Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation

Myelodysplastic Syndrome Clinical Trial

Official title:

Phase II Study of the Targeted Mutant IDH2 Inhibitor Enasidenib in Combination With Azacitidine for Relapsed/Refractory AML

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03683433
• Other study ID #: 2018-0499
• Secondary ID: NCI-2018-0191920
• Status: Recruiting
• Phase: Phase 2
• Start date: September 18, 2018
• Est. completion date: September 20, 2025

Study information

• Verified date: February 2024
• Source: M.D. Anderson Cancer Center
• Contact: Courtney DiNardo
• Phone: 713-794-1141
• Email: cdinardo[@]mdanderson.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well enasidenib and azacitidine work in treating patients with IDH2 gene mutation and acute myeloid leukemia that has come back (recurrent) or does not respond to treatment (refractory). Enasidenib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Description:

PRIMARY OBJECTIVES:

I. To determine the clinical activity of enasidenib mesylate (AG221, IDHIFA) in combination with azacitidine (AZA) for patients with relapsed/refractory acute myeloid leukemia is measured by overall response rate (ORR).

SECONDARY OBJECTIVES:

I. To determine duration of response, event-free survival (EFS), and overall survival (OS).

II. To determine the safety of enasidenib in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia (AML).

EXPLORATORY OBJECTIVES:

I. To evaluate occurrence of minimal residual disease (MRD) negative status by IDH2 mutation analysis and flow cytometry.

II. To investigate possible relationships between baseline protein and gene expression signatures and mutation profile and clinical response to the combination.

III. To evaluate the incidence and characteristics of IDH-inhibitor related differentiation syndrome (IDH-DS) with combination therapy.

OUTLINE:

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30 minutes on days 1-7 and enasidenib mesylate orally (PO) once daily (QD) beginning on day 1. Cycles repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 5 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: September 20, 2025
• Est. primary completion date: September 20, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with AML or biphenotypic or bilineage leukemia (including a myeloid component) who have failed prior therapy. Patients with isolated extramedullary AML are eligible. The World Health Organization (WHO) classification will be used for AML

• Elderly (> 60 years old) patients with newly diagnosed AML not eligible for intensive chemotherapy are also eligible

• AML patients with prior history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) regardless of prior therapy received, are eligible at the time of diagnosis of AML

• Subjects must have documented IDH2 gene mutation

• Eastern Cooperative Oncology Group (ECOG) performance status =< 3

• Adequate renal function including creatinine < 2 unless related to the disease

• Total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement

• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement

• Provision of written informed consent

• Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted

• Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment

• Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment

Exclusion Criteria:

• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)

• Active and uncontrolled comorbidities including active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia as judged by the treating physician

• Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator

• Pregnant or breastfeeding

Related Conditions & MeSH terms

• Acute Bilineal Leukemia
• Acute Biphenotypic Leukemia
• Chronic Myelomonocytic Leukemia
• IDH2 Gene Mutation
• Leukemia
• Leukemia, Biphenotypic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Recurrent Acute Myeloid Leukemia
• Refractory Acute Myeloid Leukemia

Intervention

Drug:
• Azacitidine
Given SC or IV
• Enasidenib Mesylate
Given PO

Locations

Country	Name	City	State
United States	M D Anderson Cancer Center	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Minimal residual disease (MRD)	MRD negative status and exploratory biomarkers will be summarized graphically and with descriptive statistics.	Up to 5 years
Other	Association of biomarkers to overall response	Association between molecular and cellular markers and overall response and/or resistance assessed through logistic regression analyses.	Up to 5 years
Other	Change in markers over time	Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.	Baseline up to 5 years
Primary	Overall response rate (ORR)	The study will estimate the ORR for the combination treatment, along with the Bayesian 95% credible interval. ORR will be defined as the proportion of patients who had CR (complete remission), CRh (complete remission with incomplete hematologic recovery), CRi (complete remission with incomplete count recovery), PR (partial response), and/or marrow clearance of blasts (MLFS).	Up to 5 years
Secondary	Event-free survival	Kaplan-Meier method will be used to estimate the probabilities of event-free survival.	Up to 5 years
Secondary	Overall survival (OS)	Kaplan-Meier method will be used to estimate the probabilities of overall survival.	Up to 5 years
Secondary	Disease-free survival (DFS)	Log-rank tests will be used to compare among subgroups of patients in terms of DFS or OS.	Up to 5 years
Secondary	Duration of response	Log-rank tests will be used.	Up to 5 years
Secondary	Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0		Up to 5 years

External Links

•   MD Anderson Cancer Center Website