A Phase 3 study to test the AG-120 in combination with Azacitidine in comparison with the use of Azacitidine alone in patients ≥ 18 Years of Age with previously untreated Acute Myeloid Leukemia with an IDH1 Mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Recherches Internationales Servier IRIS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

6 Feb 2018 → ongoing

Decision date (initial)

2024-11-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Institut de Recherches Internationales Servier (I.R.I.S.)

External identifiers

EU CT number

2024-514309-73-00

EudraCT number

2016-004907-30

ClinicalTrials.gov

NCT03173248

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Therapy, Pharmacoeconomic, Pharmacodynamic, Pharmacokinetic, Safety, Pharmacogenetic, Efficacy

To compare event-free survival (EFS) between AG-120 + azacitidine and placebo + azacitidine.

Secondary objectives 1

1. • To compare the complete remission (CR) rate between AG-120 + azacitidine and placebo + azacitidine. • To compare OS between AG-120 + azacitidine and placebo + azacitidine. • To compare the CR + CRh rate between AG-120 + azacitidine and placebo + azacitidine; CRh will be derived by the Sponsor • To compare the ORR between AG-120 + azacitidine and placebo + azacitidine

Conditions and MedDRA coding

Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Be ≥18 years of age and meet at least 1 of the following criteria defining ineligibility for intensive induction chemotherapy (IC): a. ≥ 75 years old b. ECOG PS = 2 c. Severe cardiac disorder (eg, congestive heart failure requiring treatment, LVEF ≤50%, or chronic stable angina) d. Severe pulmonary disorder (eg, diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%) e. Creatinine clearance <45 mL/minute f. Bilirubin >1.5 times upper limit of normal (× ULN) g. Any other comorbidity that the Investigator judges to be incompatible with intensive IC must be reviewed and approved by the Medical Monitor before study enrollment.
2. 2. Have previously untreated AML, defined according to World Health Organization criteria. Subjects with extramedullary disease alone (ie, no detectable bone marrow and no detectable peripheral blood AML) are not eligible for the study.
3. 3. Have an IDH1 mutation resulting in an R132C, R132G, R132H, R132L, or R132S substitution, as determined by central laboratory testing (using an investigational polymerase chain reaction [PCR] assay, Abbott RealTime IDH1) in their bone marrow aspirate (or peripheral blood sample if bone marrow aspirate is not available, with Medical Monitor approval). (Note: Local testing for eligibility and randomization is permitted with Medical Monitor approval; however, results must state an IDH1 mutation resulting in an R132C, R132G, R132H, R132L, or R132S substitution. Bone marrow aspirate [or peripheral blood sample if bone marrow aspirate is not available, with Medical Monitor approval] for central laboratory testing must have been sent with proof of shipment to the central laboratory prior to randomization.)
4. 4. Have an ECOG PS score of 0 to 2.
5. 5. Have adequate hepatic function, as evidenced by: a. Serum total bilirubin ≤2 × ULN, unless considered to be due to Gilbert’s disease or underlying leukemia, where it must be <3 × ULN. b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered to be due to underlying leukemia.
6. 6. Have adequate renal function, as evidenced by serum creatinine ≤2.0 × ULN or creatinine clearance >30 mL/min based on the Cockcroft-Gault glomerular filtration rate.
7. 7. Have agreed to undergo serial blood and bone marrow sampling.
8. 8. Be able to understand and willing to sign an informed consent form.
9. 9. Be willing to complete QoL assessments during study treatment and at the designated time points following treatment discontinuation.
10. 10. If female with reproductive potential, must have a negative serum pregnancy test prior to the start of study therapy. Female subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion or who have not been naturally postmenopausal for at least 24 consecutive months. Females of reproductive potential, as well as fertile men with female partners of reproductive potential, must use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent throughout the study and for 90 days (both females and males) following the last dose of study drug(s). Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization. Coadministration of AG-120 may decrease the concentrations of hormonal contraceptives.

Exclusion criteria 21

1. 1. Are candidates for intensive IC for their AML.
2. 2. Have received any prior treatment for AML with the exception of nononcolytic treatments to stabilize disease such as hydroxyurea or leukapheresis.
3. 3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS).
4. 4. Subjects who had previously received treatment for an antecedent hematologic disorder, including investigational agents, may not be randomized until a washout period of at least 5 half lives of the investigational agent has elapsed since the last dose of that agent.
5. 5. Have received prior treatment with an IDH1 inhibitor.
6. 6. Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.
7. 7. Are female and pregnant or breastfeeding.
8. 8. Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
9. 9. Exclusion Criterion #9 was removed in Protocol Amendment 5, Version 6.0.
10. 10. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
11. 11. Have a prior history of malignancy other than MDS or myeloproliferative disorder, unless the subject has been free of the disease for ≥1 year prior to the start of study treatment. However, subjects with the following history/concurrent conditions or similar indolent cancer are allowed to participate in the study: a. Basal or squamous cell carcinoma of the skin b. Carcinoma in situ of the cervix c. Carcinoma in situ of the breast d. Incidental histologic finding of prostate cancer
12. 12. Have had significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association Class (NYHA) Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
13. 13. Have a heart-rate corrected QT interval using Fridericia’s method (QTcF) ≥470 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (eg, NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF interval in the setting of bundle branch block may participate in the study.
14. 14. Have a known infection caused by human immunodeficiency virus or active hepatitis B virus (HBV) or hepatitis C virus that cannot be controlled by treatment.
15. 15. Have dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs.
16. 16. Have uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg).
17. 17. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid during Screening is only required if there is a clinical suspicion of CNS involvement by leukemia during Screening.
18. 18. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.
19. 19. Have any other medical or psychological condition deemed by the Investigator to be likely to interfere with the subject’s ability to give informed consent or participate in the study.
20. 20. 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.)
21. 21. Subjects with a known medical history of progressive multifocal leukoencephalopathy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is EFS, which is defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve CR by Week 24.

Secondary endpoints 2

1. • CR rate (CR defined as bone marrow blasts <5% and no Auer rods, absence of extramedullary disease, ANC ≥1.0 × 109/L [1000/µL], platelet count ≥100 × 109/L [100,000/µL], and independence of RBC transfusions). • OS, defined as the time from date of randomization to the date of death due to any cause.
2. • CR + CRh rate (CRh is defined as a CR with partial recovery of peripheral blood counts where ANC is >0.5 × 109/L [500/µL], and platelet count is >50 × 109/L [50,000/µL]; CRh will be derived by the Sponsor). • ORR, defined as the rate of CR, CRi (including CRp), PR, and MLFS.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Recherches Internationales Servier IRIS

Sponsor organisation

Institut De Recherches Internationales Servier IRIS

Address

22 Route 128

City

Gif Sur Yvette

Postcode

91190

Country

France

Scientific contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Public contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Third parties 12

Locations

5 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 32 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications