Details

Details

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.

IRB CLGN1915

CC 16-222

Hospital Main Campus

Phase Phase 3

Disease Leukemia - Acute Myeloid (AML)

Drug AG-221

Description

Description

Primary Objective
  • To determine the primary efficacy, measured as overall survival (OS), of AG-221 compared with conventional care regimens (CCRs) in subjects 60 years or older with AML refractory to or relapsed after second- or third-line AML therapy and positive for an IDH2 mutation
Secondary Objective(s)
  • To determine the supporting efficacy of AG-221 compared with CCRs
  • To determine the safety and tolerability of AG-221 compared with CCRs
  • To determine the effect of AG-221 compared with CCRs on Health-related Quality-of-Life
Exploratory Objective(s)
  • To determine the effect of AG-221 compared with CCRs on healthcare resource utilization
  • To determine plasma concentration of AG-221, and to explore the relationships of AG-221 exposure with efficacy, safety, pharmacodynamics and other exploratory endpoints
  • To evaluate molecular, cellular and metabolic markers which may be predictive of antitumor activity and/or resistance
Inclusion Criteria

Inclusion Criteria

  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/regimen of AML therapy (see Appendix G for the definition of prior AML line/regimen)
  4. Subject has the following disease status:
    • Refractory to or relapsed after second- or third-line/regimen of intensive therapy for AML (eg, the "7 + 3" regimen): at least 5% leukemic blasts in bone marrow; 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
  5. Subject is eligible for and willing to receive the pre-selected CCR treatment option, according to the investigator's assessment
  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
  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 Cockcroft-Gault glomerular filtration rate estimation: (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine
  9. Females of childbearing potential (FCBP)* may participate, providing they meet the following conditions:
    • Agree to abstain from sexual intercourse or to use at least two effective contraceptive methods (oral, injectable, patch, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; synthetic double-barrier contraceptive with spermicide; or vasectomized partner) at screening and throughout the study, and for 4 months following the last study treatment; 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 with a female partner of childbearing potential must agree to abstain from sexual intercourse or to the use of at least two effective contraceptive methods (eg, synthetic condoms with spermicide, etc) at screening and throughout the course of the study and should avoid fathering a child during the course of the study and for 4 months following the last study treatment (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

Exclusion Criteria

  1. Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype (Appendix B)
  2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C)
  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 in subjects with white blood cell (WBC) counts > 30 x 109/L (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
  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