Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Participants With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation

Leukemia, Myeloid, Acute Clinical Trial

— AGILE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03173248
• Other study ID #: AG120-C-009
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 26, 2017
• Est. completion date: June 30, 2026

Study information

• Verified date: April 2024
• Source: Servier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 146
• Est. completion date: June 30, 2026
• Est. primary completion date: March 18, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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.

2. 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.

3. Have an isocitrate dehydrogenase 1 (IDH1) mutation.

4. Have an ECOG PS score of 0 to 2.

5. Have adequate hepatic function.

6. Have adequate renal function.

7. Have agreed to undergo serial blood and bone marrow sampling.

8. Be able to understand and willing to sign an informed consent form (ICF).

9. Be willing to complete Quality of Life assessments during the study

10. 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.

Exclusion Criteria:

1. Are candidates for and willing to receive intensive induction chemotherapy (IC) for their AML.

2. Have received any prior treatment for AML with the exception of hydroxyurea.

3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS).

4. 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.

5. Have received prior treatment with an IDH1 inhibitor.

6. Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.

7. Are female and pregnant or breastfeeding.

8. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.

9. 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.

10. Have had significant active cardiac disease within 6 months prior to the start of the study treatment.

11. Have any condition that increases the risk of abnormal ECG or cardiac arrhythmia.

12. Have a condition that limits the ingestion or absorption of drugs administered by mouth.

13. Have uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg).

14. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia.

15. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.

16. 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.

17. 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.)

18. Have a known medical history of progressive multifocal leukoencephalopathy.

Related Conditions & MeSH terms

• AML Arising From Myelodysplastic Syndrome (MDS)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Newly Diagnosed Acute Myeloid Leukemia (AML)
• Preleukemia
• Untreated AML

Intervention

Drug:
• AG-120
Tablets administered orally
• Placebo
Tablets administered orally
• Azacitidine
Administered SC or IV

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Flinders Medical Centre	Bedford park	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Austria	Salzburger Landeskliniken	Salzburg
Austria	Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel	Wien
Brazil	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 Santa Marcelina	Sao Paulo
Brazil	Hospital Sao Jose	Sao Paulo
Brazil	Hospital Sirio Libanes	Sao Paulo
Canada	University Health Network	Toronto	Ontario
Canada	Cancer Care Manitoba	Winnipeg	Manitoba
China	Peking Union Medical College Hospital	Beijing
China	West China Hospital Sichuan University	Chengdu	Sichuan
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	Henan Cancer Hospital	Zhengzhou	Henan
Czechia	Fakultni nemocnice Ostrava	Ostrava
France	CHRU de Brest - Hopital Morvan	Brest
France	Institut dHematologie de Basse Normandie	Caen
France	CHU de Grenoble	Grenoble
France	Centre Hospitalier de Versailles CHV Hopital Andre Mignot	Le Chesnay
France	Centre Hospitalier Le Mans	Le Mans	Sarthe
France	Hotel Dieu - Nantes	Nantes	Loire-Atlantique
France	Groupe Hospitalier Necker Enfants Malades	Paris
France	Hopital Haut Leveque	Pessac	Gironde
France	Centre Hospitalier Lyon Sud	Pierre-benite	Rhone
France	CHRU de Poitiers La Miletrie	Poitiers
France	Hopital de Hautepierre	Strasbourg
France	EDOG - Institut Claudius Regaud - PPDS	Toulouse
France	Hopital Bretonneau	Tours	Indre-et-Loire
France	Institut Gustave Roussy	Villejuif
Germany	Charite - Universitatsmedizin Berlin	Berlin
Germany	Klinikum Chemnitz gGmbH	Chemnitz	Sachsen
Germany	Universitatsklinikum Essen	Essen	Nordrhein-Westfalen
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitatsklinikum Leipzig	Leipzig
Germany	LMU Klinikum der Universitat Munchen	Munchen
Germany	Universitatsklinikum Ulm	Ulm
Israel	Rabin Medical Center - PPDS	Petah Tikva
Israel	Kaplan Medical Center	Rehovot
Italy	Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori IRST - PPDS	Meldola
Italy	ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda	Milano
Italy	Ospedale San Raffaele S.r.l. - PPDS	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	ASST dei Sette Laghi - Ospedale Di Circolo E Fondazione Macchi	Varese	Lombardia
Japan	University of Fukui Hospital	Fukui
Japan	Japanese Red Cross Society Himeji Hospital	Himeji
Japan	Kobe City Medical Center General Hospital	Kobe
Japan	Matsuyama Red Cross Hospital	Matsuyama	Ehime
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggido
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System	Seoul
Korea, Republic of	Ajou University Hospital	Suwon-si	Gyeonggido
Mexico	SINACOR	Culiacan
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Mexico
Netherlands	VU Medisch Centrum	Amsterdam	Noord-Holland
Netherlands	Universitair Medisch Centrum Groningen	Nijmegen
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Instytut Hematologii i Transfuzjologii	Warszawa	Mazowieckie
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu	Wroclaw	Dolnoslaskie
Russian Federation	Kaluga Regional Clinical Hospital	Kaluga
Russian Federation	City Clinical Hospital # 40	Moscow
Spain	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron - PPDS	Barcelona
Spain	Hospital Universitario de Gran Canaria Doctor Negrin	Las Palmas de Gran Canaria	Las Palmas
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Son Espases	Palma de Mallorca	Baleares
Spain	CHUS H. Clinico U. de Santiago	Santiago de Compostela	A Coruna
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
Taiwan	Changhua Christian Medical Foundation Changhua Christian Hospital	Changhua City
Taiwan	Kaohsiung Medical University Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung City
Taiwan	Chi Mei Medical Center, Liouying	Tainan City
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Birmingham Heartlands Hospital	Birmingham	West Midlands
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Norton Cancer Institute - Suburban	Louisville	Kentucky

