Clinical trial NCT02577406: 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
Official title: A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia, Myeloid
Isocitrate Dehydrogenase
Keywords: AG-221
CC-90007
Efficacy
Safety
Leukemia
Acute myeloid meukemia
Isocitrate dehydrogenase 2 mutation
Enasidenib
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2015-10-16
Enrollment: 319
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: Inclusion Criteria:

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

1. Subject is ≥ 60 years of age at the time of signing the ICF
2. 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)
3. 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.)
4. Subject has the following disease status:

   1. 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
   2. 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
5. 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.)
6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D)
7. 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.)
8. 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)
9. 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).
10. 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)
11. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
12. 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:

1. Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype
2. Subject has AML secondary to chronic myelogenous leukemia
3. Subject has received a targeted agent against an IDH2 mutation
4. 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).
5. Subject has received non-cytotoxic or investigational agents \< 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment
6. 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.
7. Subject has persistent, clinically significant non-hematologic toxicities from prior therapies
8. 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.
9. 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)
10. Subject has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
11. 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
12. 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)
13. 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)
14. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
15. Subjects has uncontrolled hypertension (systolic blood pressure \[BP\] \> 180 mmHg or diastolic BP \> 100 mmHg)
16. Subject is a pregnant or lactating female
17. Subject has known or suspected to have hypersensitivity to any of the components of study treatment
18. 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
19. 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
20. 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)
21. 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
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
23. 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
24. Subject has any condition that confounds the ability to interpret data from the study

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization to death due to any cause (up to approximately 49 months)
Secondary outcomes:
measure: Overall Response Rate
timeFrame: From randomization up to study completion (approximately 78 months)
measure: Event-Free Survival
timeFrame: From randomization up to study completion (approximately 78 months)
measure: Duration of Response
timeFrame: From randomization up to study completion (approximately 78 months)
measure: Time to Response
timeFrame: From randomization to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 49 months)
measure: Treatment Mortality at 30 Days
timeFrame: From first dose to 30 days after first dose
measure: Treatment Mortality at 60 Days
timeFrame: From first dose to 60 days after first dose
measure: One-Year Survival Rate
timeFrame: From randomization up to 1 year post (approximately 12 months)
measure: Overall Remission Rate
timeFrame: From randomization up to approximately 49 months
measure: Complete Remission Rate
timeFrame: From randomization up to approximately 49 months
measure: Hematologic Improvement Rate
timeFrame: From randomization up to approximately 49 months
measure: The Number of Participants That Underwent Hematopoietic Stem Cell Transplantation (HSCT)
timeFrame: From randomization up to approximately 49 months
measure: Time to Treatment Failure
timeFrame: From randomization to discontinuation of study treatment due to any cause (up to approximately 49 months)
measure: The Number of Participants Experiencing Adverse Events (AEs)
timeFrame: From randomization up to study completion (approximately 78 months)
measure: The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Serum Chemistry
timeFrame: From first dose up to approximately 49 months
measure: The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Hematology
timeFrame: From first dose up to approximately 49 months
measure: The Percent of Participants Experiencing Clinically Significant Vital Sign Abnormalities
timeFrame: From first dose up to approximately 49 months
measure: The Percentage of Participants Experiencing Clinically Significant Electrocardiogram (ECG) Abnormalities
timeFrame: From first dose up to approximately 49 months
measure: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30)
timeFrame: From baseline to cycle 2 day 1 (up to approximately 1 month)
measure: Change From Baseline in EQ-5D-5L Health Utility Index
timeFrame: From baseline up to cycle 2 day 1 (up to approximately 1 month)
Other outcomes:
Locations:
city: Miami
country: United States
facility: Local Institution - 121
state: Florida
city: Orlando
country: United States
facility: University of Florida Health Cancer Center at Orlando Health
state: Florida
city: Chicago
country: United States
facility: Local Institution - 111
state: Illinois
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center Albert Einstein Cancer Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Local Institution - 128
state: New York
city: Rochester
country: United States
facility: Strong Health System
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Greenville
country: United States
facility: Local Institution - 104
state: South Carolina
city: Dallas
country: United States
facility: Baylor Sammons Cancer Center
state: Texas
city: Concord
country: Australia
facility: Local Institution - 901
state: New South Wales
city: Adelaide
country: Australia
facility: Local Institution - 904
state: South Australia
city: East Melbourne
country: Australia
facility: Local Institution - 906
city: Melbourne
country: Australia
facility: Local Institution - 905
city: Linz
country: Austria
facility: Local Institution - 803
city: Yvoir
country: Belgium
facility: Local Institution - 811
city: Porto Alegre, RS
country: Brazil
facility: Local Institution - 252
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Local Institution - 250
state: Rio Grande Do Sul
city: Jau
country: Brazil
facility: Local Institution - 251
city: Rio de Janeiro
country: Brazil
facility: Local Institution - 253
city: São Paulo
country: Brazil
facility: Local Institution - 254
city: Edmonton
country: Canada
facility: Local Institution - 202
state: Alberta
city: Winnipeg
country: Canada
facility: Local Institution - 203
state: Manitoba
city: Toronto
country: Canada
facility: Local Institution - 201
state: Ontario
city: Montreal
country: Canada
facility: Local Institution - 204
state: Quebec
city: Beijing
country: China
facility: Local Institution - 885
city: Beijing
country: China
facility: Local Institution - 884
city: Beijing
country: China
facility: Local Institution - 892
city: Chengdu, Sichuan
country: China
facility: Local Institution - 888
city: Fuzhou
country: China
facility: Local Institution - 882
city: Guangzhou, Guangdong
country: China
facility: Local Institution - 881
city: Hangzhou City
country: China
facility: Local Institution - 883
city: Shanghai
country: China
facility: Local Institution - 887
city: Shanghai
country: China
facility: Local Institution - 891
city: Zhengzhou
country: China
facility: Local Institution - 889
city: Praha
country: Czechia
facility: Local Institution - 822
city: Aalborg
country: Denmark
facility: Local Institution - 834
city: Arhus C
country: Denmark
facility: Local Institution - 833
city: Copenhagen
country: Denmark
facility: Local Institution - 831
city: Odense
country: Denmark
facility: Local Institution - 832
city: Angers
country: France
facility: Local Institution - 606
city: BOBIGNY Cedex
country: France
facility: Local Institution - 605
city: Lille
country: France
facility: Local Institution - 602
city: Marseille cedex
country: France
facility: Local Institution - 612
city: Nantes
country: France
facility: Local Institution - 601
city: Pessac
country: France
facility: Local Institution - 607
city: Pierre-Bénite Cedex
country: France
facility: Local Institution - 611
city: Toulouse Cedex
country: France
facility: Local Institution - 609
city: Versailles
country: France
facility: Local Institution - 610
city: Villejuif CEDEX
country: France
facility: Local Institution - 604
city: Dresden
country: Germany
facility: Local Institution - 403
city: Essen
country: Germany
facility: Local Institution - 413
city: Frankfurt
country: Germany
facility: Local Institution - 406
city: Hannover
country: Germany
facility: Local Institution - 401
city: Leipzig
country: Germany
facility: Local Institution - 412
city: Mainz
country: Germany
facility: Local Institution - 402
city: München
country: Germany
facility: Local Institution - 409
city: Ulm
country: Germany
facility: Local Institution - 407
city: Bologna
country: Italy
facility: Local Institution - 305
city: Brescia
country: Italy
facility: Local Institution - 304
city: Firenze
country: Italy
facility: Local Institution - 302
city: Naples
country: Italy
facility: Local Institution - 301
city: Palermo
country: Italy
facility: Local Institution - 306
city: Reggio Calabria
country: Italy
facility: Local Institution - 303
city: Roma
country: Italy
facility: Local Institution - 307
city: Hwasun-gun
country: Korea, Republic of
facility: Local Institution - 953
city: Seoul
country: Korea, Republic of
facility: Local Institution - 952
city: Krasnoyarsk
country: Russian Federation
facility: Local Institution - 861
city: Moscow
country: Russian Federation
facility: Local Institution - 864
city: Moscow
country: Russian Federation
facility: Local Institution - 863
city: Saint-Petersburg
country: Russian Federation
facility: Local Institution - 862
city: Oviedo
country: Spain
facility: Local Institution - 701
state: Asturias
city: Avda, Campanar 21
country: Spain
facility: Local Institution - 706
city: Barcelona
country: Spain
facility: Local Institution - 708
city: Barcelona
country: Spain
facility: Local Institution - 704
city: Salamanca
country: Spain
facility: Local Institution - 709
city: Sevilla
country: Spain
facility: Local Institution - 702
city: Taichung, Northern Dist.
country: Taiwan
facility: Local Institution - 942
city: Taipei, Zhongzheng Dist.
country: Taiwan
facility: Local Institution - 940
city: Taoyuan
country: Taiwan
facility: Local Institution - 941
city: Ankara
country: Turkey
facility: Local Institution - 873
city: Ankara
country: Turkey
facility: Local Institution - 872
city: Ankara
country: Turkey
facility: Local Institution - 871
city: Denizli
country: Turkey
facility: Local Institution - 874
city: Gaziantep
country: Turkey
facility: Local Institution - 875
city: Nottingham
country: United Kingdom
facility: Local Institution - 503
state: Nottinghamshire
city: London
country: United Kingdom
facility: Local Institution - 501
city: London
country: United Kingdom
facility: Local Institution - 507
city: Manchester Withington
country: United Kingdom
facility: Local Institution - 502
city: Oxford
country: United Kingdom
facility: Local Institution - 510
city: Sutton (Surrey)
country: United Kingdom
facility: Local Institution - 509
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: