Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Patients With an IDH2 Mutation

S
Sandeep Batra, MD

Primary Investigator

Enrolling By Invitation
24-18 years
All
Phase 2
10 participants needed
1 Location

Brief description of study

What is the purpose of this study?
This trial studies the side effects of enasidenib and to see how well it works in treatingwith acute myeloid leukemia that has come back after treatment (relapsed) or has been difficult to treat with chemotherapy (refractory). Patients must also have a specific genetic change, also called a mutation, in a protein called IDH2. Enasidenib may stop the growth of cancer cells by blocking the mutated IDH2 protein, which is needed for cell growth.

THIS STUDY IS ENROLLING BY INVITATION ONLY - Consistent with most oncology trials, patients are not actively “recruited,” but are screened by their physician for appropriate clinical trial(s) at the time of their routine clinic visit. Occasionally, a patient may be a self-referral or physician referral, but are still screened for appropriate clinical trials at the time of their routine clinic visit. PI and staff may send copies of relevant consent forms to these patients to look over prior to actually consenting or enrolling them. This may take place at the patient's visit at which the consent is presented or the patient's next visit to the outpatient hematology/oncology clinic.

Interested in participating? For more information about this research study or other cancer-related clinical trials at IU Simon Comprehensive Cancer Center, please contact:
IU Clinical Trials Office 
Phone: (317) 278-5632

Detailed description of study

PRIMARY OBJECTIVES:
I. To determine the safety of treatment with enasidenib mesylate (enasidenib) administered atuous daily oral dosing for a 28-day cycle up to 12 cycles in pediatric patients withDH2-mutant relapsed/refractory (R/R)-acute myeloid leukemia (AML).
II. To characterize the plasma pharmacokinetic (PK) profile of enasidenib in pediatricwith IDH2-mutant R/R-AML.
SECONDARY OBJECTIVES:
I. To investigate the pharmacodynamic (PD) relationship of oncogenic metabolite 2-hydroxyglutarate (2-HG) to enasidenib treatment in pediatric patients with IDH2-mutant R/R-AML.
II. To describe the clinical activity of enasidenib in pediatric patients with IDH2-mutant R/R-AML.
TLINE
Patients receive enasidenib 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 at 30 days, then periodically up to 1 year.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, RIley
  • Age: Between 24 Months - 18 Years
  • Gender: All

