A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 142
- 试验地点
- 99
- 主要终点
- Progression Free Survival (PFS) Defined as the Time From Randomization Until Date of Assessment of Progression or Death by Any Cause.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
- •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.
研究组 & 干预措施
Double-Blind Phase - Placebo
Placebo by mouth, twice daily
干预措施: Placebo Oral Tablet (Drug)
Double-Blind Phase - Nirogacestat
Nirogacestat 150 mg by mouth, twice daily
干预措施: Nirogacestat oral tablet (Drug)
Open-Label Phase - Nirogacestat
Nirogacestat 150 mg by mouth, twice daily
干预措施: Nirogacestat oral tablet (Drug)
结局指标
主要结局
Progression Free Survival (PFS) Defined as the Time From Randomization Until Date of Assessment of Progression or Death by Any Cause.
时间窗: 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 (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.
次要结局
- 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.(Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years)
- Objective Response Rate Using RECIST Version 1.1 Criteria.(On the first day of every 3 cycles (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(On the last day of every cycle (each cycle is 28 days) through study completion, average of 2 years.)
- Change From Baseline at Cycle 10 in the Brief Pain Inventory (BPI) Average Pain Intensity (API) Score.(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(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 European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Role Functioning.(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(Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years)