A phase 3, multicenter, double-blind, randomized, placebo-controlled study of ivosidenib or enasidenib in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome with excess blasts-2, with an IDH1 or IDH2 mutation, respectively, eligible for intensive chemotherapy.

• Age >=18 years
• Newly diagnosed AML or MDS-EB2 defined according to WHO criteria, with a
documented IDH1 or IDH2 gene mutation (as determined by the clinical trial
assay) at a specific site (IDH1 R132, IDH2 R140, IDH2 R172). AML may be
secondary to prior hematological disorders, including MDS, and/or
therapy-related . Patients may have had previous treatment with hypomethylating
agents (HMAs) for MDS. HMAs have to be stopped at least four weeks before
registration
• Patients with dual mutant FLT3 and IDH1 or IDH2 mutations may be enrolled
only if, for medical or other reasons, treatment with a FLT3 inhibitor is not
considered.
• Considered to be eligible for intensive chemotherapy.
• ECOG/WHO performance status <= 2
• Adequate hepatic function as evidenced by:
o Serum total bilirubin <= 2.5 × upper limit of normal (ULN) unless considered
due to Gilbert*s disease (e.g. a mutation in UGT1A1) (only for patients in IDH2
cohort), or leukemic involvement of the liver - following written approval by
the (Co)Principal Investigator.
o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
alkaline phosphatase (ALP) <= 3.0 × ULN, unless considered due to leukemic
involvement of the liver, following written approval by the Principal
Investigator.
• Adequate renal function as evidenced by creatinine clearance > 40 mL/min
based on the Cockroft-Gault formula for glomerular filtration rate (GFR).
• Able to understand and willing to sign an informed consent form (ICF).
• Written informed consent
• Female patient must either:
o Be of nonchildbearing potential:
* Postmenopausal (defined as at least 1 year without any menses) prior to
screening, or
* Documented surgically sterile or status posthysterectomy (at least 1 month
prior to screening)
o Or, if of childbearing potential,
* Agree not to try to become pregnant during the study and for 6 months after
the final study drug administration
* And have a negative urine or serum pregnancy test at screening
* And, if heterosexually active, agree to consistently use highly effective*
contraception per locally accepted standards in addition to a barrier method
starting at screening and throughout the study period and for 6 months after
the final study drug administration.
*Highly effective forms of birth control include:
• Consistent and correct usage of established hormonal contraceptives that
inhibit ovulation,
• Established intrauterine device (IUD) or intrauterine system (IUS),
• Bilateral tubal occlusion,
• Vasectomy (A vasectomy is a highly effective contraception method provided
the absence of sperm has been confirmed. If not, an additional highly
effective method of contraception should be used.)
• Male is sterile due to a bilateral orchiectomy.
• Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual activity during the entire period of risk
associated with the study drug. The reliability of sexual abstinence needs to
be evaluated in relation to the duration of the clinical study and the
preferred and usual lifestyle of the patient.
*List is not all inclusive. Prior to enrollment, the investigator is
responsible for confirming patient will utilize highly effective forms of birth
control per the requirements of the CTFG Guidance document *Recommendations
related to contraception and pregnancy testing in clinical trials', September
2014 (and any updates thereof) during the protocol defined period.
o Female patient must agree not to breastfeed starting at screening and
throughout the study period, and for 2 months and 1 week after the final study
drug administration.
o Female patient must not donate ova starting at screening and throughout the
study period, and for 6 months after the final study drug administration.
• Male patient and their female partners who are of childbearing potential must
be using highly effective contraception per locally accepted standards in
addition to a barrier method starting at screening and continue throughout the
study period and for 4 months and 1 week after the final study drug
administration
• Male patient must not donate sperm starting at screening and throughout the
study period and for 4 months and 1 week after the final study drug
administration.
.• Subject agrees not to participate in another interventional study while on
treatment

• Prior chemotherapy for AML or MDS-EB2 (with the exception of HMA).
Hydroxyurea is allowed for the control of peripheral leukemic blasts in
patients with leukocytosis (e.g., white blood cell [WBC] counts > 30x109/L).
• Dual IDH1 and IDH2 mutations.
• Acute promyelocytic leukemia (APL) with PML-RARA or one of the other
pathognomonic variant fusion genes/chromosome translocations.
• Blast crisis after chronic myeloid leukemia (CML).
• Known allergy or suspected hypersensitivity to Ivosidenib or Enasidenib
and/or any exipients.
• Taking medications with narrow therapeutic windows with potential interaction
with investigational medication unless the patient can be transferred to other
medications prior to enrolling or unless the medications can be properly
monitored during the study.
• Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)
transporter-sensitive substrate medications unless the patient can be
transferred to other medications within >= 5 half-lives prior to administration
of ivosidenib or enasidenib, or unless the medications can be properly
monitored during the study.
• Breast feeding at the start of study treatment.
• Active infection, including hepatitis B or C or HIV infection that is
uncontrolled at randomization. An infection controlled with an approved or
closely monitored antibiotic/antifungal treatment is allowed.
• Patients with a currently active second malignancy. Patients are not
considered to have a currently active malignancy if they have completed therapy
and are considered by their physician to be at < 30% risk of relapse within one
year. However, patients with the following history/concurrent conditions are
allowed:
o Basal or squamous cell carcinoma of the skin
o Carcinoma in situ of the cervix
o Carcinoma in situ of the breast
o Incidental histologic finding of prostate cancer
• 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 ;
myocardial infarction, unstable angina and/or stroke; or left ventricular
ejection fraction (LVEF) < 40% by ultrasound or MUGA scan obtained within 28
days prior to the start of study treatment.
• QTc interval using Fridericia*s formula (QTcF) >= 450 msec or other factors
that increase the risk of QT prolongation or arrhythmic events (e.g., heart
failure, family history of long QT interval syndrome). Prolonged QTc interval
associated with bundle branch block or pacemaking is permitted with written
approval of the (co)Principal Investigator.
• Taking medications that are known to prolong the QT interval (see Appendix
K), unless deemed critical and without a suitable alternative. In those cases,
they may be administered, but with proper monitoring (see section 10.2, Table
13)
• Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit
the ingestion or gastrointestinal absorption of orally administered drugs.
• Clinical symptoms suggestive of active central nervous system (CNS) leukemia
or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening
is only required if there is a clinical suspicion of CNS involvement by
leukemia during screening.
• A known medical history of progressive multifocal leukoencephalopathy (PML)
• Immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or severe
disseminated intravascular coagulation
• Any other medical condition deemed by the Investigator to be likely to
interfere with a patient*s ability to give informed consent or participate in
the study.
• Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule.