IDH1 Inhibition Using Ivosidenib as Maintenance Therapy for IDH1-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation

This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved ivosidenib as a treatment
for any disease.

Ivosidenib is an inhibitor of the protein IDH1. Ivosidenib is currently being studied as a
treatment for myeloid cancers like acute myeloid leukemia or myelodysplastic syndromes with
an IDH1 mutation. This study is examining whether or not ivosidenib is beneficial and
well-tolerated as an agent to prevent the relapse of IDH1-mutated acute myeloid leukemia or
other myeloid neoplasms after hematopoietic stem cell transplantation. IDH1 is an enzyme
that, when mutated, can overproduce metabolites (substances that help with metabolism) and
compounds that contribute to the growth of tumors and cancerous cells. Ivosidenib may help
block the over production of these substances and possibly reduce the chances of relapse.

Inclusion Criteria:

- Pathologically confirmed diagnosis of IDH1(R132)-mutant acute myeloid leukemia (AML),
myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). IDH1
mutations could have been detected by any mutational technique at any prior point
including at diagnosis or remission.

- Between the ages of 18 and 75 years

- Will undergo allogeneic hematopoietic stem cell transplantation (HSCT) for their
malignancy. Conditioning may be either conventional myeloablative (MAC) or reduced
intensity conditioning (RIC).

- HSCT Donor will be one of the following:

- 5/6 or 6/6 (HLA-A, B, DR) matched related donor

- 7/8 or 8/8 (HLA-A, B, DR, C) matched unrelated donor. Matching in the unrelated
setting must be at the allele level.

- Haploidentical related donor, defined as ≥ 3/6 (HLA-A, B, DR) matched --≥ 4/6
(HLA-A, B, DR) umbilical cord blood (UCB). Matching in the UCB setting is at the
antigen level. Recipients may receive either one or two UCB units. In the case of
2 UCB units, both units must have been at least 4/6 matched with the recipient.

- ECOG performance status ≤ 2

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1000/µL without growth factor support (e.g. GCSF) in
the previous 7 days

- Platelet count ≥ 50,000/µL without transfusional support in the previous 7 days

- AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 3x institutional upper limit of
normal (ULN)

- Direct bilirubin < 2.0 mg/dL

- Calculated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula)

- LVEF must be equal to or greater than 40%, as measured by MUGA scan or
echocardiogram

- Female patients of childbearing potential must have a negative pregnancy test

- The effects of ivosidenib on the developing human fetus are unknown. For this reason
female participants of child-bearing potential and male participants must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
during the entire study treatment period and through 90 days after the last dose of
treatment

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior allogeneic hematopoietic stem cell transplants.

- Evidence of relapsed/recurrent/residual disease as assessed by bone marrow aspirate
and biopsy performed within 42 days prior to study entry.

- History of other malignancy(ies) unless

- the participant has been disease-free for at least 5 years and is deemed by the
investigator to be at low risk of recurrence of that malignancy, or

- the only prior malignancy was cervical cancer in situ and/or basal cell or
squamous cell carcinoma of the skin

- Known diagnosis of active hepatitis B or hepatitis C

- Current or history of congestive heart failure New York Heart Association (NHYA) class
3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 40%, as
measured by MUGA scan or echocardiogram)

- Current or history of ventricular or life-threatening arrhythmias or diagnosis of
long-QT syndrome

- QTc interval (i.e., Friderica's correction [QTcF]) ≥ 450 ms or other factors that
increase the risk of QT prolongation or arrhythmic events (e.g., heart failure,
hypokalemia, family history of long QT interval syndrome) at screening

- Systemic infection requiring IV antibiotic therapy within 7 days preceding the first
dose of study drug, or other severe infection

- Uncontrolled intercurrent illness that would limit compliance with study requirements.

- HIV-positive participants on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with study drug. In addition, these
participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy.