Ivosidenib maintenance after allogeneic stem cell transplant for IDH1-mutant AML

A Randomized, Placebo-Controlled Phase 2 Study of IDH1 Inhibition Using Ivosidenib as Maintenance Therapy for IDH1-mutant Acute Myeloid Leukemia Following Allogeneic Stem Cell Transplantation

This trial tests whether taking ivosidenib versus a placebo after allogeneic stem cell transplant can prevent relapse in adults with IDH1-mutant AML.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 75 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Massachusetts General Hospital (Academic / other)
• Drugs / interventions: Vedolizumab, Axatilimab, Rituximab, Ruxolitinib, Methotrexate, Cyclophosphamide, prednisone
• Locations: 4 sites (Atlanta, Georgia and 3 other locations)
• Trial ID: NCT06707493 on ClinicalTrials.gov

What this trial studies

This is a prospective, randomized, placebo-controlled, single-blinded, multi-center Phase 2 study of ivosidenib as maintenance therapy after allogeneic hematopoietic stem cell transplant in patients with IDH1-mutant acute myeloid leukemia. Participants are randomized to receive ivosidenib or matched placebo for up to 24 months, with an additional 12 months of follow-up, and standard transplant care is allowed. The study plans to enroll about 75 participants at several U.S. transplant centers. Servier provides the study drug and funding, and while ivosidenib is approved for other AML indications, it is not FDA-approved specifically for post-HSCT maintenance.

Who should consider this trial

Good fit: Adults aged 18 to 75 with pathologically confirmed IDH1(R132)-mutant AML who undergo allogeneic HSCT, have ECOG performance status ≤2, and meet specified organ and marrow function requirements are ideal candidates.

Not a fit: Patients without an IDH1 mutation, those outside the 18–75 age range, or those with inadequate organ or marrow function or ECOG >2 are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could reduce relapse risk after transplant and prolong remission for patients with IDH1-mutant AML.

How similar studies have performed: IDH1 inhibitors such as ivosidenib have shown activity in IDH1-mutant AML in other settings, but using ivosidenib specifically as post-transplant maintenance is a newer and less-tested approach.

Eligibility criteria

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)

Where this trial is running

Atlanta, Georgia and 3 other locations

• Emory University Hospital — Atlanta, Georgia, United States (Recruiting)
• Massachusetts General Hospital — Boston, Massachusetts, United States (Recruiting)
• Dana Farber Cancer Institute — Boston, Massachusetts, United States (Recruiting)
• Froedtert Hospital & the Medical College of Wisconsin — Milwaukee, Wisconsin, United States (Recruiting)

Study contacts

• Principal investigator: Amir T Fathi, MD — Massachusetts General Hospital
• Study coordinator: Amir T Fathi, MD

Conditions IDH1 Mutation; Acute Myeloid Leukemia; Hematopoietic Stem Cell Transplant; hematopoietic stem cell transplantation; IDH1-mutant acute myeloid leukemia