Clinical Trials /

Enasidenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia With an IDH2 Gene Mutation

NCT03881735

Description:

This phase II trial studies how well enasidenib works in treating in patients with acute myeloid leukemia with an IDH2 gene mutation that has come back or has not responded to treatment. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. In this study we are investing if enasidenib can be used as maintenance therapy post salvage induction chemotherapy.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Enasidenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia With an IDH2 Gene Mutation
  • Official Title: A Phase II Study of Intensive Salvage Therapy Followed by Enasidenib for Patients With AML Harboring Mutations in IDH2 Who Have Failed or Been Refractory to One Prior Line of Therapy

Clinical Trial IDs

  • ORG STUDY ID: I 67118
  • SECONDARY ID: NCI-2019-00332
  • SECONDARY ID: I 67118
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT03881735

Conditions

  • Blasts Under 5 Percent of Peripheral Blood White Cells
  • Bone Marrow Blasts Decreased by 50 Percent or More Compared to Pretreatment Level
  • IDH2 Gene Mutation
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
EnasidenibAG-221, CC-90007Cohort A (enasidenib, hematopoietic cell transplantation)

Purpose

This phase II trial studies how well enasidenib works in treating in patients with acute myeloid leukemia with an IDH2 gene mutation that has come back or has not responded to treatment. Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Evaluate the effect of IDH2 inhibition following conventional high dose salvage
      chemotherapy with detectable IDH2 mutations on event free survival (EFS) in patients with
      relapsed/refractory acute myeloid leukemia (AML).

      SECONDARY OBJECTIVES:

      I. Evaluate the effect of IDH2 inhibitor maintenance therapy following intensive salvage
      therapy: i.e., rate of hematocrit (HCT), duration of maintenance therapy and overall survival
      in patients with IDH2 mutant relapsed/refractory AML.

      EXPLORATORY OBJECTIVES:

      I. Evaluate the changes in IDH2 mutational variant allelic frequency and deoxyribonucleic
      acid (DNA) methylation signature while on enasidenib therapy.

      OUTLINE: Patients are assigned to 1 of 2 cohorts.

      COHORT I: Patients receive enasidenib orally (PO) once daily (QD). Treatment repeats every 28
      days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
      Patients then undergo a hematopoietic cell transplantation (HCT) 7-14 days after treatment.
      Within 30-100 days following the transplant, patients receive enasidenib QD. Treatment
      repeats every 28 days for 24 cycles in the absence of disease progression or unacceptable
      toxicity.

      COHORT II: Patients receive enasidenib PO QD. Treatment repeats every 28 days in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 6 months and then yearly for
      5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A (enasidenib, hematopoietic cell transplantation)ExperimentalPatients receive enasidenib PO QD. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo a HCT 7-14 days after treatment. Within 30-100 days following the transplant, patients receive enasidenib QD. Treatment repeats every 28 days for 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Enasidenib
Cohort B (enasidenib)Active ComparatorPatients receive enasidenib PO QD. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
  • Enasidenib

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmed diagnosis of AML harboring a mutation in IDH2 relapsed or refractory to
             first line cytarabine/anthracycline induction chemotherapy, failed to respond to or
             relapsed following at least 2 cycles of hypomethylating agent (azacitidine,
             decitabine, sgi-110)

               -  First relapse defined as untreated hematologic relapse (according to
                  International Working Group criteria) after one line of intensive regimen for AML
                  including at least one cytarabine containing induction block with a total dose no
                  less than 700 mg/m^2 per cycle and 3 days of an anthracycline that induced a
                  complete remission (CR)/complete remission with incomplete hematologic recovery
                  (CRi)/complete remission with incomplete platelet recovery (CRp). Subjects are
                  allowed to receive induction, consolidation, transplant and/or maintenance
                  therapy prior to achieving their first CR/CRi/CRp

               -  Refractory to induction therapy is defined as never achieving CR, CRi or CRp
                  (according to International Working Group criteria) after one line of intensive
                  regimen for AML (reinduction, consolidation and/or transplant allowed) including
                  at least one cytarabine containing induction block with a total dose no less than
                  700 mg/m^2 per cycle and 3 days of an anthracycline

          -  Subjects considered eligible for intensive chemotherapy

          -  Subjects had received a first salvage within the last 60 days (day 15 to 60 following
             most recent cytarabine-based standard salvage number [#] 1 therapy) who achieved
             either > 50% reduction in blast percentage from the pre-treatment bone marrow OR < 20%
             cellularity with any blast percentage AND < 5% peripheral blood blasts

