A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of AG-120 in Combination With Azacitidine in Subjects ≥ 18 Years of Age With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 146
- 试验地点
- 172
- 主要终点
- Event-Free Survival (EFS)
研究概览
简要总结
Study AG120-C-009 is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of AG-120 (ivosidenib) + azacitidine vs placebo + azacitidine in adult participants with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy. The primary endpoint is event-free survival (EFS). The key secondary efficacy endpoints are overall survival (OS), rate of complete remission (CR), rate of CR and complete remission with partial hematologic recovery (CRh), and overall response rate (ORR). Participants eligible for study treatment based on Screening assessments will be randomized 1:1 to receive oral AG-120 or matched placebo, both administered in combination with subcutaneous (SC) or intravenous (IV) azacitidine. An estimated 200 participants will take part in the study.
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
- Triple (Participant, Care Provider, 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 and meet at least 1 of the following criteria defining ineligibility for intensive induction chemotherapy (IC): ≥ 75 years old, Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 2, severe cardiac disorder (e.g., congestive heart failure requiring treatment, left ventricular ejection fraction (LVEF), ≤50%, or chronic stable angina), severe pulmonary disorder (e.g., diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%), creatinine clearance <45 mL/minute, bilirubin >1.5 times the upper limit of normal (ULN) and/or have any other comorbidity that the Investigator judges to be incompatible with intensive IC and must be reviewed and approved by the Medical Monitor before study enrollment.
- •Have previously untreated AML, defined according to World Health Organization (WHO) criteria, with ≥ 20% leukemic blasts in the bone marrow. Participants with extramedullary disease alone (i.e., no detectable bone marrow and no detectable peripheral blood AML) are not eligible for the study.
- •Have an isocitrate dehydrogenase 1 (IDH1) mutation.
- •Have an ECOG PS score of 0 to
- •Have adequate hepatic function.
- •Have adequate renal function.
- •Have agreed to undergo serial blood and bone marrow sampling.
- •Be able to understand and willing to sign an informed consent form (ICF).
- •Be willing to complete Quality of Life assessments during the study
- •If female with reproductive potential, must have a negative serum pregnancy test prior to the start of study therapy. Females of reproductive potential, as well as fertile men and their female partners of reproductive potential, must agree to use 2 effective forms of contraception.
排除标准
- •Are candidates for and willing to receive intensive induction chemotherapy (IC) for their AML.
- •Have received any prior treatment for AML with the exception of hydroxyurea.
- •Have received a hypomethylating agent for myelodysplastic syndrome (MDS).
- •Participants who had previously received an experimental agent for MDS may not be randomized until a washout period has elapsed since the last dose of that agent.
- •Have received prior treatment with an IDH1 inhibitor.
- •Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.
- •Are female and pregnant or breastfeeding.
- •Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
- •Have a prior history of cancer other than MDS or myeloproliferative disorder, unless the participant has been free of the disease for ≥ 1 year prior to the start of study treatment.
- •Have had significant active cardiac disease within 6 months prior to the start of the study treatment.
- •Have any condition that increases the risk of abnormal ECG or cardiac arrhythmia.
- •Have a condition that limits the ingestion or absorption of drugs administered by mouth.
- •Have uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg).
- •Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia.
- •Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.
- •Have any other medical or psychological condition deemed by the Investigator to be likely to interfere with the participant's ability to give informed consent or participate in the study.
- •Are taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥5 half-lives prior to dosing, or unless the medications can be properly monitored during the study. (If equivalent medication is not available, heart rate corrected QT interval [QTc] will be closely monitored.)
- •Have a known medical history of progressive multifocal leukoencephalopathy.
研究组 & 干预措施
AG-120 + Azacitidine
Participants received AG-120 500 mg orally, once daily (QD) in combination with azacitidine 75 milligrams per square meter per day (mg/m^2/day) subcutaneously (SC) or intravenously (IV), on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation.
干预措施: AG-120 (Drug)
Placebo + Azacitidine
Participants received AG-120 matching placebo orally, QD in combination with azacitidine 75 mg/m^2/day SC or IV, on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation .
