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

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