Acute Myeloid Leukemia Clinical Trial

An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation

Summary

This is an international, multicenter, open-label, randomized, Phase 3 study comparing the efficacy and safety of AG-221 versus conventional care regimens (CCRs) in subjects 60 years or older with acute myeloid leukemia (AML) refractory to or relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase (IDH2) mutation.

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Full Description

Acute myeloid leukaemia (AML) is a form of cancer that is common in older patients. Mutations in the isocitrate dehydrogenase enzyme 2 (IDH2) have been found in approximately 15% of patients with AML.

The outcome of first line chemotherapy treatment is poor and many patients fail to attain complete remission (CR, ie refractory) or will eventually relapse. There is no single standard of care for relapsed or refractory AML. Since the prognosis is very poor there is a great need for new therapies.

Inhibition of the mutant IDH2 enzyme may represent a promising targeted therapy for AML. AG-221 is a small molecule inhibitor of the IDH2 enzyme, designed to preferentially target the mutant IDH2 variants. Data from the ongoing first-in-human study has shown AG-221 to be generally well tolerated and demonstrated CR in patients with IDH2 mutation positive relapsed or refractory AML.

The study purpose is to test the safety and efficacy of AG-221 compared with conventional care regimens (CCR), which include best supportive care (BSC) only, azacitidine plus BSC, low-dose cytarabine plus BSC or intermediate-dose cytarabine plus BSC, in patients with late stage AML refractory to or relapsed after second or third line therapy and positive for the IDH2 mutation. Patients will be randomly assigned to receive open-label tablets of AG-221 or one of the CCR on continuous 28-day treatment cycles. The trial duration is expected to be 78 months which includes 42 months enrollment, approximately 7 months treatment and a follow-up period.

Study procedures include: vital signs, physical exams, ECGs, ECHO, urine/blood samples, bone marrow aspirates and/or biopsies and peripheral blood to test for IDH2 and assess treatment response. Bone marrow, blood, cheek swab samples will be used for genetic tests.

This study is being sponsored by Celgene Corporation. Approximately 316 participants will take part in the study.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

Subject is ≥ 60 years of age at the time of signing the ICF
Subject has primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO classification (Appendix B)
Subject has received second- or third-line of AML therapy (see Appendix G for the definition of prior AML line; note that, for subjects having AML secondary to prior higher risk [Intermediate-2 or High risk according to the International Prognostic Scoring System] MDS treated with a hypomethylating agent [eg, azacitidine or decitabine], the hypomethylating therapy can be counted as a line if there is disease progression to AML during or shortly [eg, within 60 days] after the hypomethylating therapy.)

Subject has the following disease status:

Refractory to or relapsed after second- or third-line of intensive therapy for AML (eg, the "7 + 3" regimen):

at least 5% leukemic blasts in bone marrow (the minimum number of treatment cycles of the intensive therapy is per the investigator's discretion); or

Refractory to or relapsed after second- or third-line low-intensity AML therapy (eg, LDAC, azacitidine or decitabine):

at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles

Subject is eligible for and willing to receive the pre-selected CCR treatment option, according to the investigator's assessment (Note: Subjects with degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation, should not receive cytarabine.)
Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D)
Subject has IDH2 gene mutations tested centrally (using the "investigational use only"PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and peripheral blood, and confirmed positive in bone marrow aspirate and/or peripheral blood. (Note: in the event that the central laboratory result is delayed and precludes acute clinical management of a subject who has confirmed IDH2 gene mutation by local evaluation, the subject may be eligible for randomization with approval by the Medical Monitor.)

