Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Participants With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation
- Conditions
- Newly Diagnosed Acute Myeloid Leukemia (AML)Untreated AMLAML Arising From Myelodysplastic Syndrome (MDS)Leukemia, Myeloid, Acute
- Interventions
- Registration Number
- NCT03173248
- Lead Sponsor
- Institut de Recherches Internationales Servier
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 146
- 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 2.
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description AG-120 + Azacitidine AG-120 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. Placebo + Azacitidine Placebo 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 . AG-120 + Azacitidine 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. Placebo + Azacitidine 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 .
- Primary Outcome Measures
Name Time Method Event-Free Survival (EFS) 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.
- Secondary Outcome Measures
Name Time Method Complete Remission Rate (CR Rate) Up to approximately 52 months CR rate is defined as the proportion of participants who achieve a CR. A Cochran-Mantel-Haenszel (CMH) test will be used to compare CR rate between the 2 treatment arms.
Overall Survival (OS) Up to approximately 52 months OS is defined as the time from date of randomization to the date of death due to any cause. Kaplan-Meier (KM) curves and KM estimates of OS will be presented for each treatment arm.
CR + Complete Remission With Partial Hematologic (CRh) Rate Up to approximately 52 months CR + CRh rate is defined as the proportion of participants who achieve a CR or CRh. CRh is defined as a CR with partial recovery of peripheral blood counts (less than 5% bone marrow blasts, absolute neutrophil count (ANC) greater than 0.5 × 10\^9/liter (L) 500/microliter (μL)\], and platelets greater than 50 × 10\^9/L \[50,000/μL\]). A CMH test will be used to compare the CR + CRh rate between the 2 treatment arms.
Objective Response Rate (ORR) Up to approximately 52 months ORR is defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery \[CRp\]), partial remission (PR), and morphologic leukemia-free state (MLFS). The best response is calculated using the following hierarchy: CR, followed by CRi (including CRp), followed by PR and MLFS. A summary of best response by treatment arm will be produced. A CMH test will be used to compare ORR between the 2 treatment arms.
CR + CRi (Including CRp) Rate Up to approximately 52 months The CR + CRi (including CRp) rate is defined as the proportion of participants who achieve a CR or CRi (including CRp). A CMH test will be used to compare the CR + CRi (including CRp) rate between the 2 treatment arms.
Duration of CR (DOCR) Up to approximately 52 months DOCR will be calculated as the date of the first occurrence of CR to the date of first documented disease relapse, or death. DOCR is only defined for participants who achieve a CR.
Duration of CRh (DOCRh) Up to approximately 52 months DOCRh will be calculated as the date of the first occurrence of CR or CRh to the date of first documented disease relapse or death. DOCRh is only defined for participants who achieve a CR or CRh.
Duration of Response (DOR) Up to approximately 52 months DOR will be calculated as the date of the first response to the date of first documented disease relapse, disease progression, or death. DOR is only defined for participants who achieve a CR, CRi (including CRp), PR, and/or MLFS.
Duration of CRi (DOCRi) Up to approximately 52 months DOCRi will be calculated as the date of the first occurrence of CR or CRi (including CRp) to the date of the first documented relapse or death. DOCRi is only defined for participants who achieve a CR or CRi (including CRp).
Time to CR (TTCR) Up to approximately 52 months TTCR will be assessed from the date of randomization to the date of first occurrence of CR. TTCR is only defined for participants who achieve a CR.
Time to CRh (TTCRh) Up to approximately 52 months TTCRh will be assessed from the date of randomization to the date of first occurrence of CR or CRh. TTCRh is only defined for participants who achieve a CR or CRh.
Time to Response (TTR) Up to approximately 52 months TTR will be assessed from the date of randomization to the date of the first response. TTR is only defined for participants who achieve a CR, CRi (including CRp), PR, and/or MLFS.
Time to CRi (TTCRi) Up to approximately 52 months TTCRi will be assessed from the date of randomization to the date of first occurrence of CR or CRi (including CRp). TTCRi is only defined for participants who achieve a CR or CRi (including CRp).
Percentage of Participants With Abnormalities in Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) for Left Ventricular Ejection Fraction (LVEF) Up to approximately 52 months LVEF is determined by ECHO or MUGA scan in participants.
Percentage of Participants With Abnormalities in Clinical Laboratory Tests Up to approximately 52 months Clinical laboratory assessments will include hematology, serum chemistry, coagulation.
Percentage of Participants With Abnormalities in Vital Sign Measurements Up to approximately 52 months Vital signs will include body temperature, respiratory rate, blood pressure, and heart rate.
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 Adverse Events (AEs) Up to approximately 52 months An AE is defined as any untoward medical occurrence in a clinical investigation participant administered an investigational medicinal product; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.
Percentage of Participants With Serious Adverse Events (SAEs) Up to approximately 52 months An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Rate of Infection Up to approximately 52 months Percentage of Participants With AEs of Special Interest (AESIs) Up to approximately 52 months AESIs are AEs that are not solicited local or systemic AEs, they are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESIs include protocol-specified QT prolongation, isocitrate dehydrogenase (IDH) differentiation syndrome and leukocytosis.
Units of Platelets and Red Blood Cells (RBC) Infused Up to approximately 52 months All measures that are indicative of clinical benefit are measured like number of units of platelet and RBC infused.
Change From Baseline in the EORTC EQ-5D-5L Questionnaire Up to approximately 52 months The EORTC EQ-5D-5L questionnaire measures quality of life and spans 5 dimensions, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, which are used to build a composite of the participant's health status.
Percentage of Participants Using Concomitant Medications Up to approximately 52 months Participants receiving concomitant medications will be adequately monitored by ECG controls, drug concentration (where applicable), and serum electrolytes (i.e., potassium and magnesium).
Percentage of Participants With Adverse Events Leading to Discontinuation or Death Up to approximately 52 months An AE is defined as any untoward medical occurrence in a clinical investigation participant administered an investigational medicinal product; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.
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 The EORTC QLQ-C30 questionnaire measures quality of life and consists of 30 questions that are incorporated into 5 functional domains (physical, role, cognitive, emotional, and social); a global health status/global quality of life; 3 symptom scales (fatigue, pain, and nausea and vomiting); and 6 single items that assess additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and the perceived financial burden of treatment experienced by participants with cancer.
Percentage of Participants With CR With IDH1 Mutation Clearance (MC) Up to approximately 52 months CR with IDH1 MC is defined as a response of CR where there is no evidence of the IDH1 mutation by molecular techniques to below the level of detection (0.02%-0.04%) for ≥1 on-treatment time point. A CMH test will be used to compare the rate of CR between 2 treatment arms.
Percentage of Participants With Drug Exposure, Dose Modifications and Dose Intensities Up to approximately 52 months The number of doses administered, total dose, duration of treatment, dose intensity, and the proportion of participants with dose modifications, will be summarized by treatment arm.
Circulating Plasma Concentration of AG-120 Up to approximately 52 months Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.
Circulating Plasma Concentration of 2-HG Up to approximately 52 months Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.
Trial Locations
- Locations (90)
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Shamir Medical Center Assaf Harofeh
🇮🇱Tzrifin, Israel
Norton Cancer Institute - Suburban
🇺🇸Louisville, Kentucky, United States
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
Chi Mei Medical Center, Liouying
🇨🇳Tainan City, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
CHU de Grenoble
🇫🇷Grenoble, France
Hopital de Hautepierre
🇫🇷Strasbourg, France
EDOG - Institut Claudius Regaud - PPDS
🇫🇷Toulouse, France
CHRU de Poitiers La Miletrie
🇫🇷Poitiers, France
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Flinders Medical Centre
🇦🇺Bedford park, South Australia, Australia
Salzburger Landeskliniken
🇦🇹Salzburg, Austria
Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel
🇦🇹Wien, Austria
