<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03785964</url>
  </required_header>
  <id_info>
    <org_study_id>NIR-DT-301</org_study_id>
    <nct_id>NCT03785964</nct_id>
  </id_info>
  <brief_title>Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)</brief_title>
  <acronym>DeFi</acronym>
  <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)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>SpringWorks Therapeutics, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>SpringWorks Therapeutics, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates nirogacestat (PF-03084014) in the treatment of desmoid tumor/aggressive&#xD;
      fibromatosis (DT/AF). In the double-blind phase, half of the participants will receive&#xD;
      nirogacestat while the other half will receive placebo. Once participants are eligible to&#xD;
      roll into the open-label phase, they will receive nirogacestat.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Desmoid tumors, also referred to as aggressive fibromatosis, are rare, locally invasive, slow&#xD;
      growing soft tissue tumors. Although considered benign because of their inability to&#xD;
      metastasize, desmoid tumors can cause significant morbidity and occasionally mortality in&#xD;
      patients.&#xD;
&#xD;
      Nirogacestat (PF-03084014) is a potent, small molecule, selective, reversible, noncompetitive&#xD;
      inhibitor of γ-secretase (GS) with a potential antitumor activity.&#xD;
&#xD;
      Nirogacestat is being investigated for the treatment of desmoid tumors due to its ability to&#xD;
      bind to GS, blocking proteolytic activation of Notch receptors. Previous clinical study data&#xD;
      have shown that Notch signaling plays an important role in cancer development. Hence,&#xD;
      inhibition of Notch signaling is an important strategy for therapeutic treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 17, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Actual">April 7, 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>Yes</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <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).&#xD;
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.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>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.</measure>
    <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</time_frame>
    <description>Progression will be determined radiographically using RECIST v1.1 criteria by an independent, blinded, central radiologic review, or clinically as assessed by the Investigator.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>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.</measure>
    <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</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate using RECIST Version 1.1 criteria.</measure>
    <time_frame>On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response for participants whose best response is CR or PR.</measure>
    <time_frame>On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor volume changes from baseline as measured by MRI volumetric.</measure>
    <time_frame>On the first day of every 6 cycles (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in patient reported outcome (PRO) scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Symptom Scale (GODDESS);.</measure>
    <time_frame>Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
    <description>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 &quot;none&quot; to &quot;as bad as you can imagine,&quot; with a 24-hour recall period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in PRO scores using the Brief Pain Inventory (BPI) short form.</measure>
    <time_frame>Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
    <description>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 &quot;no pain&quot; to &quot;pain as bad as you can imagine,&quot; with a 24-hour recall period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>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.</measure>
    <time_frame>On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in PRO scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Impact Scale (GODDESS);</measure>
    <time_frame>On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
    <description>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 &quot;none of the time&quot; to &quot;all of the time&quot; to measure frequency, with a 7-day recall period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>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.</measure>
    <time_frame>Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">142</enrollment>
  <condition>Desmoid Tumor</condition>
  <condition>Aggressive Fibromatosis</condition>
  <arm_group>
    <arm_group_label>Double-Blind Phase - Nirogacestat</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nirogacestat 150 mg by mouth, twice daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Double-Blind Phase - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo 150 mg by mouth, twice daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Open-Label Phase - Nirogacestat</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nirogacestat 150 mg by mouth, twice daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nirogacestat oral tablet</intervention_name>
    <description>Nirogacestat tablet</description>
    <arm_group_label>Double-Blind Phase - Nirogacestat</arm_group_label>
