Clinical Trials /

Ixazomib (MLN9708) in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT02030405

Description:

This phase 2 trial studies how well ixazomib(MLN9708) works in treating study participants with relapsed or refractory acute myeloid leukemia. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ixazomib (MLN9708) in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase 2 Study of Single-Agent MLN9708 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia With Mutated Nucleophosmin-1

Clinical Trial IDs

  • ORG STUDY ID: IRB-28771
  • SECONDARY ID: NCI-2013-02231
  • SECONDARY ID: P30CA124435
  • SECONDARY ID: HEMAML0028
  • NCT ID: NCT02030405

Conditions

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
ixazomibMLN9708, proteasome inhibitorIxazomib (MLN9708)

Purpose

This phase 2 trial studies how well ixazomib(MLN9708) works in treating patients with relapsed or refractory acute myeloid leukemia. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVE:

      Determine the best response including complete remission (CR), CR with incomplete recovery
      (CRi), and partial remission (PR) after 3 cycles of treatment with MLN9708 (ixazomib) in
      patients with nucleophosmin (NPM)1-mutated acute myeloid leukemia (AML) (following the
      LeukemiaNet1 guidelines for response criteria).

      SECONDARY OBJECTIVES:

        -  Determine the duration of remission in all responders after treatment with MLN9708
           defined as the time of documented remission until relapse.

        -  Determine the 1 year overall survival, which will be measured from time of study entry
           to the earlier of death from any cause or end of follow up at 1 year.

        -  Establish toxicity and tolerability of MLN9708 treatment in AML, including
           non-hematologic toxicities grade 3 or above as specified by Common Terminology Criteria
           for Adverse Events (CTCAE) version 4.0.

      OUTLINE:

      Patients receive ixazomib orally (PO) on days 1, 4, 8, and 11. Treatment repeats every 21
      days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Ixazomib (MLN9708)ExperimentalPatients receive ixazomib PO on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
  • ixazomib

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of relapsed or refractory AML of any French American British (FAB) subtype
             except M3 and NPM1 genetic mutation detected by molecular assay; AML patients treated
             at Stanford have NPM1 molecular mutation status checked routinely at time of diagnosis
             in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory

          -  Male or female patients and no race-ethnic restrictions

          -  Patients are unwilling, or who are determined to be medically unfit for or resistant
             to standard intensive induction chemotherapy; patients who are medically unfit will be
             determined by the treating primary hematologist and the principal investigator
             (including but not limited to evaluation of co-morbidities, and response and
             complications to previous AML treatment strategy)

          -  Eastern Cooperative Oncology Group (ECOG) 0 to 2

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Female patients who:

               -  Are postmenopausal for at least 1 year before the screening visit, OR

               -  Are surgically sterile, OR

               -  If they are of childbearing potential, agree to practice 2 effective methods of
                  contraception, at the same time, from the time of signing the informed consent
                  form through 90 days after the last dose of study drug, AND

               -  Must also adhere to the guidelines of any treatment-specific pregnancy prevention
                  program, if applicable, OR

               -  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation,
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
                  of contraception)

          -  Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree
             to one of the following:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 90 days after the last dose of study drug, OR

               -  Must also adhere to the guidelines of any treatment-specific pregnancy prevention
                  program, if applicable, OR

               -  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the subject; (periodic abstinence (eg, calendar, ovulation,
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
                  of contraception)

          -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN

          -  Calculated creatinine clearance ≥ 30 mL/min

        Exclusion Criteria:

          -  Female patient who are lactating or have a positive serum pregnancy test during the
             screening period

          -  Major surgery within 14 days before enrollment

          -  Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days
             will be considered a sufficient interval between treatment and administration of
             MLN9708

          -  Known active and uncontrolled central nervous system (CNS) involvement of leukemia (a
             lumbar puncture does not need to be performed as a part of screening)

          -  Have a significant uncontrolled infection active infection

          -  Have other severe concurrent disease or serious organ dysfunction involving the heart,
             kidney, liver or other organ system that may place the patient at undue risk to
             undergo treatment including uncontrolled hypertension, uncontrolled cardiac
             arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial
             infarction within the past 6 months

          -  Systemic treatment, within 14 days before the first dose of MLN9708, with strong
             inhibitors of cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2)
             (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family
             3, subfamily A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole,
             ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin,
             rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo
             biloba or St. John's wort

          -  Known ongoing or active systemic infection, active hepatitis B or C virus infection,
             or known human immunodeficiency virus (HIV) positive

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of MLN9708 including difficulty

          -  Diagnosed or treated for another malignancy within 2 years before study enrollment or
             previously diagnosed with another malignancy and have any evidence of residual
             disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone complete resection; this does not preclude
             previous diagnosis of acute myeloid leukemia or myelodysplastic syndrome

          -  Patient has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical
             examination during the screening

          -  Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 21 days of the start of this trial and
             throughout the duration of this trial

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:9 weeks
Safety Issue:
Description:Overall response rate after 3 cycles of treatment (9 weeks) was assessed as complete remission (CR); CR with incomplete recovery (CRi); and partial remission (PR) with MLN9708, in patients with NPM1-mutated AML by LeukemiaNet1 guidelines: CR is defined as either a full CR, or a CR with incomplete recovery. Although achievement of CR has unique clinical significance for improved overall survival and relapsed free survival compared to achievement of CR with incomplete platelet recovery, the latter is still a clinically meaningful response, as it is independently superior to resistant disease. Partial remission (PR) is defined as meeting all hematologic criteria for CR with an allowance for 5% to 25% bone marrow blasts or decrease of pretreatment bone marrow blast percentage by at least 50%. Stable disease is defined as a change in bone marrow aspirate blast count within 10% of baseline. Relapsed disease is defined as reappearance of blasts in the blood or bone marrow blasts

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:1 year
Safety Issue:
Description:Overall survival (OS) from time of study entry to the earlier of death from any cause or end of follow up at 1 year

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Bruno C. Medeiros

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