Unicamp Universidade Estadual de Campinas
🇧🇷Campinas, Sao Paulo, Brazil
Hospital Amaral Carvalho
🇧🇷Jau, Sao Paulo, Brazil
Instituto Nacional de Cancer
🇧🇷Rio De Janeiro, Brazil
Hospital Sirio Libanes
🇧🇷Sao Paulo, Brazil
Hospital Sao Jose
🇧🇷Sao Paulo, Brazil
Hospital Santa Marcelina
🇧🇷Sao Paulo, Brazil
Cancer Care Manitoba
🇨🇦Winnipeg, Manitoba, Canada
University Health Network
🇨🇦Toronto, Ontario, Canada
Henan Cancer Hospital
🇨🇳Zhengzhou, Henan, China
West China Hospital Sichuan University
🇨🇳Chengdu, Sichuan, China
Peking Union Medical College Hospital
🇨🇳Beijing, China
Guangdong Provincial People's Hospital
🇨🇳Guangzhou, China
The First Affiliated Hospital, College of Medicine, Zhejiang University
🇨🇳Hangzhou, China
Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences
🇨🇳Tianjin, China
Fakultni nemocnice Ostrava
🇨🇿Ostrava, Czechia
Hopital Haut Leveque
🇫🇷Pessac, Gironde, France
Hopital Bretonneau
🇫🇷Tours, Indre-et-Loire, France
Hotel Dieu - Nantes
🇫🇷Nantes, Loire-Atlantique, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre-benite, Rhone, France
Centre Hospitalier Le Mans
🇫🇷Le Mans, Sarthe, France
CHRU de Brest - Hopital Morvan
🇫🇷Brest, France
Institut dHematologie de Basse Normandie
🇫🇷Caen, France
Centre Hospitalier de Versailles CHV Hopital Andre Mignot
🇫🇷Le Chesnay, France
Groupe Hospitalier Necker Enfants Malades
🇫🇷Paris, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Universitatsklinikum Essen
🇩🇪Essen, Nordrhein-Westfalen, Germany
Klinikum Chemnitz gGmbH
🇩🇪Chemnitz, Sachsen, Germany
Charite - Universitatsmedizin Berlin
🇩🇪Berlin, Germany
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Universitatsklinikum Leipzig
🇩🇪Leipzig, Germany
LMU Klinikum der Universitat Munchen
🇩🇪Munchen, Germany
Universitatsklinikum Ulm
🇩🇪Ulm, Germany
Rabin Medical Center - PPDS
🇮🇱Petah Tikva, Israel
Kaplan Medical Center
🇮🇱Rehovot, Israel
ASST dei Sette Laghi - Ospedale Di Circolo E Fondazione Macchi
🇮🇹Varese, Lombardia, Italy
Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori IRST - PPDS
🇮🇹Meldola, Italy
Ospedale San Raffaele S.r.l. - PPDS
🇮🇹Milano, Italy
ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda
🇮🇹Milano, Italy
Fondazione IRCCS Policlinico San Matteo di Pavia
🇮🇹Pavia, Italy
Ospedale Infermi di Rimini
🇮🇹Rimini, Italy
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
🇮🇹Torino, Italy
Matsuyama Red Cross Hospital
🇯🇵Matsuyama, Ehime, Japan
University of Fukui Hospital
🇯🇵Fukui, Japan
Japanese Red Cross Society Himeji Hospital
🇯🇵Himeji, Japan
Kobe City Medical Center General Hospital
🇯🇵Kobe, Japan
National Cancer Center
🇰🇷Goyang-si, Gyeonggido, Korea, Republic of
Ajou University Hospital
🇰🇷Suwon-si, Gyeonggido, Korea, Republic of
Pusan National University Hospital
🇰🇷Busan, Korea, Republic of
Severance Hospital Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
SINACOR
🇲🇽Culiacan, Mexico
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
🇲🇽Mexico, Mexico
VU Medisch Centrum
🇳🇱Amsterdam, Noord-Holland, Netherlands
Universitair Medisch Centrum Groningen
🇳🇱Nijmegen, Netherlands
Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu
🇵🇱Wroclaw, Dolnoslaskie, Poland
Instytut Hematologii i Transfuzjologii
🇵🇱Warszawa, Mazowieckie, Poland
Uniwersyteckie Centrum Kliniczne
🇵🇱Gdansk, Poland
Kaluga Regional Clinical Hospital
🇷🇺Kaluga, Russian Federation
City Clinical Hospital # 40
🇷🇺Moscow, Russian Federation
CHUS H. Clinico U. de Santiago
🇪🇸Santiago de Compostela, A Coruna, Spain
Hospital Universitario Son Espases
🇪🇸Palma de Mallorca, Baleares, Spain
Hospital Universitario Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Hospital Universitario de Gran Canaria Doctor Negrin
🇪🇸Las Palmas de Gran Canaria, Las Palmas, Spain
Hospital Universitario Vall d'Hebron - PPDS
🇪🇸Barcelona, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸Madrid, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Virgen del Rocio - PPDS
🇪🇸Sevilla, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸Valencia, Spain
Hospital Clinico Universitario Lozano Blesa
🇪🇸Zaragoza, Spain
Changhua Christian Medical Foundation Changhua Christian Hospital
🇨🇳Changhua City, Taiwan
Kaohsiung Medical University Hospital
🇨🇳Kaohsiung, Taiwan
China Medical University Hospital
🇨🇳Taichung City, Taiwan
Birmingham Heartlands Hospital
🇬🇧Birmingham, West Midlands, United Kingdom
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