Ivosidenib for the Treatment of Clonal Cytopenia of Undetermined Significance
This phase II trial test whether ivosidenib works in improving blood counts in patients with clonal cytopenia of undetermined significance and an IDH1 mutation (change). Clonal cytopenia of undetermined significance is a condition in which low levels of certain kinds of blood cells occur without a known cause, may lead to myelodysplastic syndrome or acute myeloid leukemia. Giving ivosidenib may can shrink or stabilize cancer with a change in the IDH1 gene and improve blood counts.
Inclusion Criteria
- Unexplained cytopenia for at least 6 months. Cytopenia is defined as the presence of >= 1 blood count indexes below the following thresholds: * Hemoglobin (Hgb) < 10 g/dL * Absolute neutrophil count (ANC) < 1.8 x 10^9/L * Platelets < 100 x 10^9/L
- IDH1 gene mutation (R132), performed locally, at a frequency >= 2%.
- At least 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (IULN)
- Serum total bilirubin < 1.5 x IULN (an upper limit of bilirubin 5 mg/dL is acceptable if it can be attributed to Gilbert’s syndrome or erythropoiesis)
- Serum creatinine < 2 x IULN or creatinine clearance > 50 mL/min by Cockcroft Gault glomerular filtration rate estimation
- The effects of ivosidenib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days after the last dose of ivosidenib. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and for 90 days after the last dose of ivosidenib
- Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)
Exclusion Criteria
- Indication of hematologic disease by bone marrow biopsy within 1 month of study entry. * Evidence of disease progression from time of bone marrow biopsy to enrollment based on investigator review of symptoms and complete blood counts
- Active malignancy (defined as > 1 cm disease on most recent computed tomography [CT] scan in the past 6 months)
- Currently receiving therapy for solid tumor malignancy
- Currently receiving any other investigational agents
- Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
- A history of allergic reactions attributed to compounds of similar chemical or biologic composition to ivosidenib or other agents used in the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 72 hours of study entry
- Heartrate corrected QT interval (QTc) > 450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g. heart failure, hypokalemia, family history of long QT interval syndrome)
- Known medical history of progressive multifocal leukoenceophalopathy (PML)
- Currently taking medications known to be CYP3A4 strong inducers and sensitive substrates
Additional locations may be listed on ClinicalTrials.gov for NCT05030441.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To determine whether treatment with ivosidenib can induce a hematologic response in patients with clonal cytopenia of undetermined significance (CCUS), thereby establishing that ivosidenib can modify the biology of the disease.
SECONDARY OBJECTIVES:
I. To determine whether ivosidenib modifies the biology of CCUS.
II. To determine acute myeloid leukemia (AML)- or myelodysplastic syndrome (MDS)-free survival among patients with CCUS treated with ivosidenib.
III. To evaluate the safety of ivosidenib among individuals with CCUS.
IV. Duration of hematologic response in individuals with CCUS.
EXPLORATORY OBJECTIVES:
I. To evaluate C-reactive protein (CRP) levels, 2-hydroxyglutarate (2HG) levels before, during, and after treatment with ivosidenib.
II. To characterize the effects of ivosidenib on cellular differentiation.
III. To characterize the effects of ivosidenib on promotor methylation patterns.
IV. To evaluate the effects of ivosidenib on gene expression.
V. To evaluate changes in the gene mutation status of leukemic cells after treatment with ivosidenib.
VI. To assess the clonal structure of co-occurring non-IDH1 mutations by use of single-cell sequencing.
VII. To compare changes in variant allele frequency (VAF) of IDH1 mutations and the rate of detection of new mutations during the study period in individuals who are receiving ivosidenib compared with external cohorts of individuals with IDH1 mutations.
VIII. Evaluate changes in systolic and diastolic dysfunction during treatment with ivosidenib.
OUTLINE:
Patients receive ivosidenib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days for up to 5 years (approximately 65 cycles) in the absence of disease progression or unacceptable toxicity. Patients also undergo buccal swab and blood sample collection and bone marrow biopsy and/or aspiration and may undergo transthoracic echocardiography (TTE) on study.
After completion of study treatment, patients are followed up at 30 days.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorKelly Bolton
- Primary ID202110038
- Secondary IDsNCI-2021-13106
- ClinicalTrials.gov IDNCT05030441