Ivosidenib as Post-HSCT Maintenance for AML

Inclusion Criteria:

• Pathologically confirmed diagnosis of IDH1(R132)-mutant acute myeloid leukemia (AML). IDH1 mutations could have been detected by any mutational technique at anyprior point including at diagnosis or remission.

• Between the ages of 18 and 75 years

• Will undergo allogeneic hematopoietic stem cell transplantation (HSCT) for theirmalignancy. Conditioning may be either conventional myeloablative (MAC) or reducedintensity conditioning (RIC). There will be no restrictions on type of graft source.

• 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 7days.

• AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 3x institutional upper limitof 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 orechocardiogram

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

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

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Prior allogeneic hematopoietic stem cell transplants.

• Morphologically relapsed or refractory disease, as assessed by bone marrow aspirateand 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 theinvestigator to be at low risk of recurrence of that malignancy, or

• the only prior malignancy was cervical cancer in situ and/or basal cell orsquamous 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 oflong-QT syndrome

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

• Uncontrolled intercurrent illness that would limit compliance with studyrequirements.

Post-transplantation Pre-Treatment Criteria Treatment may begin at any time between day 45 and day 90 following stem cell transplantation.

However, at time of treatment start, it must be ensured that:

• The patient has continued willingness and interest in participating in the study.

• There is no systemic infection requiring IV antibiotic therapy within 7 dayspreceding the first dose of study drug, or other severe infection

• Chimerism studies reveal that ≥ 70% of blood or bone marrow cells, or of the CD33expressing fraction, are of donor origin,

• There is no acute graft versus host disease (GVHD), requiring an equivalent dose of ≥ 0.5mg/kg/day of prednisone within one week of starting ivosidenib / placebo, orhave escalation of systemic immunosuppression in terms of increase ofcorticosteroids or addition of new agent/modality within two weeks of startingivosidenib / placebo.

• For prophylaxis for GVHD, agents that are permitted for administration on study:

• Tacrolimus

• Cyclosporine

• Sirolimus

• Cyclophosphamide

• Mycophenolate Mofetil

• Methotrexate

• ATG

• Ruxolitinib

• Vedolizumab

• As standards of care may change, any other prophylactic agents used should bediscussed with the PI.

• Investigational agents, defined as not approved for any indication, are forbiddenunless the participant comes off study.

• Agents used to treat GVHD that are permitted for administration on study:

• Any agent used in prophylaxis may be continued (see list above)

• Ruxolitinib

• Etanarcept

• ATG

• Belumosidil

• Axatilimab

• Rituximab

• Fecal microbiota transplantation

• Alpha1-Antitrypsin

• Pregnyl

• Extracorporal photopheresis (ECP)

• As standards of care may change, any other treatment agents used should bediscussed with the PI.

• Investigational agents, defined as not approved for any indication, areforbidden unless the participant comes off study.

• There is no evidence of relapsed/recurrent/residual disease.

• Prior to the start of ivosidenib / placebo administration, the participant must haveadequate hematological function, defined as:

• ANC ≥ 1000/µL

• Platelets ≥ 50,000/µL

and adequate organ function defined as

• Direct bilirubin level < 2.0 mg/dL

• AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 3x institutional upper limit ofnormal (ULN)

• No presence of congestive heart failure, defined by New York Heart Association (NHYA) criteria as class 3 or 4

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