    <arm_group_label>Open-Label Phase - Nirogacestat</arm_group_label>
    <other_name>PF-03084014</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Sugar pill manufactured to mimic nirogacestat 50 mg tablet</description>
    <arm_group_label>Double-Blind Phase - Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Double-Blind Key Inclusion Criteria:&#xD;
&#xD;
          -  Participant has histologically confirmed DT/AF (by local pathologist prior to informed&#xD;
             consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of&#xD;
             the screening visit scan.&#xD;
&#xD;
          -  Participant has:&#xD;
&#xD;
               1. Treatment naïve, measurably progressing DT/AF that is deemed not amenable to&#xD;
                  surgery without the risk of significant morbidity; OR&#xD;
&#xD;
               2. Recurrent, measurably progressing DT/AF following at least one line of therapy;&#xD;
                  OR&#xD;
&#xD;
               3. Refractory, measurably progressing DT/AF following at least one line of therapy.&#xD;
&#xD;
          -  Participant has a DT/AF tumor where continued progressive disease will not result in&#xD;
             immediate significant risk to the participant.&#xD;
&#xD;
          -  Participant agrees to provide archival or new tumor tissue for re-confirmation of&#xD;
             disease.&#xD;
&#xD;
          -  If participant is currently being treated with any therapy for the treatment of DT/AF,&#xD;
             this must be completed at least 28 days (or 5 half-lives, whichever is longer) prior&#xD;
             to first dose of study treatment. All toxicities from prior therapy must be resolved&#xD;
             to ≤ Grade 1 or clinical baseline.&#xD;
&#xD;
          -  Participants who are receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs)&#xD;
             as treatment for conditions other than DT/AF must be receiving them prior to the&#xD;
             documented DT/AF progressive disease (inclusion criteria 2) and on a stable dose for&#xD;
             at least 28 days prior to first dose of study treatment.&#xD;
&#xD;
          -  Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at&#xD;
             screening.&#xD;
&#xD;
          -  Participant has adequate organ and bone marrow function.&#xD;
&#xD;
        Double-Blind Key Exclusion Criteria:&#xD;
&#xD;
          -  Participant has known malabsorption syndrome or preexisting gastrointestinal&#xD;
             conditions that may impair absorption of nirogacestat.&#xD;
&#xD;
          -  Participant has experienced any of the following within 6 months of signing informed&#xD;
             consent: clinically significant cardiac disease (New York Heart Association Class III&#xD;
             or IV), myocardial infarction, severe/unstable angina, coronary/peripheral artery&#xD;
             bypass graft, symptomatic congestive heart failure, cerebrovascular accident,&#xD;
             transient ischemic attack, or symptomatic pulmonary embolism.&#xD;
&#xD;
          -  Participant has an abnormal QT interval at screening.&#xD;
&#xD;
          -  Participant is using concomitant medications that are known to prolong the QT/QTcF&#xD;
             interval including Class Ia and Class III antiarrhythmics at the time of informed&#xD;
             consent. Non-antiarrhythmic medications which may prolong the QT/QTcF interval are&#xD;
             allowed provided the participant does not have additional risk factors for Torsades de&#xD;
             Pointes (TdP)&#xD;
&#xD;
          -  Participant has congenital long QT syndrome.&#xD;
&#xD;
          -  Participant has a history of additional risk factors for Torsades de Pointes (TdP)&#xD;
             (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).&#xD;
&#xD;
          -  Participant has had lymphoma, leukemia, or any malignancy within the past 5 years at&#xD;
             the time of informed consent, except for any locally recurring cancer that has been&#xD;
             treated curatively (e.g., resected basal or squamous cell skin cancer, superficial&#xD;
             bladder cancer, carcinoma in situ of the cervix or breast), with no evidence of&#xD;
             metastatic disease for 3 years at the time of informed consent.&#xD;
&#xD;
          -  Participant has current or chronic history of liver disease or known hepatic or&#xD;
             biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).&#xD;
&#xD;
          -  Participant previously received or is currently receiving therapy with GS inhibitors&#xD;
             or anti-Notch antibody therapy.&#xD;
&#xD;
          -  Participant is currently using any treatment for DT/AF including tyrosine kinase&#xD;
             inhibitors (TKIs), NSAIDs (chronic daily use) or any investigational treatment 28 days&#xD;
             (or 5 half-lives, whichever is longer) prior to the first dose of study treatment.&#xD;
&#xD;
        OR&#xD;
&#xD;
        Participant has started any treatment for DT/AF after the documented DT/AF progressive&#xD;
        disease.&#xD;
&#xD;
          -  Participant is currently using or anticipates using food or drugs that are known&#xD;
             strong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or strong CYP3A inducers&#xD;
             within 14 days prior to the first dose of study treatment.&#xD;
&#xD;
          -  Participant has a positive human immunodeficiency virus antibody test.&#xD;
&#xD;
          -  Participant has presence of Hepatitis B surface antigen at screening.&#xD;
&#xD;
          -  Participant has a positive Hepatitis C antibody or Hepatitis C ribonucleic acid (RNA)&#xD;
             test result at screening or within 3 months prior to starting study treatment.&#xD;
&#xD;
          -  Participant is unable to tolerate MRI or for whom MRI is contraindicated.&#xD;
&#xD;
          -  Participant with active or chronic infection at the time of informed consent and&#xD;
             during the screening period.&#xD;
&#xD;
          -  Participant has experienced other severe acute or chronic medical or psychiatric&#xD;
             conditions within 1 year of signing informed consent.&#xD;
&#xD;
          -  Participant is unable to comply with study related procedures (including, but not&#xD;
             limited to, the completion of electronic patient report outcomes (ePROs), or the ePRO&#xD;
             questionnaires are not available in the participant's preferred language).&#xD;
&#xD;
        Open-Label Key Inclusion&#xD;
&#xD;
          -  Participant is enrolled in the double-blind phase when the estimated number of PFS&#xD;
             events have been observed and the primary PFS analysis has been completed; OR&#xD;
&#xD;
          -  Participant is randomized to receive placebo in the double-blind phase and Central&#xD;
             Imaging Review determines that the participant has radiographic progressive disease;&#xD;
             OR&#xD;
&#xD;
          -  Participant is randomized to receive nirogacestat in the double-blind phase and&#xD;
             Central Imaging Review determines that the participant has radiographic progressive&#xD;
             disease but the participant is deriving clinical benefit without significant toxicity&#xD;
             (as determined by the investigator).&#xD;
&#xD;
          -  Participant has adequate organ and bone marrow function&#xD;
&#xD;
        Open-Label Key Exclusion&#xD;
&#xD;
          -  Participant requires surgery to prevent organ dysfunction.&#xD;
&#xD;
          -  Participant has prematurely discontinued from the double-blind phase for any reason&#xD;
             other than radiographic progressive disease (as determined by Central Imaging Review).&#xD;
&#xD;
          -  Participant developed a concurrent illness/condition that, in the opinion of the&#xD;
             investigator, would represent a risk to overall health if they enroll in this study.&#xD;
&#xD;
          -  Participant has initiated a new treatment for DT/AF after the Central Imaging Review&#xD;
             determines that a participant has radiographic progressive disease.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bernd Kasper, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mannheim University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Arkansas Children's Hospital</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC/Norris Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ronald Regan UCLA Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford Cancer Center</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF Mission Bay</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarcoma Oncology Research Center</name>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <zip>90403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Colorado Hospital-Anschutz Cancer Pavillion (ACP)</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital at Yale-New Haven</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington Cancer Institute at MedStar Washington Hospital Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Florida</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sylvester Comprehensive Cancer Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern Memorial Hospital</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hosptial (MGH)</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute (DFCI)</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington Univerisity School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwell Health</name>
      <address>
        <city>Lake Success</city>
        <state>New York</state>
        <zip>11042</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>DUMC/Duke Cancer Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Childrens's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science Univeristy-Center for Health &amp; Healing</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Abramson Cancer Center at Pennsylvania Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fox Chase Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Ceter</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henry-Joyce Cancer Clinic</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UT Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Texas MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Cancer Care Alliance</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Clinical Science Center</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Froedtert Hospital &amp; the Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Jules Bordet-Medical Onocology</name>
      <address>
        <city>Brussels</city>
        <zip>1000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cliniques Universitaires Saint-Luc, Institut Roi Albert II</name>
      <address>
        <city>Brussels</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UZ Gent</name>
      <address>
        <city>Gent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UZ Leuven</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Margaret Cancer Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McGill University Health Centre</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H4A3JI</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helios Klinikum Berlin-Buch</name>
      <address>
        <city>Berlin</city>
        <zip>13125</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsmedizin Mannheim</name>
      <address>
        <city>Mannheim</city>
        <zip>D-68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS Istituto Ortopedico Rizzoli</name>
      <address>
        <city>Bologna</city>
        <zip>40136</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto di Candiolo IRCCS Oncologia Medica</name>
      <address>
        <city>Candiolo</city>
        <zip>10060</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione IRCCS Instituto Nazionale dei Tumori di Milano</name>
      <address>
        <city>Milano</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico Unvrsitario Campus Bio-Medico</name>
      <address>
        <city>Roma</city>
        <zip>00128</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radboud University Medical Centre</name>
      <address>
        <city>Nijmegen</city>
        <state>Gelderland</state>
        <zip>6525GA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Netherlands Cancer Institute</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leiden University Medical Center (LUMC)</name>
      <address>
        <city>Leiden</city>
        <zip>23333</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Oncology, University College of London Hospital</name>
      <address>
        <city>London</city>
        <zip>NW12PG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal Marsden NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SW36JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Canada</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>France</country>
  </removed_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 2018</study_first_posted>
  <disposition_first_submitted>March 28, 2023</disposition_first_submitted>
  <disposition_first_submitted_qc>March 28, 2023</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">April 3, 2023</disposition_first_posted>
  <last_update_submitted>June 26, 2023</last_update_submitted>
  <last_update_submitted_qc>June 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>PF-03084014</keyword>
  <keyword>GSI</keyword>
  <keyword>gamma secretase inhibitor</keyword>
  <keyword>notch pathway</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fibromatosis, Aggressive</mesh_term>
    <mesh_term>Fibroma</mesh_term>
    <mesh_term>Aggression</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nirogacestat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_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.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03785964
org study id: NIR-DT-301
nct id: NCT03785964
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
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.
measure: 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
description: Progression will be determined radiographically using RECIST v1.1 criteria by an independent, blinded, central radiologic review, or clinically as assessed by the Investigator.
measure: 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
measure: 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
description: 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.
measure: 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
measure: 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
measure: 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
description: 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.
measure: 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
description: 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.
measure: 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
description: 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.
measure: 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
description: 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.
measure: 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
description: 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.
arm group label: Double-Blind Phase - Nirogacestat
arm group type: Experimental
description: Nirogacestat 150 mg by mouth, twice daily
arm group label: Double-Blind Phase - Placebo
arm group type: Placebo Comparator
description: Placebo 150 mg by mouth, twice daily
arm group label: Open-Label Phase - Nirogacestat
arm group type: Experimental
description: Nirogacestat 150 mg by mouth, twice daily
intervention type: Drug
intervention name: Nirogacestat oral tablet
description: Nirogacestat tablet
arm group label: Double-Blind Phase - Nirogacestat
arm group label: Open-Label Phase - Nirogacestat
other name: PF-03084014
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Sugar pill manufactured to mimic nirogacestat 50 mg tablet
arm group label: Double-Blind Phase - Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bernd Kasper, MD
role: Principal Investigator
affiliation: Mannheim University Medical Center
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country: Belgium
country: Canada
country: Germany
country: Italy
country: Netherlands
country: United Kingdom
country: United States
country: France
responsible party type: Sponsor
mesh term: Fibromatosis, Aggressive
mesh term: Fibroma
mesh term: Aggression
mesh term: Nirogacestat
sharing ipd: Yes
ipd 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.