A PHASE 1B/2 OPEN-LABEL, RANDOMIZED STUDY OF 2 COMBINATIONS OF ISOCITRATE DEHYDROGENASE (IDH) MUTANT TARGETED THERAPIES PLUS AZACITIDINE: ORAL AG-120 PLUS SUBCUTANEOUS AZACITIDINE AND ORAL AG-221 PLUS SC AZACITIDINE IN SUBJECTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA HARBORING AN IDH1 OR AN IDH2 MUTATION, RESPECTIVELY, WHO ARE NOT CANDIDATES TO RECEIVE INTENSIVE INDUCTION CHEMOTHERAPY

Phase 2

Recruiting

Conditions: cancer of the blood
10024324

Registration Number: NL-OMON54569

Lead Sponsor: Celgene Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 12

Inclusion Criteria

Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is >= 18 years of age at the time of signing the informed consent
form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any
study-related
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other
protocol
requirements.
4. Subject has newly diagnosed, primary (ie, de novo) or secondary (progression
of
MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML according to
the
WHO classification (Appendix B) with >= 20% leukemic blasts in the bone marrow:
a. Have an IDH1 or IDH2 gene mutation (R132, R140, or R172)
o IDH mutational status will be assessed locally; for sites without local
testing
capabilities, a referral lab will be identified.
b. By the investigator*s assessment who are not candidates to receive intensive
IC.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status
of 0, 1
or 2 (Appendix D).
6. Subject has adequate organ function defined as:
• Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase
(AST/SGOT) and alanine aminotransferase (ALT/SGPT) <= 3 x ULN, unless
considered due to leukemic organ involvement.
• Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can
be
attributed to ineffective erythropoiesis, 3 times the upper limit of normal for
Gilbert*s
syndrome (eg, a gene mutation in UGT1A1), or leukemic organ involvement.
• Serum creatinine < 2 x ULN or 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 x (Scr)-1.154 x (Age)-0.0203 x (0.742 if female) x
(1.1212 if African American)
7. Agree to serial bone marrow aspirate/biopsies.
8. Females of childbearing potential (FCBP)* may participate, providing they
meet the
following conditions:
• Agree to practice true abstinence or to use at least two 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
a vasectomized partner is a highly effective birth control method provided that
partner is the sole sexual partner of the FCBP trial participant and that a
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; 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 Period
(note that
the screening serum pregnancy test can be used as the test prior to the start
of study
treatment in the Treatment Period if it is performed within the 72-hour
timeframe).
9. Male subjects (with a female partner of childbearing

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 (CML).
3. Subject has received a targeted agent against an IDH1 or IDH2 mutation.
4. Subject has received prior systemic anticancer therapy, HSCT, or
radiotherapy for AML.
Note that hydroxyurea is allowed prior to enrollment for the control of
peripheral leukemic blasts in subjects with leukocytosis (however,
hydroxyurea should not be given within 72 hours prior to and after
administration of azacitidine). For subjects with secondary AML (eg, MDS or
MPN) treatment for prior
cancer is not exclusionary; full treatment information will be collected within
the CRF. The use of all trans retinoic acid (ATRA) for suspected APL is not
exclusionary provided it is discontinued prior to initiation of treatment in
the protocol
5. Subject has received more than 1 cycle of prior treatment with azacitidine
or subject has received any prior treatment with decitabine for MDS.
6. 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.
7. Subject has immediate life-threatening, severe complications of leukemia
such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation.
8. 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; 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.
9. 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)
10. Subject is known seropositive for or has active viral infection with human
immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV)
or
hepatitis C virus (HCV)
11. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or
other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered
orally
12. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180
mmHg or
diastolic BP > 100 mmHg)
13. 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:
phenytoin
(CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
tizanidine (CYP1A2).