Enasidenib as Maintenance Therapy in Treating Patients With Acute Myeloid Leukemia With IDH2 Mutation After Donor Stem Cell Transplant

Pilot Trial of Enasidenib (AG-221) Maintenance Post Allogeneic Hematopoietic Cell Transplantation in Patients With IDH2 Mutation

This phase I trial studies the side effects of using enasidenib as maintenance therapy in treating patients with acute myeloid leukemia with IDH2 mutation following donor stem cell transplant. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Enasidenib Mesylate

Detailed Description

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of enasidenib mesylate as maintenance therapy in post hematopoietic cell transplantation (HCT) patients.

SECONDARY OBJECTIVES:

I. Assess overall and leukemia free survival in patients post allogeneic HCT. II. Estimate relapse incidence, non-relapse mortality, graft versus host disease (GVHD) and relapse free survival (GRFS) in patients receiving enasidenib mesylate maintenance therapy.

EXPLORATORY OBJECTIVES:

I. Monitor disease status among subset of patients with minimal residual disease (MRD) positive disease when starting to receive enasidenib mesylate by multiparameter flow cytometry post allogeneic HCT on patients bone marrow (BM) on days +100 and +365.

II. Investigate clearance of IDH2 mutation post HCT by next generation sequencing-polymerase chain reaction (NGS-PCR) testing on the bone marrow specimens on days +100 and +365 and in peripheral blood every 3 months till 2 year follow up.

III. Investigate mIDH2 variant allele fraction (VAF) by droplet digital PCR (ddPCR) BEAMing technology on bone marrow specimens on days +100 and +365.

OUTLINE:

Patients receive enasidenib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and periodically thereafter up to 2 years.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies

  • If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Eastern Cooperative Oncology Group (ECOG) =< 2 or Karnofsky performance status (KPS) >= 70
• Recipients of allogeneic HCT - all stem cell sources including sibling, unrelated, mismatched related/unrelated, cord and haploidentical transplant patients will be included
• Conditioning regimen: Investigator's choice based on center guidelines
• GvHD prophylaxis: sirolimus + tacrolimus or tacrolimus + methotrexate or investigator choice
• Patients must have acute myeloid leukemia (AML) with IDH2 mutation at diagnosis. Day 30 marrow post HCT should show evidence of morphologic remission with < 5% bone marrow blasts. Patients with MRD either by flow cytometry or IDH2 mutation testing will be allowed
• Patients with previous therapy with IDH2 inhibitors will be included
• Absolute neutrophil count (ANC) > 1000 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
• Hemoglobin >= 9.5 gm% (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
• Platelets > 50,000/mm^3 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)

• Platelets >= 20,000/mm^3 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)

  • NOTE: Patients with lower counts can enroll if infection cytomegalovirus (CMV)/human herpesvirus 6 (HHV6) etc. is being treated actively
• Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
• Total bilirubin < 2.0 mg/dl-exception permitted in patients with Gilbert's Syndrome (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
• Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x ULN, patients with abnormal liver function tests (LFTs) in the context of active GVHD will not be included (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
• Creatinine clearance of >= 40/min/1.73 m^2 for participants with creatinine levels above institutional normal per 24 hour urine test or the Cockcroft-Gault formula (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)

• Corrected QT (QTc) =< 480 ms

  • Note: To be performed within 28 days prior to day 1 of protocol therapy

• Seronegative for human immunodeficiency virus (HIV) antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin [RPR])

  • If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Active diarrhea considered clinically significant and may impair oral drug administration
• Clinically significant uncontrolled illness

• Active infection requiring antibiotics

  • Active infection. Patients with treated viral, bacterial or fungal infections that are controlled on therapy will be allowed to participate
• Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
• Diagnosis of Gilbert's disease
• Other active malignancy. Participants with history of prior malignancy treated with curative intent who achieved complete response (CR) more than 2 years before study entry are eligible. This exclusion rule does not apply to non-melanoma skin tumors and in-situ cervical cancer
• Females only: Pregnant or breastfeeding
• Active grade II-IV acute GVHD and/or requiring systemic steroids with prednisone dose equivalent of >= 0.25 mg/kg at end of 4 weeks
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants, who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (enasidenib mesylate); Patients receive enasidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Enasidenib Mesylate; Given PO; Other Names: 2-Methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol Methanesulfonate; 2-Propanol, 2-Methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-, Methanesulfonate (1:1); AG-221 Mesylate; CC-90007; Enasidenib Methanesulfonate; Idhifa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (AEs)	Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).	Up to 30 days post treatment completion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Will be analyzed using the Kaplan-Meier curves.	From starting enasidenib to date of death, assessed up to 2 years
Leukemia free survival (LFS)	Will be analyzed using the Kaplan-Meier curves.	From starting enasidenib to date of relapse or death, assessed up to 2 years
Time to relapse	Time to relapse will be censored at the last disease assessment if patients are known to be alive and leukemia free.	From starting enasidenib to date of relapse, assessed up to 2 years
Non-relapse mortality (NRM)	Will be analyzed using the curves of cumulative incidence.	From starting enasidenib to date of death from other causes than relapse, assessed up to 2 years
Graft versus host disease (GvHD)-free relapse free survival (GRFS)	Will be analyzed using the Kaplan-Meier curves.	At 1 year mark of starting enasidenib

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal residual disease (MRD) disappearance (bone marrow [BM])	Monitor disease status among subset of patients with MRD positive disease by multiparameter flow cytometry post allogeneic hematopoietic cell transplantation (HCT) on patients BM.	At days 100 and 365
IDH2 mutation clearance (BM and peripheral blood)	Investigate clearance of IDH2 mutation post HCT by next generation sequencing-polymerase chain reaction (NGS-PCR) testing on the bone marrow specimens.	At days 100 and 365 and up to 2 years
mIDH2 variant allele fraction (BM)	mIDH2 variant allele fraction (VAF) by droplet digital PCR (ddPCR) BEAMing technology on bone marrow specimens.	At days 100 and 365

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Amandeep Salhotra, City of Hope Medical Center

Publications and helpful links

General Publications

• Shallis RM, Podoltsev NA. Maintenance therapy for acute myeloid leukemia: sustaining the pursuit for sustained remission. Curr Opin Hematol. 2021 Mar 1;28(2):110-121. doi: 10.1097/MOH.0000000000000637.

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2019
• Primary Completion (Estimated): December 15, 2024
• Study Completion (Estimated): December 15, 2024

Study Registration Dates

• First Submitted: October 31, 2018
• First Submitted That Met QC Criteria: October 31, 2018
• First Posted (Actual): November 2, 2018

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: 18117 (Other Identifier: City of Hope Comprehensive Cancer Center); NCI-2018-02371 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No