Sponsors (1)

Lead Sponsor	Collaborator
Institut de Recherches Internationales Servier

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Brazil,  Canada,  China,  Czechia,  France,  Germany,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-Free Survival (EFS)	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.	Up to Week 24
Secondary	Complete Remission Rate (CR Rate)	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.	Up to approximately 52 months
Secondary	Overall Survival (OS)	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.	Up to approximately 52 months
Secondary	CR + Complete Remission With Partial Hematologic (CRh) Rate	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.	Up to approximately 52 months
Secondary	Objective Response Rate (ORR)	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.	Up to approximately 52 months
Secondary	CR + CRi (Including CRp) Rate	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.	Up to approximately 52 months
Secondary	Duration of CR (DOCR)	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.	Up to approximately 52 months
Secondary	Duration of CRh (DOCRh)	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.	Up to approximately 52 months
Secondary	Duration of Response (DOR)	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.	Up to approximately 52 months
Secondary	Duration of CRi (DOCRi)	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).	Up to approximately 52 months
Secondary	Time to CR (TTCR)	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.	Up to approximately 52 months
Secondary	Time to CRh (TTCRh)	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.	Up to approximately 52 months
Secondary	Time to Response (TTR)	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.	Up to approximately 52 months
Secondary	Time to CRi (TTCRi)	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).	Up to approximately 52 months
Secondary	Percentage of Participants With Abnormalities in Vital Sign Measurements	Vital signs will include body temperature, respiratory rate, blood pressure, and heart rate.	Up to approximately 52 months
Secondary	Percentage of Participants With Abnormalities in Eastern Cooperative Oncology Group Performance Status (ECOG PS)		Up to approximately 52 months
Secondary	Percentage of Participants With Abnormalities in 12-lead Electrocardiograms (ECGs)		Up to approximately 52 months
Secondary	Percentage of Participants With Abnormalities in Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) for Left Ventricular Ejection Fraction (LVEF)	LVEF is determined by ECHO or MUGA scan in participants.	Up to approximately 52 months
Secondary	Percentage of Participants With Abnormalities in Clinical Laboratory Tests	Clinical laboratory assessments will include hematology, serum chemistry, coagulation.	Up to approximately 52 months
Secondary	Percentage of Participants With Adverse Events (AEs)	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.	Up to approximately 52 months
Secondary	Percentage of Participants With AEs of Special Interest (AESIs)	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.	Up to approximately 52 months
Secondary	Percentage of Participants With Serious Adverse Events (SAEs)	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.	Up to approximately 52 months
Secondary	Percentage of Participants With Adverse Events Leading to Discontinuation or Death	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.	Up to approximately 52 months
Secondary	Percentage of Participants Using Concomitant Medications	Participants receiving concomitant medications will be adequately monitored by ECG controls, drug concentration (where applicable), and serum electrolytes (i.e., potassium and magnesium).	Up to approximately 52 months
Secondary	Units of Platelets and Red Blood Cells (RBC) Infused	All measures that are indicative of clinical benefit are measured like number of units of platelet and RBC infused.	Up to approximately 52 months
Secondary	Rate of Infection		Up to approximately 52 months
Secondary	Number of Days Spent Hospitalized		Up to approximately 52 months
Secondary	Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) QLC-C30 Questionnaire	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.	Up to approximately 52 months
Secondary	Change From Baseline in the EORTC EQ-5D-5L Questionnaire	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.	Up to approximately 52 months
Secondary	Percentage of Participants With CR With IDH1 Mutation Clearance (MC)	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.	Up to approximately 52 months
Secondary	Percentage of Participants With Drug Exposure, Dose Modifications and Dose Intensities	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.	Up to approximately 52 months
Secondary	Circulating Plasma Concentration of AG-120	Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.	Up to approximately 52 months
Secondary	Circulating Plasma Concentration of 2-HG	Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.	Up to approximately 52 months