Inclusion Criteria:
  • Patient must have AML with an IDH2 mutation identified from a peripheral blood or bonew sample at the time of diagnosis and/or relapsed/refractory disease
  • Patient must have bone marrow assessment (aspiration or biopsy) with > 5% leukemicblasts by morphology and/or flow cytometry in at least one of the following clinical
    • Second or greater relapse after chemotherapy or hematopoietic stem cell(HSCT)
    • Refractory after >= 2 attempts at induction therapy
  • Relapsed patients
    • Must not have received prior re-induction therapy for this relapse
    • Each block of chemotherapy (i.e., cytarabine, daunorubicin and etoposide [ADE],ytarabine and mitoxantrone [MA]) is a separate re-induction attempt
    • Donor lymphocyte infusion (DLI) is considered a re-induction attempt
  • Refractory patients
    • Each attempt at induction therapy may include up to two chemotherapy courses
  • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
    years of age. Patients who are unable to walk because of paralysis, but who are up inwheelchair, will be considered ambulatory for the purpose of assessing the
  • Patient's current disease state must be one for which there is no known curativeherapy or therapy proven to prolong survival with an acceptable quality of life
  • Evaluation of cerebrospinal fluid (CSF) is only required if there is a clinicaluspicion of central nervous system (CNS) involvement by leukemia during eligibilityg. Should a patient be found to have CNS2 or CNS3 status by CSF prior togibility screening, patient may receive intrathecal chemotherapy > 72 hours priorg study drug. CNS1 status must be established before starting study drug
  • Patients must have fully recovered from the acute toxic effects of all priorherapy and must meet the following minimum duration from priordirected therapy prior to enrollment. If after the required timeframe, theumerical eligibility criteria are met, e.g., blood count criteria, the patient isdered to have recovered adequately
    • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.The duration of this interval must be discussed with the study chair and theudy-assigned research coordinator prior to enrollment
      • >= 14 days must have elapsed after the completion of other cytotoxic therapywith the exception of hydroxyurea. Additionally, patients must have fullyvered from all acute toxic effects of prior therapy. NOTE: Cytoreductionwith hydroxyurea must be discontinued >= 24 hours prior to the start ofherapy
      • Intrathecal chemotherapy must be completed >= 72 hours prior to the start ofhe first cycle of treatment
    • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
      reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after thedose of agent. The duration of this interval must be discussed with theudy chair and the study-assigned research coordinator prior to enrollment
    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,d toxicity related to prior antibody therapy must be recovered to grade =< 1
    • Corticosteroids: If used to modify immune adverse events related to priorherapy, >= 14 days must have elapsed since last dose of corticosteroid
    • Hematopoietic growth factors: >= 14 days after the last dose of a long-actinggrowth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. Forgents that have known adverse events occurring beyond 7 days afterdministration, this period must be extended beyond the time during which adversevents are known to occur. The duration of this interval must be discussed withhe study chair and the study research coordinator
    • Interleukins, interferons and cytokines (other than hematopoietic growth): >= 21 days after the completion of interleukins, interferon orytokines (other than hematopoietic growth factors)
    • Stem cell Infusions (with or without total body irradiation [TBI]):
      • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stemusion including DLI or boost infusion:
        • >= 60 days after infusion for bone marrow or stem cell transplant and
        • >= 4 weeks after infusion for any stem cell infusion including DLI orboost infusion
        • There must be no evidence of graft versus host disease (GVHD)
      • Autologous stem cell infusion including boost infusion: >= 42 days
    • Cellular Therapy: >= 42 days after the completion of any type of cellular therapy
      (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
    • XRT/external beam irradiation including protons: >= 14 days after local XRT; >=150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >=2 days if other substantial bone marrow (BM) radiation
    • Radiopharmaceutical therapy (e.g., radiolabeled antibody,131I-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administereddiopharmaceutical therapy
    • Study-specific limitations on prior therapy: small molecule investigationalgents: >= 14 days or > 5 half-lives must have elapsed from the last dose of thegent, whichever is greater
  • Platelet count >= 20,000/mm^3 (may receive platelet transfusions). These patients must
    not be known to be refractory to red cell or platelet transfusion
  • Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
  • Creatinine clearance or radioisotope glomerular filtration rate [GFR] >= 70/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
    • Age: Maximum serum creatinine (mg/dL)
      • 2 to < 6 years: 0.8 (male and female)
      • 6 to < 10 years: 1 (male and female)
      • 10 to < 13 years: 1.2 (male and female)
      • 13 to < 16 years: 1.5 (male); 1.4 (female
      • >= 16 years: 1.7 (male); 1.4 (female)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
    age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225/L. For the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin >= 2 g/dL
  • Left ventricular ejection fraction of >= 50% by echocardiogram
  • Regulatory Requirements
    • All patients and/or their parents or legal authorized representatives must sign awritten informed consent. Assent, when appropriate, will be obtained according toutional guidelines
    • All institutional, Food and Drug Administration (FDA), and National Cancerute (NCI) requirements for human studies must be met
Exclusion Criteria:
  • AML associated with Down syndrome or t(15;17) is not eligible for study
  • Pregnant or breast-feeding women will not be entered on this study due to risks ofd teratogenic adverse events as seen in animal/human studies. Pregnancy testsust be obtained in girls who are post-menarchal. Males or females of reproductivey not participate unless they have agreed to use an effectiveve method for the duration of study therapy and for 4 months after the lastdose of enasidenib. Abstinence is an acceptable method of birth control. It is notknown if enasidenib is present in breast milk. Breastfeeding is not recommended duringherapy or for at least 30 days after the last dose of enasidenib
  • Concomitant Medications:
    • Corticosteroids: Patients receiving corticosteroids who have not been on a stabledecreasing dose of corticosteroid for at least 7 days prior to enrollment aregible. If used to modify immune adverse events related to prior therapy,>= 14 days must have elapsed since last dose of corticosteroid. The use ofds to manage the side effect of IDH inhibitor-associateddifferentiation syndrome (IDH-DS), is permitted on study
    • Investigational drugs: Patients who are currently receiving anothervestigational drug are not eligible
    • Anti-cancer agents: Patients who are currently receiving other anti-cancer agentsgible (except leukemia patients receiving hydroxyurea, which may beued until 24 hours prior to start of protocol therapy; the use ofhydroxyurea to manage the side effect of IDH-DS, is permitted on study)
    • Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine,us or other agents to prevent graft-versus-host disease post bone marrowgible for this trial
  • Patients must be able to swallow intact tablets whole.
    • Patients with known hypersensitivity to any of the components of enasidenib aregible.
    • Patients with prior exposure to enasidenib or another IDH2 inhibitor are notgible.
    • Patients taking the following drugs will be excluded from study entry unlesshese drugs are discontinued or patients are transferred to a medicallyble alternative > 5 half-lives before the first dose of enasidenib.
      • Drugs with a narrow therapeutic range that are sensitive substrates of thewing cytochrome P450 (CYP) enzymes: CYP2C8 (e.g. paclitaxel), 2C9 (e.g.henytoin and warfarin), 2C19 (e.g. s-mephenytoin), 2D6 (e.g. thioridazine),d 1A2 (e.g. theophylline and tizanidine).
      • Breast cancer resistant protein (BCRP) transporter-sensitive substrateuvastatin
  • Patients with the following leukemia complications are not eligible for this trial:
    • No intrathecal chemotherapy is permitted on study. Prior to study enrollment,brospinal fluid (CSF) evaluation is only required if there is a clinicaluspicion for CNS leukemia. Clinical signs of CNS leukemia (such as facial nervey, brain/eye involvement or hypothalamic syndrome) are not eligible for this
    • Immediately life-threatening, severe complications of leukemia includinguncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminatedvascular coagulation
  • Infection: Patients who have an uncontrolled infection or patients with known human
    immunodeficiency virus (HIV) or active hepatitis B or C are not eligible
  • Patients who have received a prior solid organ transplantation are not eligible
  • Patients who in the opinion of the investigator may not be able to comply with they monitoring requirements of the study are not eligible

Updated on 12 Sep 2024. Study ID: ADVL18P1, PHO-COG-ADVL18P1, 2004365475
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