Clinical Trials /

MLN 9708 in Induction and Consolidation for Adults With AML >= 60 Years of Age

NCT02582359

Description:

This research study is evaluating drugs called Millennium 9708 (referred to as MLN9708) in combination with standard therapy for acute myeloid leukemia (AML) consisting of daunorubicin and cytarabine as a possible treatment for the patient AML.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MLN 9708 in Induction and Consolidation for Adults With AML >= 60 Years of Age
  • Official Title: Phase I Dose Escalation Study of Millennium 9708 in Combination With Induction and Consolidation Chemotherapy in Adults >= 60 Years With Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 15-276
  • NCT ID: NCT02582359

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
MLN9708IxazomibMLN9708
CytarabineCytosar-U®, Ara-C, ArabinosylcytosineMLN9708
DaunorubicinCerubidine®MLN9708

Purpose

This research study is evaluating drugs called Millennium 9708 (referred to as MLN9708) in combination with standard therapy for acute myeloid leukemia (AML) consisting of daunorubicin and cytarabine as a possible treatment for the patient AML.

Detailed Description

      This research study is a clinical trial comprised of two Phase I portions an induction
      treatment (initial treatment), and a consolidation treatment (which is given later). The
      patient is being asked to participate in one or both phase I portions of this study.

      A phase I study tests the safety of an investigational drug or combination of drugs. Phase I
      studies also try to define the appropriate dose of the investigational drugs to use for
      further studies. "Investigational" means that the drug combination is being studied. It also
      means that the FDA (U.S. Food and Drug Administration) has not approved the drug combination
      for the participant's type of cancer.

      In this research study, the investigators are studying the safety and tolerability of MLN9708
      in combination with standard treatment for adults 60 years of age or older with AML.

      In the first phase I portion of treatment ("induction") participants will receive MLN9708 in
      combination with daunorubicin and cytarabine. Once the maximally tolerated dose (MTD) of
      MLN9708 is established in this induction portion, up to 36 additional participants will be
      enrolled in the portion focusing on consolidation.

      The drugs daunorubicin and cytarabine have been approved by the FDA (U.S. Food and Drug
      Administration). MLN9708 is not approved by the FDA.
    

Trial Arms

NameTypeDescriptionInterventions
MLN9708ExperimentalPhase I dose escalation study of MLN9708 with induction chemotherapy MLN9708 -oral on predetermined days per cycle Cytarabine, continuous infusion for predetermined duration and dosage Daunorubicin short IV infusion or rapid injection for predetermined Phase I dose escalation study of MLN9708 with consolidation chemotherapy after establishment of MTD with induction
  • MLN9708
  • Cytarabine
  • Daunorubicin

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female patients 60 years or older.

          -  Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the patient at any time without prejudice to future medical care.

          -  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 (e.g., calendar, ovulation,
                  symptothermal, post-ovulation methods) and withdrawal are not acceptable methods
                  of contraception.]

          -  Patients must have a diagnosis of AML according to the World Health Organization (WHO)
             criteria. Therapy-related and secondary AML (arising after a period of myelodysplasia
             [MDS]) allowed. Prior treatment for MDS with hypomethylator-based therapy and
             lenalidomide allowed, but not allowed if used after the diagnosis of AML is made,
             since enrollment to this study is not for relapsed AML.

          -  Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
             status 0, 1, or 2. Performance status of 3 permissible if related to disease.

          -  Patients must meet the following clinical laboratory criteria:

               -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) unless related
                  to disease or patient known to have underlying Gilbert's disease.

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

               -  Calculated creatinine clearance ≥ 30 mL/min (see Section 12.2).

        Exclusion Criteria:

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

          -  Failure to have fully recovered (ie, ≤Grade 1 toxicity) from the reversible effects of
             prior chemotherapy as stated in Section 5.1.4.

          -  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 the
             MLN9708.

          -  Suspected AML-related central nervous system involvement. A lumbar puncture (LP) is
             not required to exclude central nervous system (CNS) disease.

          -  Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
             unstable angina, or myocardial infarction within the past 6 months.

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

          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of treatment according to this protocol.

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.

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

          -  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 non-melanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone complete resection.

          -  Patient has ≥ Grade 1 neuropathy, sensory, with or without pain, motor, or autonomic,
             on clinical examination during the screening period.

          -  Participation in other clinical trials involving investigational agents within 21 days
             of the start of this trial and throughout the duration of this trial.

          -  Prior chemotherapy treatment for AML (Prior treatment with hydroxyurea and/or
             leukapheresis to control white blood cell count acceptable). Prior chemotherapy for
             MDS or myeloproliferative neoplasms (MPN) such as azacitidine, decitabine, and
             thalidomide, is permitted, but such treatments once MDS or MPN has transformed to AML
             is not permitted.

          -  Acute promyelocytic leukemia(APL) by WHO criteria [AML with t(15;17)]

          -  Cardiac ejection fraction (EF) < 40%

          -  Systemic treatment, during or within 48 hours of the first dose of MLN9708, with
             strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors
             of 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.
             The washout period will be extended to 2 days if patients are receiving extended
             release ciprofloxacin. For this protocol prophylactic antibiotics are not recommended,
             at least not until 48 hours after the last dose of study drug (given on Day 12), when
             the patient may be neutropenic. For patients with fever and/or infections, cefepime
             and ambisome are acceptable.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD/recommended phase 2 dose (RP2D) of MLN9708 in combination with induction chemotherapy
Time Frame:1 year
Safety Issue:
Description:Safety of MLN9708 in induction

Secondary Outcome Measures

Measure:Dose Limiting Toxicities of MLN9708
Time Frame:1 year
Safety Issue:
Description:Generally by NCI CTCAE: grade 3 neuropathy, grade 3 non-hematological toxicity that does not resolve to grade 2, grade 4 hematological toxicity not due to persistent AML that persists
Measure:Disease Free Survival (DFS)
Time Frame:2 Years: Complete remission (CR) or complete remission without platelet recovery (CRp) to relapse or death, whichever comes first, for patients who receive study drug in induction and regardless of consolidation therapy
Safety Issue:
Description:Duration in weeks or months from determination of remission to time of relapse or death
Measure:Overall Survival (OS)
Time Frame:2 Years
Safety Issue:
Description:Duration in weeks or months from day 1 of protocol treatment to time of death
Measure:Remission Rate
Time Frame:2 years
Safety Issue:
Description:Percentage of patients starting day 1 treatment that achieve a remission (CR or CRp)
Measure:Relationship between CD74 expression and remission, DFS, OS
Time Frame:2 Years
Safety Issue:
Description:Degree of CD74 expression on leukemia blasts compared to the rate of remission and length of DFS and OS.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Acute Myeloid Leukemia

Last Updated