This Phase 1b/2 study is an open-label, randomized, multicenter trial to evaluate the safety
and efficacy of oral AG-120 + Subcutaneous (SC) azacitidine and oral AG-221 + SC azacitidine
in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively. The
study population consists of subjects who are not candidates to receive intensive Inductive
chemotherapy (IC). The study comprises a Phase 1b dose-finding and AG-120 expansion stage and
a Phase 2 randomized stage.
Inclusion Criteria:
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age 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 with ≥ 20% leukemic blasts in the bone marrow: -Have an Isocitrate
dehydrogenase 1 (IDH1) or Isocitrate dehydrogenase 2 (IDH2) gene mutation (R132, R140,
or R172)
- IDH mutational status will be assessed locally; for sites without local testing
capabilities, a referral lab will be identified.
- By the investigator's assessment who are not candidates to receive intensive
Inductive chemotherapy (IC).
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or
2.
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 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 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 ** 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 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 at least 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 must agree to practice true abstinence from sexual intercourse or agree
to the use of highly effective contraceptive methods (as described above) with
non-pregnant female partners of child bearing 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 at least 4 months following the last study treatment (6
months following last dose of azacitidine in Canada). Furthermore, the male subject
must agree to use a condom while treated with azacitidine and for at least 4 months
following the last azacitidine dose.
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 Isocitrate dehydrogenase 1 (IDH1) or
Isocitrate dehydrogenase 2 (IDH2) mutation.
4. Subject has received prior systemic anticancer therapy, HSCT, or radiotherapy for AML.
Note: 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 Myelodysplastic syndromes (MDS).
- Clarification: Subjects with newly diagnosed Acute myeloid leukemia (AML) who are
currently receiving their 1st cycle of azacitidine (7 days) can be screened for the
study. On study, Cycle 1 must be started at 28 days (+/- 3 days) after initiation of
the pre-study azacitidine.
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, Myeloproliferative neoplasm
(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).
14. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
substrate rosuvastatin; subject should be excluded from the study unless he/she can be
transferred to other medications at least 5 half-lives prior to the start of study
treatment.
15. 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).
16. Subject has known or suspected hypersensitivity to any of the components of study
therapy.
17. Subject is taking medications that are known to prolong the QT interval unless he/she
can be transferred to other medications within ≥ 5 half-lives prior to the start of
study treatment.
18. Subject has Heart rate-corrected QT (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.
19. Female subject who is pregnant or lactating.
20. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study.
21. Subject has any condition, including the presence of laboratory abnormalities that
places the subject at unacceptable risk if he/she were to participate in the study.
22. Subject has any condition that confounds the ability to interpret data from the study.
