human immunodeficiency virus antibody test. Participant has presence of Hepatitis B surface antigen at screening. Participant has a positive Hepatitis C antibody or Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to starting study treatment. Participant is unable to tolerate MRI or for whom MRI is contraindicated. Participant with active or chronic infection at the time of informed consent and during the screening period. Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year of signing informed consent. Participant is unable to comply with study related procedures (including, but not limited to, the completion of electronic patient report outcomes (ePROs), or the ePRO questionnaires are not available in the participant's preferred language). Open-Label Key Inclusion Participant is enrolled in the double-blind phase when the estimated number of PFS events have been observed and the primary PFS analysis has been completed; OR Participant is randomized to receive placebo in the double-blind phase and Central Imaging Review determines that the participant has radiographic progressive disease; OR Participant is randomized to receive nirogacestat in the double-blind phase and Central Imaging Review determines that the participant has radiographic progressive disease but the participant is deriving clinical benefit without significant toxicity (as determined by the investigator). Participant has adequate organ and bone marrow function Open-Label Key Exclusion Participant requires surgery to prevent organ dysfunction. Participant has prematurely discontinued from the double-blind phase for any reason other than radiographic progressive disease (as determined by Central Imaging Review). Participant developed a concurrent illness/condition that, in the opinion of the investigator, would represent a risk to overall health if they enroll in this study. Participant has initiated a new treatment for DT/AF after the Central Imaging Review determines that a participant has radiographic progressive disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-Blind Phase - Nirogacestat<br>Nirogacestat 150 mg by mouth, twice daily | Drug: Nirogacestat oral tablet<br>* Nirogacestat tablet<br>* Other names: PF-03084014;|
| Placebo Comparator: Double-Blind Phase - Placebo<br>Placebo 150 mg by mouth, twice daily | Drug: Placebo Oral Tablet<br>* Sugar pill manufactured to mimic nirogacestat 50 mg tablet<br>|
| Experimental: Open-Label Phase - Nirogacestat<br>Nirogacestat 150 mg by mouth, twice daily | Drug: Nirogacestat oral tablet<br>* Nirogacestat tablet<br>* Other names: PF-03084014;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of progression free survival (PFS) events as defined as the time from randomization until date of assessment of progression or death by any cause. | Progression will be determined radiographically using RECIST v1.1 criteria by an independent, blinded, central radiologic review, or clinically as assessed by the Investigator. | On the first day of every 3 cycles (each cycle is 28 days) until disease progression is observed or death, whichever comes first, assessed up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of adverse events (AEs) according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. |  | Weekly for cycle 1, last day of cycle 2, first day of cycle 4 and then the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years | 
| Overall response rate using RECIST Version 1.1 criteria. | Overall response rate is defined as the proportion of participants with complete response (CR) + partial response (PR) assessed by central reader using RECIST v1.1 criteria. | On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years | 
| Duration of response for participants whose best response is CR or PR. |  | On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years | 
| Tumor volume changes from baseline as measured by MRI volumetric. |  | On the first day of every 6 cycles (each cycle is 28 days) through study completion, an average of 2 years | 
| Change from baseline in patient reported outcome (PRO) scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Symptom Scale (GODDESS);. | This PRO will measure desmoid tumor symptoms by evaluating change from baseline. The items are evaluated on an 11-point numeric rating scale (NRS) form 0-10 measure severity from none to as bad as you can imagine, with a 24-hour recall period. | Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years | 
| Change from baseline in PRO scores using the Brief Pain Inventory (BPI) short form. | This PRO will measure clinical pain by evaluating change from baseline. It consists of 9 questions and will utilize an 11-point NRS from 0-10 measure severity from no pain to pain as bad as you can imagine, with a 24-hour recall period. | Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years | 
| Change in baseline in PRO scores using the Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF) short form 10a plus 3 additional items from PROMIS item banks. | This PRO will measure self-reported capability of physical activities by evaluating change from baseline. This includes the functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back), as well as instrumental activities of daily living, such as running errands. The PROMIS PF short form 10a plus (consisting) of 10 questions plus 3 additional questions from the PROMIS item bank will be used with a 7-day recall period. | On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years | 
| Change from baseline in PRO scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Impact Scale (GODDESS); | This PRO will measure desmoid tumor impacts by evaluating change from baseline. The items are evaluated either on an 11-point NRS to measure severity, or a 5-point Likert Scale ranging from none of the time to all of the time to measure frequency, with a 7-day recall period. | On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years | 
| Change from baseline in PRO scores using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC) QLQ-C30. | This PRO will measure the health-related quality of life of cancer patients by evaluated change from baseline. It consists of 30 questions overall with a 4-point scale and incorporates 5 functional scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation and diarrhea) and perceived financial impact of disease. | Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSI, PF-03084014, gamma secretase inhibitor, notch pathway