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

• ClinicalTrials.gov Identifier: NCT03785964
• Recruitment Status: Active, not recruiting
• First Posted: December 24, 2018
• Last Update Posted: June 28, 2023
• Sponsor: SpringWorks Therapeutics, Inc.
• Information provided by (Responsible Party): SpringWorks Therapeutics, Inc.

Tracking Information

• First Submitted Date: December 17, 2018
• First Posted Date: December 24, 2018
• Last Update Posted Date: June 28, 2023
• Actual Study Start Date: April 17, 2019
• Actual Primary Completion Date: April 7, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 29, 2021)

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. [ 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 ]

Progression will be determined radiographically using RECIST v1.1 criteria by an independent, blinded, central radiologic review, or clinically as assessed by the Investigator.

Original Primary Outcome Measures (submitted: December 20, 2018)

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 using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Criteria. [ 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 ]

The documented date of progression will be determined by an independent, blinded, central radiologic review.

Current Secondary Outcome Measures (submitted: April 29, 2021)

• 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. [ Time Frame: 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. [ Time Frame: On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• Duration of response for participants whose best response is CR or PR. [ Time Frame: 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. [ Time Frame: 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);. [ Time Frame: Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• Change from baseline in PRO scores using the Brief Pain Inventory (BPI) short form. [ Time Frame: Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• 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. [ Time Frame: On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• Change from baseline in PRO scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Impact Scale (GODDESS); [ Time Frame: On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• 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. [ Time Frame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.

Original Secondary Outcome Measures (submitted: December 20, 2018)

• 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. [ Time Frame: 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. [ Time Frame: On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years ]
  Overall response rate is defined as the proportion of participants with complete response (CR) + partial response (PR).
• Duration of response for participants whose best response is CR or PR. [ Time Frame: 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. [ Time Frame: 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 Memorial Sloan Kettering/Desmoid Tumor Research Foundation Desmoid Tumor Symptom Scale (MSK/DTRF DTSS). [ Time Frame: Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• Change from baseline in PRO scores using the Brief Pain Inventory (BPI) short form. [ Time Frame: Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• 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. [ Time Frame: On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• Change from baseline in PRO scores using the Memorial Sloan Kettering/Desmoid Tumor Research Foundation Desmoid Tumor Impact Scale (MSK/DTRF DTIS). [ Time Frame: On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.
• 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. [ Time Frame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

For the double-blind phase, the participant, investigator, and all other clinical site personnel will be blinded to the assigned treatment allocation. All sponsor personnel will also be blinded except for the sponsor's quality assurance designee(s), safety designee(s), and clinical supply material designee(s).

Once participants are eligible, they will roll into the open-label phase where they will receive nirogacestat. In the open-label phase, the participant, investigator, all other clinical site personnel, and the sponsor are not blinded.

Primary Purpose: Treatment

Condition

• Desmoid Tumor
• Aggressive Fibromatosis

Intervention

• Drug: Nirogacestat oral tablet
  Nirogacestat tablet
  Other Name: PF-03084014
• Drug: Placebo Oral Tablet
  Sugar pill manufactured to mimic nirogacestat 50 mg tablet

Study Arms

• Experimental: Double-Blind Phase - Nirogacestat
  Nirogacestat 150 mg by mouth, twice daily
  Intervention: Drug: Nirogacestat oral tablet
• Placebo Comparator: Double-Blind Phase - Placebo
  Placebo 150 mg by mouth, twice daily
  Intervention: Drug: Placebo Oral Tablet
• Experimental: Open-Label Phase - Nirogacestat
  Nirogacestat 150 mg by mouth, twice daily
  Intervention: Drug: Nirogacestat oral tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 29, 2021): 142
• Original Estimated Enrollment (submitted: December 20, 2018): 94
• Estimated Study Completion Date: December 31, 2023
• Actual Primary Completion Date: April 7, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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:

  1. Treatment naïve, measurably progressing DT/AF that is deemed not amenable to surgery without the risk of significant morbidity; OR
  2. Recurrent, measurably progressing DT/AF following at least one line of therapy; OR
  3. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Germany, Italy, Netherlands, United Kingdom, United States
• Removed Location Countries: France

Administrative Information

• NCT Number: NCT03785964
• Other Study ID Numbers: NIR-DT-301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: SpringWorks Therapeutics is committed to data transparency and sharing data to further research while maintaining the privacy and confidentiality of research participants. Pertinent patient-level data from completed registrational clinical trials will be made available by SpringWorks to qualified researchers upon approval of reasonable requests following de-identification/anonymization pursuant to applicable law.

• Current Responsible Party: SpringWorks Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: SpringWorks Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Bernd Kasper, MD; Mannheim University Medical Center

• PRS Account: SpringWorks Therapeutics, Inc.
• Verification Date: June 2023