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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
142
Nirogacestat tablet
Sugar pill manufactured to mimic nirogacestat 50 mg tablet
Progression Free Survival (PFS) 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 (Eisenhauer, 2009) or clinically as assessed by the investigator. Clinical progression is defined as the onset or worsening of symptoms resulting in a global deterioration of health status causing the permanent discontinuation from study treatment and the initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for DT/AF. Events of clinical progression will be adjudicated by an independent blinded central Endpoint Adjudication Committee (EAC) which will qualify events of clinical progression for inclusion in the PFS endpoint prior to study unblinding according to an EAC Review Charter.
Time frame: 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
Objective Response Rate Using RECIST Version 1.1 Criteria.
Objective response rate (ORR) is defined as the proportion of participants having a confirmed Best Overall Response (BOR) of CR or PR by central reader using RECIST v1.1 criteria. Responses obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of ORR. However, any responses, which occurred after a new anticancer therapy was received, will not be included. ORR is presented by percentages of responders.
Time frame: On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline at Cycle 10 in the Brief Pain Inventory (BPI) Average Pain Intensity (API) Score.
The Brief Pain Inventory consists of 9 questions and utilizes a 11-point Numerical pain Rating Scale from 0-10 measuring severity from "no pain" to "pain as bad as you can imagine," with a 24-hour recall period. Average Pain Intensity is calculated as the 7-day average (when results on at least 4 days for a VISIT are available) of Brief Pain Inventory Question #3 - Worst Pain in last 24 hours. A lower score indicates greater pain relief. The minimum and maximum of the actual score are (0, 8) for Nirogacestat and (0,9) for Placebo, respectively. A positive change from Baseline value indicates worsening of Average Pain Intensity and a negative change from Baseline value indicates improvement of Average Pain Intensity. The minimum and maximum of change from baseline score are (-7, 3) for Nirogacestat and (-5, 5) for Placebo, respectively.
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Arkansas Children's Hospital
Little Rock, Arkansas, United States
USC/Norris Comprehensive Cancer Center
Los Angeles, California, United States
Ronald Regan UCLA Medical Center
Los Angeles, California, United States
Stanford Cancer Center
Palo Alto, California, United States
UCSF Mission Bay
San Francisco, California, United States
Sarcoma Oncology Research Center
Santa Monica, California, United States
University of Colorado Hospital-Anschutz Cancer Pavilion (ACP)
Aurora, Colorado, United States
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut, United States
Washington Cancer Institute at MedStar Washington Hospital Center
Washington D.C., District of Columbia, United States
Mayo Clinic Florida
Jacksonville, Florida, United States
...and 42 more locations
Time frame: 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 at Cycle 10 in the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Tumor Symptom Scale (DTSS) - Total Score
The DEsmoid Tumor Symptom Scale is an 11-point, numeric rating scale from 0 to 10 to measure severity from "none" to "as bad as you can imagine," with a 24-hour recall period. The Total Symptom Score is calculated as the mean of Pain items (Items 1-3) as a single score, then a mean of this with items 4-7). Weekly summary scores will be created by averaging the daily scores over the 7 days period prior to each visit. A weekly score will be derived only if 4 or more out of 7 days period have non-missing scores. The weekly summary score will be used in analyses. If no weekly summary score is calculable, the participant will have data considered as missing at that visit. Higher scores represent worse symptom severity. The minimum and maximum of the actual score are (0,7) for Nirogacestat and (0,10) for Placebo. A positive change from Baseline value indicated worsening of symptoms. The minimum and maximum of change from baseline are (-6,1) for Nirogacestat and (-4,5) for Placebo.
Time frame: 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 the GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Tumor Impact Scale (DTIS) - Physical Functioning Domain Score
The items are evaluated on 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. The Physical Function Domain Score are calculated as the average Item 01 Moving, Item 02 Reaching (Freq), Item 06 Vigorous Activity, Item 7 Moderate Activity, and Item 08 Accomplished Less. Higher scores represent worst impact severity. The minimum and maximum of the actual score are (1, 5) for Nirogacestat and (1,5) for Placebo, respectively. A positive change from baseline value indicates worsening impact and a negative change from baseline value indicates improvement in impact. The minimum and maximum of change from baseline score are (-3, 0) for Nirogacestat and (-1, 2) for Placebo, respectively.
Time frame: On the last day of every cycle (each cycle is 28 days) through study completion, average of 2 years.
Change From Baseline at Cycle10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale.
The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A high score for the global health status/QoL represents a high QoL. The minimum and maximum of the actual score are (33, 100) for Nirogacestat and (8,92) for Placebo, respectively. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of global health status. The minimum and maximum of change from baseline score are (-58, 67) for Nirogacestat and (-67, 42) for Placebo, respectively.
Time frame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning
The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A high score for a Physical functional scale represents a high/healthy level of functioning. The minimum and maximum of the actual score are (27, 100) for Nirogacestat and (7,100) for Placebo, respectively. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of physical functioning scores. The minimum and maximum of change from baseline score are (-7, 40) for Nirogacestat and (-40, 27) for Placebo, respectively.
Time frame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Role Functioning.
The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of global health status and functioning scores. The minimum and maximum of change from baseline score are (-17, 83) for Nirogacestat and (-100, 50) for Placebo, respectively.
Time frame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years