Subject has adequate organ function defined as:

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 3 x upper limit of normal (ULN), unless considered due to leukemic organ involvement, following review by the Medical Monitor; and
Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome (eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review by the Medical Monitor; and
Creatinine clearance > 30 mL/min based on the Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR):

GFR (mL/min/1.73 m2) = 175 × (serum creatinine)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

Females of childbearing potential (FCBP)* may participate, providing they meet the following conditions:

Agree to practice true abstinence from sexual intercourse or to use highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen-only associated with inhibition of ovulation, oral, injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization [note that vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success]) at screening and throughout the study, and for 4 months following the last study treatment (6 months following the last dose of cytarabine); and
Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG) pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
Have a negative serum or urine (investigator's discretion under local regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Phase (note that the screening serum pregnancy test can be used as the test prior to the start of study treatment in the Treatment Phase if it is performed within the 72-hour timeframe).
Male subjects must agree to practice true abstinence from sexual intercourse or to the use of highly effective contraceptive methods (as described above) with non-pregnant female partners of childbearing potential at screening and throughout the course of the study, and should avoid conception with their partners during the course of the study and for 4 months following the last study treatment (6 months following the last dose of cytarabine; 6 months following the last dose of azacitidine in Canada)
Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
Subject is willing and able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype
Subject has AML secondary to chronic myelogenous leukemia
Subject has received a targeted agent against an IDH2 mutation
Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to the start of study treatment. Note that hydroxyurea is allowed prior to the start of study treatment for the control of leukocytosis (however, hydroxyurea should not be given within 72 hours prior to and after administration of azacitidine).
Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment
Subject has undergone HSCT within 60 days prior to the start of study treatment, or on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). The use of a stable dose of oral steroid post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
Subject has persistent, clinically significant non-hematologic toxicities from prior therapies
Subject has or is suspected of having central nervous system (CNS) leukemia. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening.
Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
Subject has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
Subject has significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment

Subject has prior history of malignancy, other than MDS, MPN or AML, 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 are allowed:

Basal or squamous cell carcinoma of the skin
Carcinoma in situ of the cervix
Carcinoma in situ of the breast
Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system)
Subject is known seropositive or active infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)
Subject is a pregnant or lactating female
Subject has known or suspected to have hypersensitivity to any of the components of study treatment
Subject is taking those medications (listed in Section 8.2) that are known to prolong QT interval unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment
Subject has QTc interval (ie, Fridericia's correction [QTcF]) ≥ 450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome) at screening
Subject is taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment: paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)
Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive substrate rosuvastatin should be excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment
Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
Subject has any condition that confounds the ability to interpret data from the study

Study is for people with:

Acute Myeloid Leukemia

Phase:

Phase 3

Estimated Enrollment:

319

Study ID:

NCT02577406

Recruitment Status:

Completed

Sponsor:

Celgene

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There are 86 Locations for this study

See Locations Near You

Local Institution - 121
Miami Florida, 33136, United States
University of Florida Health Cancer Center at Orlando Health
Orlando Florida, 32806, United States
Local Institution - 111
Chicago Illinois, 60637, United States
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack New Jersey, 07601, United States
Montefiore Medical Center Albert Einstein Cancer Center
Bronx New York, 10467, United States
Roswell Park Cancer Institute
Buffalo New York, 14263, United States
Local Institution - 128
New York New York, 10029, United States
Strong Health System
Rochester New York, 14642, United States
Duke University Medical Center
Durham North Carolina, 27705, United States
University Hospitals Cleveland Medical Center
Cleveland Ohio, 44106, United States
Cancer Center Of The Carolinas
Greenville South Carolina, 29615, United States
Baylor Sammons Cancer Center
Dallas Texas, 75246, United States
Local Institution - 901
Concord New South Wales, 2139, Australia
Local Institution - 904
Adelaide South Australia, 5000, Australia
Local Institution - 906
East Melbourne , 3002, Australia
Local Institution - 905
Melbourne , 3004, Australia
Local Institution - 803
Linz , 4020, Austria
Local Institution - 811
Yvoir , 5530, Belgium
Local Institution - 252
Porto Alegre, RS Rio Grande Do Sul, 90035, Brazil
Local Institution - 250
Porto Alegre Rio Grande Do Sul, 90020, Brazil
Local Institution - 251
Jau , 17210, Brazil
Local Institution - 253
Rio de Janeiro , 20211, Brazil
Local Institution - 254
São Paulo , 01308, Brazil
Local Institution - 202
Edmonton Alberta, T6G2V, Canada
Local Institution - 203
Winnipeg Manitoba, R3E O, Canada
Local Institution - 201
Toronto Ontario, M5G 2, Canada
Local Institution - 204
Montreal Quebec, H3A 1, Canada
Local Institution - 885
Beijing , 10008, China
Local Institution - 884
Beijing , 10019, China
Local Institution - 892
Beijing , 10085, China
Local Institution - 888
Chengdu, Sichuan , 61004, China
Local Institution - 883
Hangzhou City , 31000, China
Local Institution - 887
Shanghai , 20002, China
Local Institution - 891
Shanghai , 20043, China
Local Institution - 889
Zhengzhou , 0, China
Local Institution - 822
Praha , 128 0, Czechia
Local Institution - 834
Aalborg , DK-90, Denmark
Local Institution - 831
Copenhagen , 2100, Denmark
Local Institution - 832
Odense , DK-50, Denmark
Local Institution - 606
Angers , 49033, France
Local Institution - 605
BOBIGNY Cedex , 93009, France
Local Institution - 602
Lille , 59037, France
Local Institution - 612
Marseille cedex , 13273, France
Local Institution - 607
Pessac , 33604, France
Local Institution - 611
Pierre-Bénite Cedex , 69495, France
Local Institution - 609
Toulouse Cedex , 31009, France
Local Institution - 610
Versailles , 78000, France
Local Institution - 604
Villejuif CEDEX , 94805, France
Local Institution - 413
Essen , 45122, Germany
Local Institution - 406
Frankfurt , 60590, Germany
Local Institution - 401
Hannover , 30625, Germany
Local Institution - 412
Leipzig , 04103, Germany
Local Institution - 409
München , 81377, Germany
Local Institution - 305
Bologna , 40138, Italy
Local Institution - 304
Brescia , 25123, Italy
Local Institution - 302
Firenze , 50139, Italy
Local Institution - 301
Naples , 80131, Italy
Local Institution - 306
Palermo , 90146, Italy
Local Institution - 303
Reggio Calabria , 89100, Italy
Local Institution - 307
Roma , 00133, Italy
Local Institution - 953
Hwasun-gun , 519-8, Korea, Republic of
Local Institution - 952
Seoul , 137-7, Korea, Republic of
Local Institution - 861
Krasnoyarsk , 66002, Russian Federation
Local Institution - 864
Moscow , 12318, Russian Federation
Local Institution - 863
Moscow , 12930, Russian Federation
Local Institution - 862
Saint-Petersburg , 19102, Russian Federation
Local Institution - 701
Oviedo Asturias, 33011, Spain
Local Institution - 706
Avda, Campanar 21 , 46009, Spain
Local Institution - 708
Barcelona , 08035, Spain
Local Institution - 704
Barcelona , 8036, Spain
Local Institution - 709
Salamanca , 37007, Spain
Local Institution - 702
Sevilla , 41013, Spain
Local Institution - 942
Taichung, Northern Dist. , 404, Taiwan
Local Institution - 940
Taipei, Zhongzheng Dist. , 10002, Taiwan
Local Institution - 941
Taoyuan , 333, Taiwan
Local Institution - 873
Ankara , 06100, Turkey
Local Institution - 872
Ankara , 06200, Turkey
Local Institution - 871
Ankara , 6500, Turkey
Local Institution - 874
Denizli , 20070, Turkey
Local Institution - 875
Gaziantep , 27310, Turkey
Local Institution - 503
Nottingham Nottinghamshire, NG5 1, United Kingdom
Local Institution - 501
London , EC1A , United Kingdom
Local Institution - 507
London , SE5 9, United Kingdom
Local Institution - 502
Manchester Withington , M20 4, United Kingdom
Local Institution - 510
Oxford , OX3 9, United Kingdom
Local Institution - 509
Sutton (Surrey) , SM2 5, United Kingdom

How clear is this clinincal trial information?

Study is for people with:

Acute Myeloid Leukemia

Phase:

Phase 3

Estimated Enrollment:

319

Study ID:

NCT02577406

Recruitment Status:

Completed

Sponsor:


Celgene

How clear is this clinincal trial information?

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