Ivosidenib as Post-HSCT Maintenance for AML

This is a prospective, placebo-controlled, randomized, single-blinded, multi-center, phase II study of the mutant IDH1 inhibitor, ivosidenib, compared to placebo in participants with AML after HCT. This study is examining whether or not ivosidenib is beneficial as an agent to prevent the relapse of IDH1-mutated acute myeloid leukemia after hematopoietic stem cell transplantation. The U.S. Food and Drug Administration (FDA) has not approved ivosidenib for this indication following HCT but it has been approved for other uses.

The research study procedures include screening for eligibility and study treatment including evaluations and follow-up. The HCT and any standard treatment before and after the HCT is standard of care.

The estimated length of participation in the study is 3.5 years from screening to the end of planned follow-up, including up to 24 months of study treatment. After the 24-month period, participants are followed for up to 12 additional months. It is expected that about 75 people will take part in this research study.

Servier, a pharmaceutical company, is supporting this research study by providing ivosidenib/placebo and funding for research activities.

Inclusion criteria

• Pathologically confirmed diagnosis of IDH1(R132)-mutant acute myeloid leukemia (AML). 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). 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 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.
• Morphologically relapsed or refractory 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
• Uncontrolled intercurrent illness that would limit compliance with study requirements.

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 days preceding the first dose of study drug, or other severe infection
• Chimerism studies reveal that ≥ 70% of blood or bone marrow cells, or of the CD33 expressing 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, or have escalation of systemic immunosuppression in terms of increase of corticosteroids or addition of new agent/modality within two weeks of starting ivosidenib / 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 be discussed with the PI.
• Investigational agents, defined as not approved for any indication, are forbidden unless 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 be discussed with the PI.
• Investigational agents, defined as not approved for any indication, are forbidden 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 have adequate 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 of normal (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)