A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 187
- 试验地点
- 47
- 主要终点
- Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)
研究概览
简要总结
Study AG120-C-005 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of orally administered AG-120. Participants, all personnel involved in the evaluation of participants' response to treatment (e.g., Investigators, study coordinators, study pharmacists), and designated Sponsor team members will be blinded to study treatment. Participants are required to have a histologically-confirmed diagnosis of isocitrate dehydrogenase-1 (IDH1) gene-mutated cholangiocarcinoma that is not eligible for curative resection, transplantation, or ablative therapies prior to enrollment. IDH1 mutation testing will be performed at participating investigative sites. Participants must have progression of disease and have received at least 1 but not more than 2 prior treatment regimens for advanced disease (nonresectable or metastatic). All participants must have received either a gemcitabine or a 5 fluorouracil (5-FU) based chemotherapy regimen.
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
- Double (Participant, Investigator)
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
- •Be ≥18 years of age.
- •Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably collected within the last 3 years) of nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation, or ablative therapies.
- •Have documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent banked tumor tissue available) based on central laboratory testing (R132C/L/G/H/S mutation variants tested).
- •Have an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1
- •Have an expected survival of ≥3 months.
- •Have at least one evaluable and measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.
- •Participants who have received prior local therapy (including but not limited to embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or within the field and has shown ≥20% growth in size since post-treatment assessment.
- •Have documented disease progression following at least 1 and no more than 2 prior systemic regimens for advanced disease (nonresectable or metastatic). Participants must have received at least 1 gemcitabine- or 5-FU-containing regimen for advanced cholangiocarcinoma. Participants who have received systemic adjuvant chemotherapy will be permitted provided there is documented disease progression during or within 6 months of completing the therapy.
- •Exclusion criteria:
- •Received a prior IDH inhibitor.
- •Received systemic anticancer therapy or an investigational agent <2 weeks prior to Day 1 (washout from prior immune based anticancer therapy is 4 weeks). In addition, the first dose of study treatment should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
- •Received radiotherapy to metastatic sites of disease <2 weeks prior to Day
- •Underwent hepatic radiation, chemoembolization, and radiofrequency ablation <4 weeks prior to Day
- •Have known symptomatic brain metastases requiring steroids. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and have radiographically stable disease for at least 3 months prior to study entry. Note: up to 10 mg per day of prednisone equivalent will be allowed.
排除标准
- 未提供
研究组 & 干预措施
AG-120
Participants received AG-120 500 mg, tablet, orally, once a day (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.
干预措施: AG-120 (Drug)
Placebo
Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120.
干预措施: Placebo (Drug)
After Cross over to AG-120
Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
干预措施: AG-120 (Drug)
结局指标
主要结局
Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)
时间窗: From the date of randomization to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)
PFS is defined as the time from date of randomization to the date of first documented disease progression as assessed by the IRC using Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1, or date of death due to any cause, whichever occurred first. Disease progression was defined as greater than or equal to (≥)20 percent (%) increase in sum of the diameter of target lesions, taking as reference the smallest sum diameter recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm) or the appearance of 1 or more new lesions.
次要结局
- Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 Years))
- Percentage of Participants Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events(From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years))
- DOR as Assessed by the IRC Per RECIST v1.1(From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years))
- Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21)(Cycle 2 Day 1 and Cycle 3 Day 1)
- Accumulation Ratio Based on AUC0-4 (Racc AUC0-4)(Post-dose Cycle 2 Day 1 (each cycle = 28 days))
- Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4(Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days))
- ORR as Assessed by the IRC Per RECIST v1.1(From the date of randomization up to confirmed CR or PR (Up to approximately 2 years))
- Duration of Response (DOR) as Assessed by the Investigator(From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years))
- Percentage of Participants With Change Based on HRQOL: Patient Global Impression of Change (PGI-C)(Cycle 2 Day 1 and Cycle 3 Day 1)
- Time to Reach Maximal Plasma Concentration (Tmax) of AG-120(Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days))
- Percentage of Participants With Clinically Significant Grade 3 or Higher Vital Signs AEs(From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years))
- Percentage of Participants Who Required At Least One Concomitant Medications During the Treatment(From first dose of study drug up to 28 days after last dose (Up to approximately 4 Years))
- Percentage of Participants With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S)(Cycle 2 Day 1 and Cycle 3 Day 1)
- Percentage of Participants With Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response(Cycle 3 Day 1)
- Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score(Cycle 3 Day 1)
- Accumulation Ratio Based on Cmax (Racc Cmax)(Post-dose Cycle 2 Day 1 (each cycle = 28 days))
- Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4(Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days))
- Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough(Post-dose Cycle 2 Day 1 (each cycle = 28 days))
- Overall Survival (OS)(From date of randomization until the date of death due to any cause (Up to approximately 2 years))
- Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1(From the date of randomization up to confirmed CR or PR (Up to approximately 2 years))
- Time to Response (TTR) as Assessed by the Investigator(From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years))
- TTR as Assessed by the IRC Per RECIST v1.1(From the date of randomization up to the date of first documented CR or PR (Up to approximately 2 years))
- Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores(Cycle 2 Day 1 and Cycle 3 Day 1)
- Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status(Baseline)
- Percentage of Participants With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events(Pre-dose C1D1, C2D1; Post-dose C1D1, C1D15, C2D1 and Day 1 of C3D1 and all cycles thereafter up to last dose plus 28 days (Up to approximately 4 years))
- PFS as Determined by Investigator(From the date of randomization to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years))
- Maximum Observed Plasma Concentration (Cmax) of AG-120(Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days))
- Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24)(Post-dose of Cycle 2 Day 1 (each cycle = 28 days))
- Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough(Post-dose Cycle 2 Day 1 (each cycle = 28 days))
- Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value)(Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days))
- Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4)(Post-dose of Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days))