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

          -  Normal total blood serum bilirubin with the exception of elevation due to Gilbert?s
             disease (within 72 hours of enrollment)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x upper
             limit of normal (ULN) (within 72 hours of enrollment)

          -  Adequate renal function within 72 hours of enrollment, defined as blood creatinine =<
             1.5 x ULN

          -  Women of childbearing potential must have a negative serum or urine pregnancy test
             within 72 hours prior to enrollment and either commit to continued abstinence from
             heterosexual intercourse or begin one acceptable method of birth control pills or
             barrier contraception. Should a woman become pregnant or suspect she is pregnant while
             she or her partner is participating in this study, she should inform her treating
             physician immediately

          -  Men must use a latex condom during any sexual contact with women of childbearing
             potential

          -  Willing to adhere to protocol specific requirements

          -  Clinically significant toxic effects of prior therapy (except hydroxyurea) resolved to
             grade =< 1 before the start of study

          -  Participant or legal representative must understand the investigational nature of this
             study and sign an Independent Ethics Committee/Institutional Review Board approved
             written informed consent form prior to receiving any study related procedure

        Exclusion Criteria:

          -  Acute promyelocytic leukemia (APL)

          -  Subject has or is suspected of having central nervous system (CNS) leukemia.
             Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
             suspected during screening

          -  Clinically active or unstable graft-versus-host disease (GVHD) requiring treatment
             that precludes administration of chemotherapy as defined in this protocol

          -  Prior anti-leukemia therapy within 5 x the half-life for other investigational agents
             and consolidation chemotherapy within last 14 days

               -  Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e.,
                  control of white blood count [WBC]) are allowed but should be discontinued at
                  least 24 hours prior to enrollment. Other agents used strictly with palliative
                  intent might be allowed during this period after discussing with principal
                  investigator

          -  Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic
             steatohepatitis, sclerosing cholangitis)

          -  Subject is known seropositive or active infection with human immunodeficiency virus
             (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)

          -  Subject has active uncontrolled systemic fungal, bacterial, or viral infection
             (defined as ongoing signs/symptoms related to the infection without improvement
             despite appropriate antibiotics, antiviral therapy, and/or other treatment)

          -  Pregnant or nursing female participants

          -  Subjects of childbearing potential not willing to use adequate contraception

          -  Subject has significant active cardiac disease within 6 months prior to the start of
             study treatment, including New York Heart Association (NYHA) class III or IV
             congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or left
             ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
             acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment

          -  Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions
             that in the opinion of the investigator may impair the participation in the study or
             the evaluation of safety and/or efficacy

          -  Subject has immediately life-threatening, severe complications of leukemia such as
             uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
             intravascular coagulation

          -  Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
             conditions that limit the ingestion or gastrointestinal absorption of drugs
             administered orally

          -  Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
             diastolic BP > 90 mmHg)

          -  Subject has known (or suspected to have) hypersensitivity to any of the components of
             study treatment

          -  Subject has 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

          -  Subject is taking the following sensitive CYP substrate medications that have a narrow
             therapeutic range are excluded from the study unless the subject can be transferred to
             other medications at least 5 half-lives prior to the start of study treatment:
             phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
             tizanidine (CYP1A2)

          -  Subject who is taking the breast cancer resistance protein (BCRP)
             transporter-sensitive substrate (i.e., rosuvastatin) should be excluded from the study
             unless the subject can be transferred to other medications at least 5 half-lives prior
             to the start of study treatment

          -  Subject has prior history of malignancy, other than myelodysplastic syndrome (MDS),
             myeloproliferative neoplasm (MPN) or AML. However, subjects with the following
             history/concurrent conditions are allowed:

               -  Basal or squamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

               -  Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
                  node, metastasis clinical staging system)

          -  Concurrent participation in another therapeutic clinical trial

          -  Unwilling or unable to follow protocol requirements

          -  Any condition which in the investigator?s opinion deems the participant an unsuitable
             candidate to receive study drug
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS) in each cohort
Time Frame:At 12 months
Safety Issue:
Description:Defined as the binomial proportion of evaluable patients who are alive and disease free 12 months after enrollment. Two-sided 95% Jeffreys confidence interval estimates will be used to describe the plausible range for the true EFS rate in each patient group. The EFS rates will be estimated separately for each cohort, on an intent-to-treat basis.

Secondary Outcome Measures

Measure:Success rate of hematopoietic cell transplantation (HCT)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Median duration of maintenance therapy in both cohorts
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall survival in each cohort
Time Frame:At 12 and 24 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated