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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 (IDHENTIFY)

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ClinicalTrials.gov Identifier: NCT02577406
Recruitment Status : Recruiting
First Posted : October 16, 2015
Last Update Posted : May 24, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE October 14, 2015
First Posted Date  ICMJE October 16, 2015
Last Update Posted Date May 24, 2019
Actual Study Start Date  ICMJE December 30, 2015
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2018)
Overall survival [ Time Frame: Up to approximately 49 months ]
Time from randomization to death due to any cause
Original Primary Outcome Measures  ICMJE
 (submitted: October 14, 2015)
Overall survival [ Time Frame: Up to approximatly 28 months ]
Time from randomization to death due to any cause
Change History Complete list of historical versions of study NCT02577406 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2018)
  • Overall response rate [ Time Frame: Up to approximately 49 months ]
    The rate of morphologic leukemia-free state (MLFS) + Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
  • Event-free survival [ Time Frame: Up to approximately 49 months ]
    Time from randomization to documented morphologic relapse, PD according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria or death from any cause, whichever occurs first
  • Duration of response [ Time Frame: Up to approximately 49 months ]
    Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, Progressive disease (PD) according to modified IWG AML response criteria or death due to any cause, whichever occurs first
  • Time to response [ Time Frame: Up to approximately 49 months ]
    Time from randomization to first documented MLFS/CR/CRi/CRp/PR according to modified IWG AML response criteria
  • Treatment mortality at 30 and 60 days [ Time Frame: At 30 and 60 days after treatment start ]
    Rate of death from any cause within 30 and 60 days of initiation of study treatment
  • One-year survival [ Time Frame: Up to approximately 49 months ]
    The probability of survival at 1 year from randomization
  • Overall remission rate [ Time Frame: Up to approximately 49 months ]
    Rate of CR + CRi + CRp according to modified IWG AML response criteria
  • Complete remission rate [ Time Frame: Up to approximately 49 months ]
    Rate of CR according to modified IWG AML response criteria
  • Hematologic improvement rate [ Time Frame: Up to approximately 49 months ]
    Rate of Hematologic improvement neutrophil response (HI-N) + Hematologic improvement platelet response (HI-P) + Hematologic improvement erythroid response (HI-E) according to International Working Group (IWG) Myelodysplastic syndromes (MDS) Hematologic improvement (HI) criteria
  • Rate of Hematopoietic stem cell transplantation (HSCT) [ Time Frame: Up to approximately 49 months ]
    Rate of bridge-to-HSCT through study treatment
  • Time to treatment failure [ Time Frame: Up to approximately 49 months ]
    Time from randomization to discontinuation of study treatment due to any cause response criteria or death due to any cause, whichever occurs first
  • Adverse Events (AEs) [ Time Frame: Up to approximately 78 months ]
    Number of participants with adverse events
  • European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) [ Time Frame: Up to approximately 49 months ]
    A validated quality of life measure applicable to subjects with any cancer diagnosis. .
  • EuroQoL Group EQ-5D-5L Health Questionnaire [ Time Frame: Up to approximately 49 months ]
    A standardized instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status, and is applicable to a wide range of health conditions and treatments.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 14, 2015)
  • Overall response rate [ Time Frame: Up to approximatly 28 months ]
    The rate of morphologic leukemia-free state (MLFS) + Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
  • Event-free survival [ Time Frame: Up to approximatly 28 months ]
    Time from randomization to documented morphologic relapse, PD according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria or death from any cause, whichever occurs first
  • Duration of response [ Time Frame: Up to approximatly 28 months ]
    Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, Progressive disease (PD) according to modified IWG AML response criteria or death due to any cause, whichever occurs first
  • Time to response [ Time Frame: Up to approximatly 28 months ]
    Time from randomization to first documented MLFS/CR/CRi/CRp/PR according to modified IWG AML response criteria
  • Treatment mortality at 30 and 60 days [ Time Frame: At 30 and 60 days after treatment start ]
    Rate of death from any cause within 30 and 60 days of initiation of study treatment
  • One-year survival [ Time Frame: Up to approximatly 28 months ]
    The probability of survival at 1 year from randomization
  • Overall remission rate [ Time Frame: Up to approximatly 28 months ]
    Rate of CR + CRi + CRp according to modified IWG AML response criteria
  • Complete remission rate [ Time Frame: Up to approximatly 28 months ]
    Rate of CR according to modified IWG AML response criteria
  • Hematologic improvement rate [ Time Frame: Up to approximatly 28 months ]
    Rate of Hematologic improvement neutrophil response (HI-N) + Hematologic improvement platelet response (HI-P) + Hematologic improvement erythroid response (HI-E) according to International Working Group (IWG) Myelodysplastic syndromes (MDS) Hematologic improvement (HI) criteria
  • Rate of Hematopoietic stem cell transplantation (HSCT) [ Time Frame: Up to approximatly 28 months ]
    Rate of bridge-to-HSCT through study treatment
  • Time to treatment failure [ Time Frame: Up to approximatly 28 months ]
    Time from randomization to discontinuation of study treatment due to any cause response criteria or death due to any cause, whichever occurs first
  • Adverse Events (AEs) [ Time Frame: Up to approximatly 28 months ]
    Number of participants with adverse events
  • European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) [ Time Frame: Up to approximatly 28 months ]
    A validated quality of life measure applicable to subjects with any cancer diagnosis. .
  • EuroQoL Group EQ-5D-5L Health Questionnaire [ Time Frame: Up to approximatly 28 months ]
    A standardized instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status, and is applicable to a wide range of health conditions and treatments.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia, Myeloid
  • Isocitrate Dehydrogenase
Intervention  ICMJE
  • Drug: AG-221
    Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days
  • Other: BSC
    Best supportive care includes, hydroxyurea for leukocytosis and/or differentiation-like syndrome, anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support
  • Drug: Azacitidine
    continuous 28-day cycles of azacitidine 75 mg/m2/day SC for 7 days, plus BSC
  • Drug: Low-dose cytarabine (LDAC)
    continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC
  • Drug: Intermediate-dose cytarabine (IDAC)
    28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after IDAC therapy concludes per standard institutional practice
Study Arms  ICMJE
  • Experimental: AG-221 plus Best supportive care (BSC)
    Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.
    Interventions:
    • Drug: AG-221
    • Other: BSC
  • Active Comparator: Conventional care regimen (CCR)
    Continuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.
    Interventions:
    • Other: BSC
    • Drug: Azacitidine
    • Drug: Low-dose cytarabine (LDAC)
    • Drug: Intermediate-dose cytarabine (IDAC)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 21, 2017)
316
Original Estimated Enrollment  ICMJE
 (submitted: October 14, 2015)
280
Estimated Study Completion Date  ICMJE July 28, 2022
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Brazil,   Canada,   China,   Czechia,   Denmark,   France,   Germany,   Italy,   Korea, Republic of,   Russian Federation,   Spain,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02577406
Other Study ID Numbers  ICMJE AG-221-AML-004
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Kazunobu Kato, MD Celgene Corporation
PRS Account Celgene
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP