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Ivosidenib as Maintenance Therapy in Treating Patients with IDH1-mutant Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelomonocytic Leukemia following Stem Cell Transplant

Trial Status: Active

This phase I trial studies the best dose and side effects of ivosidenib as maintenance therapy in treating patients with IDH1-mutant acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia following stem cell transplant. Ivosidenib is an inhibitor of the protein IDH1. IDH1 is an enzyme that, when mutated, can overproduce metabolites (substances that help with metabolism) and compounds that contribute to the growth of cancer cells. Ivosidenib may help block the over production of these substances and possibly reduce the chances of relapse in patients with IDH1-mutant myeloid cancers.

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
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count >= 1000/uL without growth factor support (e.g. granulocyte colony stimulating factor [GCSF]) in the previous 7 days. This criterion does not apply to patients with myelodysplastic syndromes, myeloproliferative neoplasms in leukemic phase, or CMML, who will not necessarily be expected to achieve marrow recovery prior to HSCT
  • Platelet count >= 50,000/uL without transfusional support in the previous 7 days. This criterion does not apply to patients with myelodysplastic syndromes, myeloproliferative neoplasms in leukemic phase, or CMML, who will not necessarily be expected to achieve marrow recovery prior to HSCT
  • Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) < 3 x institutional upper limit of normal (ULN)
  • Alkaline phosphatase < 3 x institutional ULN
  • Direct bilirubin < 2.0 mg/dL
  • Calculated creatinine clearance >= 40 mL/min (Cockcroft-Gault formula)
  • Left ventricular ejection fraction (LVEF) must be equal to or greater than 40%, as measured by multigated acquisition scan (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
  • For patients with acute myeloid leukemia, morphologically relapsed or refractory disease, as assessed by bone marrow aspirate and biopsy performed within 42 days prior to study entry, is exclusionary. For patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, the presence of less than 5% myeloblasts is allowed on a bone marrow biopsy 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
  • Corrected QT (QTc) interval (i.e., Fridericia’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 uncontrolled infection
  • Uncontrolled intercurrent illness that would limit compliance with study requirements
  • Human immunodeficiency virus (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

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Mark J. Levis

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Robert Jon Soiffer
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Amir Tahmasb Fathi
Phone: 617-724-1124

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: ACTIVE
Contact: Samantha Buls

PRIMARY OBJECTIVES:

I. To identify the recommended phase 2 dose (RP2D) of ivosidenib in patients with IDH1-mutant myeloid neoplasms after hematopoietic stem cell transplantation.

II. To explore the safety and tolerability of ivosidenib in patients with IDH1-mutant myeloid neoplasms in the post-stem cell transplant setting.

SECONDARY OBJECTIVES:

I. To detect and categorize, according to severity, ivosidenib-related toxicities in patients with IDH1-mutant myeloid neoplasms receiving ivosidenib after hematopoietic stem cell transplantation.

II. To examine the cumulative incidence of acute graft versus host disease (GVHD) from start of ivosidenib in patients with IDH1-mutant myeloid neoplasms who receive ivosidenib after hematopoietic stem cell transplantation.

III. To examine the cumulative incidence of chronic GVHD from start of ivosidenib in patients with IDH1-mutant myeloid neoplasms who receive ivosidenib after hematopoietic stem cell transplantation.

IV. To monitor plasma and marrow 2-hydroxyglutarate levels in patients with IDH1-mutant myeloid neoplasms who receive ivosidenib after hematopoietic stem cell transplantation.

V. To assess IDH clonal evolution and mutational burden in patients with IDH1-mutant myeloid neoplasms who receive ivosidenib after hematopoietic stem cell transplantation.

VI. To measure minimal residual disease (MRD) in patients with IDH1-mutant myeloid neoplasms who receive ivosidenib after hematopoietic stem cell transplantation, through measurement of mutant IDH1 (mIDH1) allelic burden.

EXPLORATORY OBJECTIVES:

I. To examine the rate of relapse of IDH1-mutant myeloid neoplasms in patients receiving ivosidenib after hematopoietic stem cell transplantation.

II. To examine relapse-free survival in patients with IDH1-mutant myeloid neoplasms who receive ivosidenib after hematopoietic stem cell transplantation.

III. To examine overall survival in patients with IDH1-mutant myeloid neoplasms who receive ivosidenib after hematopoietic stem cell transplantation.

OUTLINE: This is a dose-escalation study.

Patients receive ivosidenib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 24 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Amir Tahmasb Fathi

  • Primary ID 18-123
  • Secondary IDs NCI-2018-03528
  • Clinicaltrials.gov ID NCT03564821