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
Condition: Leukemia, Myeloid; Isocitrate Dehydrogenase
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: AG-221; BSC; Azacitidine; Low-dose cytarabine (LDAC); Intermediate-dose cytarabine (IDAC)
Intervention description: Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days; Best supportive care includes, hydroxyurea for leukocytosis and/or differentiation-like syndrome, anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support; continuous 28-day cycles of azacitidine 75 mg/m2/day SC for 7 days, plus BSC; continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC; 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
Intervention MeSH terms: Cytarabine; Azacitidine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 319.0
Sex: All
Minimum age: 60 Years
Healthy volunteers: No
Keywords: AG-221; CC-90007; Efficacy; Safety; Leukemia; Acute myeloid meukemia; Isocitrate dehydrogenase 2 mutation; Enasidenib

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.
    

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