Clinical Trial: Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or Physicians Choice of Treatment Administered to Patients With Relapsed or Refracto

Brief Summary: The purpose of this study is to determine whether dexamethasone plus IXAZOMIB improves hematologic response, 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician's choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis.

Detailed Summary:

The drug being tested in this study is called IXAZOMIB. IXAZOMIB was being tested to treat people who have relapsed or Refractory Systemic Light Chain (AL) Amyloidosis.

The study will enroll approximately 248 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

  • IXAZOMIB 4 mg plus Dexamethasone 20 mg

  • Physician's choice: Participants will receive one of the following treatment options as selected by the physician:

    1. Dexamethasone 20 mg
    2. Dexamethasone 20 mg + Melphalan 0.22 mg/kg
    3. Dexamethasone 20 mg + Cyclophosphamide 500 mg
    4. Dexamethasone 20 mg + Thalidomide 200 mg
    5. Dexamethasone 20 mg + Lenalidomide 15 mg
    6. All participants will be asked to take oral formulation of the drugs. In both treatment arms, each participant will continue to receive sequential cycles of therapy until disease progression, unacceptable toxicity, or until the study is terminated, whichever occurs first. Participants in Arm B receiving melphalan and dexamethasone will be treated to best response plus 2 additional cycles.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 112 months (9.3 years), including 84 months of enrollment and 28 months of follow-up after the last participant is enrolled.


Sponsor: Millennium Pharmaceuticals, Inc.

Current Primary Outcome:

  • Percentage Of Participants With Overall Hematologic Response [ Time Frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death which occurs first (approximately 9.3 years) ]
    Overall Hematologic Response was defined as the percentage of participants with Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR) based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as assessed by an Adjudication Committee. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of Free Light Chain (FLC) ratio. VGPR: Differential Free Light Chain (difference between involved and uninvolved FLC levels; dFLC) < 40 mg/L. PR: ≥50% reduction in dFLC.
  • 2-Year Vital Organ (Heart Or Kidney) Deterioration And Mortality Rate [ Time Frame: Monthly or until death (Up to 2 years) ]
    Cardiac (Heart) deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. Vital organ deterioration will be evaluated by an Adjudication Committee.


Original Primary Outcome:

  • Number of patients with overall hematologic response [ Time Frame: Assessed every 4 weeks (median length of the endpoint assessment period is projected to be approximately 36 months) ]
    Complete response, very good partial response and partial response
  • 2-year vital organ deterioration and mortality rate [ Time Frame: Monthly for up to 2 years or until death ]
    Rate of hospitalization for congestive heart failure or progression to end stage renal disease or death at 2 years


Current Secondary Outcome:

  • Percentage Of Participants With Complete Hematologic Response [ Time Frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (approximately 9.3 years) ]
    Complete Hematologic Response was defined as the percentage of participants with CR based on central laboratory results and the 2010 ISA Consensus Criteria as assessed by an Adjudication Committee. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of FLC ratio.
  • Overall Survival [ Time Frame: From the date of randomization until death (approximately 9.3 years) ]
    Overall survival is defined as the time from the date of randomization to the date of death.
  • Progression Free Survival (PFS) [ Time Frame: From date of randomization until discontinuation of study drug due to disease progression or unacceptable toxicity, or death which occurs first (approximately 9.3 years) ]
    PFS is defined as the time from the date of randomization to the date of first documentation of hematologic disease progression, or organ (cardiac or renal) progression, or death due to any cause, whichever occurs first according to central laboratory results and ISA criteria as evaluated by an Adjudication Committee.
  • Hematologic Disease Progression Free Survival [ Time Frame: From date of randomization until discontinuation of study drug due to disease progression or unacceptable toxicity, or death which occurs first (approximately 9.3 years) ]
    Hematologic disease PFS is defined as the time from the date of randomization to the date of first documentation of hematologic PD according to central laboratory results and ISA criteria as evaluated by an Adjudication Committee, or death due to any cause, whichever occurs first.
  • Time To Vital Organ (Heart Or Kidney) Deterioration And Mortality Rate [ Time Frame: From randomization to time of vital organ deterioration or death (approximately 9.3 years) ]
    Time to vital organ deterioration or death defined as the time from randomization to vital organ (heart or kidney) deterioration or death, whichever occurs first. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to ESRD with the need for maintenance dialysis or renal transplantation.
  • Percentage Of Participants With Best Vital Organ (Cardiac And/Or Kidney) Response [ Time Frame: From randomization until discontinuation of study drug due to disease progression or unacceptable toxicity, or death which occurs first (approximately 9.3 years) ]
    Vital organ (heart and kidney) response rate is defined as the percentage of participants who achieved vital organ response according to central laboratory results and ISA criteria as evaluated by an Adjudication Committee. A vital organ response is defined as response of 1 or 2 of the involved vital organs with no change from Baseline in the rest of involved vital organs.
  • Vital Organ Progression Free Survival [ Time Frame: From randomization until discontinuation of study drug due to disease progression or unacceptable toxicity, or death which occurs first (approximately 9.3 years) ]
    Vital organ PFS is defined as the time from the date of randomization to the date of first documentation of progression of vital organ (heart or kidney) according to central laboratory results and ISA criteria as evaluated by an Adjudication Committee, or death due to any cause, whichever occurs first.
  • Duration of Hematologic Response [ Time Frame: From time of first documented response to disease progression (up to 9.3 years) ]
    Duration of hematologic response (DOR) is defined as the time from the date of first documentation of a hematologic response to the date of first documented hematologic disease progression according to central laboratory results and ISA criteria as determined by an Adjudication Committee.
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose of study drug through 30 days after administration of the last dose of study drug (approximately 9.3 years) ]
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
  • Time To Treatment Failure (TTF) [ Time

    Original Secondary Outcome:

    • Number of patients with complete hematologic response [ Time Frame: Assessed every 4 weeks (median length of the endpoint assessment period is projected to be approximately 36 months) ]
      Overall complete hematologic response
    • Overall Survival [ Time Frame: Monthly up to 5 years ]
      Time from randomization to the date of death
    • Progression free survival [ Time Frame: Monthly up to 5 years ]
      Time from date of randomization to the date of first documentation of disease progression or death, whichever occurs first
    • Hematologic Disease Progression Free Survival [ Time Frame: Monthly up to 5 years ]
      Time from the date of randomization to the date of first documented hematologic disease progression or death, whichever occurs first
    • Time to vital organ deterioration and mortality rate [ Time Frame: Monthly up to 5 years ]
      Time from date of randomization to the first date of either death or hospitalization for congestive heart failure or progression to endstage renal disease
    • Number of patients with cardiac and/or kidney response [ Time Frame: Every 3 cycles until disease progression ]
      Overall organ response rate
    • Vital Organ Progression Free Survival [ Time Frame: Every 3 cycles until disease progression ]
      Time from the date of randomization to the date of first documentation of progression of vital organ, or death, whichever occurs first
    • Duration of Hematologic Response [ Time Frame: Monthly up to 5 years ]
      Time from the date of first documentation of hematologic response to the date of first documented hematologic disease progression
    • Number of adverse events [ Time Frame: Monthly up to 5 years ]
      Adverse events, serious adverse events, assessment of clinical laboratory values from the date of signing of the informed consent form through 30 days after the last dose of study drug.
    • Time to treatment failure [ Time Frame: Monthly up to 5 years ]
      Time from date of randomization to the date of first documented treatment failure
    • Time To Subsequent Anticancer Treatment [ Time Frame: Monthly up to 5 years ]
      Time from date of randomization to the start date of subsequent anticancer treatment
    • Results of Quality of Life Assessment [ Time Frame: At screening; Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Day 1 of every 3 cycles until disease progression ]
    • Number of medical encounters patient experiences [ Time Frame: At screening; Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Day 1 of every 3 cycles until disease progression ]
      Number of admissions to an inpatient and outpatient setting for any reason (including length of stay, inpatient, outpatient, reason, number of missing days from work or other activities by patient or care-giver and EQ-5D scores questionnaire data
    • Time to reach plasma concentration [ Time Frame: Cycle 1, Days 1 and 14; Cycle 2, Days 1 and 14; Cycles 3-10, Day 1 ]
      Pharmacokinetics
    • Investigate the association of clinical outcomes and polymorphic genes [ Time Frame: At screening ]
      Analysis of relevant signaling pathway genes in whole blood samples


    Information By: Takeda

    Dates:
    Date Received: August 2, 2012
    Date Started: December 26, 2012
    Date Completion: September 1, 2018
    Last Updated: March 22, 2017
    Last Verified: March 2017