干预措施: Placebo (Drug)
AG-120 + Azacitidine
Participants received AG-120 500 mg orally, once daily (QD) in combination with azacitidine 75 milligrams per square meter per day (mg/m^2/day) subcutaneously (SC) or intravenously (IV), on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation.
干预措施: Azacitidine (Drug)
Placebo + Azacitidine
Participants received AG-120 matching placebo orally, QD in combination with azacitidine 75 mg/m^2/day SC or IV, on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation .
干预措施: Azacitidine (Drug)
结局指标
主要结局
Event-Free Survival (EFS)
时间窗: Up to Week 24
EFS was defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure was defined as failure to achieve complete remission (CR) by Week 24. CR: Bone marrow blasts \<5% and no Auer rods; absence of extramedullary disease; Absolute neutrophil count (ANC) ≥1.0 × 10\^9 per litre (10\^9/L) (1000 per microlitre \[1000/μL\]); platelet count ≥100 × 10\^9/L (100,000/μL); independence of red blood cell transfusions. Participants who had an EFS event (relapse or death) after, 2 or more missing disease assessments were censored at the last adequate disease assessment documenting no relapse before the missing assessments. The reported data represents the Kaplan-Meier median value.
次要结局
- Complete Remission Rate (CR Rate)(Up to approximately 52 months)
- Overall Survival (OS)(Up to approximately 52 months)
- CR + Complete Remission With Partial Hematologic (CRh) Rate(Up to approximately 52 months)
- Objective Response Rate (ORR)(Up to approximately 52 months)
- CR + CRi (Including CRp) Rate(Up to approximately 52 months)
- Duration of CR (DOCR)(Up to approximately 52 months)
- Duration of CRh (DOCRh)(Up to approximately 52 months)
- Duration of Response (DOR)(Up to approximately 52 months)
- Duration of CRi (DOCRi)(Up to approximately 52 months)
- Time to CR (TTCR)(Up to approximately 52 months)
- Time to CRh (TTCRh)(Up to approximately 52 months)
- Time to Response (TTR)(Up to approximately 52 months)
- Time to CRi (TTCRi)(Up to approximately 52 months)
- Percentage of Participants With Abnormalities in Vital Sign Measurements(Up to approximately 52 months)
- Percentage of Participants With Abnormalities in 12-lead Electrocardiograms (ECGs)(Up to approximately 52 months)
- Percentage of Participants With Abnormalities in Eastern Cooperative Oncology Group Performance Status (ECOG PS)(Up to approximately 52 months)
- Percentage of Participants With Abnormalities in Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) for Left Ventricular Ejection Fraction (LVEF)(Up to approximately 52 months)
- Percentage of Participants With Abnormalities in Clinical Laboratory Tests(Up to approximately 52 months)
- Percentage of Participants With Adverse Events (AEs)(Up to approximately 52 months)
- Percentage of Participants With Serious Adverse Events (SAEs)(Up to approximately 52 months)
- Rate of Infection(Up to approximately 52 months)
- Percentage of Participants With AEs of Special Interest (AESIs)(Up to approximately 52 months)
- Units of Platelets and Red Blood Cells (RBC) Infused(Up to approximately 52 months)
- Percentage of Participants Using Concomitant Medications(Up to approximately 52 months)
- Change From Baseline in the EORTC EQ-5D-5L Questionnaire(Up to approximately 52 months)
- Percentage of Participants With Adverse Events Leading to Discontinuation or Death(Up to approximately 52 months)
- Number of Days Spent Hospitalized(Up to approximately 52 months)
- Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) QLC-C30 Questionnaire(Up to approximately 52 months)
- Percentage of Participants With CR With IDH1 Mutation Clearance (MC)(Up to approximately 52 months)
- Percentage of Participants With Drug Exposure, Dose Modifications and Dose Intensities(Up to approximately 52 months)
- Circulating Plasma Concentration of AG-120(Up to approximately 52 months)
- Circulating Plasma Concentration of 2-HG(Up to approximately 52 months)