Clinical trial NCT03173248: Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Participants With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Newly Diagnosed Acute Myeloid Leukemia (AML)
Untreated AML
AML Arising From Myelodysplastic Syndrome (MDS)
Leukemia, Myeloid, Acute
Keywords: Acute Myeloid Leukemia
Leukemia
Azacitidine
AG-120
ivosidenib
Lead sponsor: Servier
Sponsor class: INDUSTRY
First posted: 2017-06-01
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Event-Free Survival (EFS)
timeFrame: Up to Week 24
Secondary outcomes:
measure: Complete Remission Rate (CR Rate)
timeFrame: Up to approximately 52 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 52 months
measure: CR + Complete Remission With Partial Hematologic (CRh) Rate
timeFrame: Up to approximately 52 months
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 52 months
measure: CR + CRi (Including CRp) Rate
timeFrame: Up to approximately 52 months
measure: Duration of CR (DOCR)
timeFrame: Up to approximately 52 months
measure: Duration of CRh (DOCRh)
timeFrame: Up to approximately 52 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 52 months
measure: Duration of CRi (DOCRi)
timeFrame: Up to approximately 52 months
measure: Time to CR (TTCR)
timeFrame: Up to approximately 52 months
measure: Time to CRh (TTCRh)
timeFrame: Up to approximately 52 months
measure: Time to Response (TTR)
timeFrame: Up to approximately 52 months
measure: Time to CRi (TTCRi)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Abnormalities in Vital Sign Measurements
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Abnormalities in Eastern Cooperative Oncology Group Performance Status (ECOG PS)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Abnormalities in 12-lead Electrocardiograms (ECGs)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Abnormalities in Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) for Left Ventricular Ejection Fraction (LVEF)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Abnormalities in Clinical Laboratory Tests
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With AEs of Special Interest (AESIs)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Serious Adverse Events (SAEs)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Adverse Events Leading to Discontinuation or Death
timeFrame: Up to approximately 52 months
measure: Percentage of Participants Using Concomitant Medications
timeFrame: Up to approximately 52 months
measure: Units of Platelets and Red Blood Cells (RBC) Infused
timeFrame: Up to approximately 52 months
measure: Rate of Infection
timeFrame: Up to approximately 52 months
measure: Number of Days Spent Hospitalized
timeFrame: Up to approximately 52 months
measure: Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) QLC-C30 Questionnaire
timeFrame: Up to approximately 52 months
measure: Change From Baseline in the EORTC EQ-5D-5L Questionnaire
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With CR With IDH1 Mutation Clearance (MC)
timeFrame: Up to approximately 52 months
measure: Percentage of Participants With Drug Exposure, Dose Modifications and Dose Intensities
timeFrame: Up to approximately 52 months
measure: Circulating Plasma Concentration of AG-120
timeFrame: Up to approximately 52 months
measure: Circulating Plasma Concentration of 2-HG
timeFrame: Up to approximately 52 months
Other outcomes:
Locations:
city: Louisville
country: United States
facility: Norton Cancer Institute - Suburban
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bedford park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Salzburg
country: Austria
facility: Salzburger Landeskliniken
city: Wien
country: Austria
facility: Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel
city: Campinas
country: Brazil
facility: Unicamp Universidade Estadual de Campinas
state: Sao Paulo
city: Jau
country: Brazil
facility: Hospital Amaral Carvalho
state: Sao Paulo
city: Rio De Janeiro
country: Brazil
facility: Instituto Nacional de Cancer
city: Sao Paulo
country: Brazil
facility: Hospital Sirio Libanes
city: Sao Paulo
country: Brazil
facility: Hospital Sao Jose
city: Sao Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Chengdu
country: China
facility: West China Hospital Sichuan University
state: Sichuan
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
city: Hangzhou
country: China
facility: The First Affiliated Hospital, College of Medicine, Zhejiang University
city: Tianjin
country: China
facility: Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Pessac
country: France
facility: Hopital Haut Leveque
state: Gironde
city: Tours
country: France
facility: Hopital Bretonneau
state: Indre-et-Loire
city: Nantes
country: France
facility: Hotel Dieu - Nantes
state: Loire-Atlantique
city: Pierre-benite
country: France
facility: Centre Hospitalier Lyon Sud
state: Rhone
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
state: Sarthe
city: Brest
country: France
facility: CHRU de Brest - Hopital Morvan
city: Caen
country: France
facility: Institut dHematologie de Basse Normandie
city: Grenoble
country: France
facility: CHU de Grenoble
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles CHV Hopital Andre Mignot
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: Poitiers
country: France
facility: CHRU de Poitiers La Miletrie
city: Strasbourg
country: France
facility: Hopital de Hautepierre
city: Toulouse
country: France
facility: EDOG - Institut Claudius Regaud - PPDS
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Essen
country: Germany
facility: Universitatsklinikum Essen
state: Nordrhein-Westfalen
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
state: Sachsen
city: Berlin
country: Germany
facility: Charite - Universitatsmedizin Berlin
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
city: Munchen
country: Germany
facility: LMU Klinikum der Universitat Munchen
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Petah Tikva
country: Israel
facility: Rabin Medical Center - PPDS
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Tzrifin
country: Israel
facility: Shamir Medical Center Assaf Harofeh
city: Varese
country: Italy
facility: ASST dei Sette Laghi - Ospedale Di Circolo E Fondazione Macchi
state: Lombardia
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori IRST - PPDS
city: Milano
country: Italy
facility: Ospedale San Raffaele S.r.l. - PPDS
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo di Pavia
city: Rimini
country: Italy
facility: Ospedale Infermi di Rimini
city: Torino
country: Italy
facility: Azienda Ospedaliera Citta della Salute e della Scienza di Torino
city: Matsuyama
country: Japan
facility: Matsuyama Red Cross Hospital
state: Ehime
city: Fukui
country: Japan
facility: University of Fukui Hospital
city: Himeji
country: Japan
facility: Japanese Red Cross Society Himeji Hospital
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggido
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
state: Gyeonggido
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Culiacan
country: Mexico
facility: SINACOR
city: Mexico
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
state: Noord-Holland
city: Nijmegen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu
state: Dolnoslaskie
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
state: Mazowieckie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kaluga
country: Russian Federation
facility: Kaluga Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: City Clinical Hospital # 40
city: Santiago de Compostela
country: Spain
facility: CHUS H. Clinico U. de Santiago
state: A Coruna
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Baleares
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Barcelona
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Doctor Negrin
state: Las Palmas
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa
city: Changhua City
country: Taiwan
facility: Changhua Christian Medical Foundation Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Taichung City
country: Taiwan
facility: China Medical University Hospital
city: Tainan City
country: Taiwan
facility: Chi Mei Medical Center, Liouying
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: West Midlands
Study officials:
References:
citation: Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, Heuser M, Calado RT, Schuh AC, Yeh SP, Daigle SR, Hui J, Pandya SS, Gianolio DA, de Botton S, Dohner H. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022 Apr 21;386(16):1519-1531. doi: 10.1056/NEJMoa2117344.