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A Study of Oral Ixazomib Maintenance Therapy After Initial Therapy in Participants With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation (SCT)

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ClinicalTrials.gov Identifier: NCT03748953
Recruitment Status : Recruiting
First Posted : November 21, 2018
Last Update Posted : June 3, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Tracking Information
First Submitted Date  ICMJE November 16, 2018
First Posted Date  ICMJE November 21, 2018
Last Update Posted Date June 3, 2019
Actual Study Start Date  ICMJE January 24, 2019
Estimated Primary Completion Date September 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2018)
Progression-Free Survival (PFS) [ Time Frame: From randomization to progressive disease (PD) or death from any cause (until 60 death events or the full analysis (FA) for overall survival (OS) in global study, whichever occurs later [approximately 88 months]) ]
PFS is defined as the time from randomization to the first occurrence of PD as evaluated by an independent review committee (IRC) or death from any cause, whichever occurs first. PD is defined as >=25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved free light chain (FLC) levels (absolute increase >10 mg/dL); bone marrow plasma cell percent >/=10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03748953 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2018)
  • Overall Survival (OS) [ Time Frame: From randomization to every 12 weeks during follow-up after PD on next line therapy (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    OS is measured as the time of randomization to the date of death.
  • Percentage of Participants who Achieve or Maintain Best Response Before PD or up to Subsequent Therapy [ Time Frame: From randomization to PD or death from any cause (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    Response will be assessed as per IMWG criteria. Best response will include partial responses (PR), very good partial response (VGPR) and complete response (CR). PR is defined as >=50% reduction of serum M-component, urinary M- component by >=90% to <200 mg/24-hour reduction; >=50% in the difference between involved and uninvolved FLC; bone marrow plasma cells (PC) >/= 30%; reduction >/= 50% reduction in the soft tissue size. VGPR is defined as serum or urine M-component detectable by immunofixation but not on electrophoresis; >=90% reduction in serum or urine M-component level <100 mg/24 hour. CR is defined as negative immunofixation on the serum and urine; soft tissue plasmacytomas disappearance; <5% PCs in bone marrow.
  • Duration of Complete Response (CR) [ Time Frame: From randomization to PD or death from any cause (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    Duration of CR is defined as the time from the date of randomization or the date of CR to the date of first documentation of PD. CR is defined as negative immunofixation on the serum and urine; soft tissue plasmacytomas disappearance; <5% PCs in bone marrow.
  • Time to Progression (TTP) [ Time Frame: From randomization to PD or death from any cause (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    TTP is defined as the time from the date of randomization to the date of first documentation of PD. PD is defined as >=25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL); bone marrow plasma cell percent >/=10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development.
  • Second Progression-Free Survival (PFS2) [ Time Frame: Every 12 weeks from the start of next-line therapy to second disease progression or death (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    PFS2 is defined as the time from the start of next-line therapy to second disease progression using IMWG criteria, or death from any cause. PD is defined as >=25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL); bone marrow plasma cell percent >/=10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development.
  • Time to Next-Line Therapy (TTNT) [ Time Frame: From randomization to PD or death from any cause (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    TTNT is defined as the time from the date of randomization to the date of the first dose of next-line antineoplastic therapy.
  • Time to End of the Next Line of Therapy [ Time Frame: From randomization to PD or death from any cause (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    Time to end of next-line therapy is defined as the time from the date of randomization to the date of last dose of next-line antineoplastic therapy.
  • Duration of Next-Line Therapy [ Time Frame: From start of next-line therapy up to PD2 (until approximately 60 death events have been reported or the FA for OS in global study, whichever occurs later, or termination of the study by the sponsor [approximately 88 months]) ]
    Duration of next-line therapy is defined as the time from the date of onset of next-line therapy to the date of the last dose or PD2. PD2 is s defined as >=25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL); bone marrow plasma cell percent >/=10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development.
  • Percentage of Participants With A New Primary Malignancy [ Time Frame: From randomization to PD or death from any cause (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    Percentage of participants with a new primary malignancy will be reported.
  • Percentage of Participants with Conversion from Minimal Residual Disease (MRD) Positive to MRD Negative, or the Maintenance of MRD Negativity [ Time Frame: Up to 26 cycles (each cycle of 28 days), 24 months ]
    MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD. MRD will be assessed using next generation sequencing (NGS) methodology.
  • Overall (OS) Survival in High-Risk Cytogenetic Population [ Time Frame: From randomization to every 12 weeks during follow-up after PD on next line therapy (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    OS will be measured as the time from the date of randomization to the date of death. High-risk population will include but not be limited to participants carrying mutations including, but not limited to, del17, t(4;14), or t(14;16).
  • Progression-Free Survival (PFS) in High-Risk Cytogenetic Population [ Time Frame: From randomization to PD or death from any cause (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    PFS is defined as the time from randomization to the first occurrence of PD as evaluated by an IRC. PD is defined as >=25% increase from lowest value in serum M component or urine M-component; difference between involved and uninvolved FLC levels (absolute increase >10 mg/dL); bone marrow plasma cell percent >/=10%; new bone lesions or soft tissue plasmacytomas development or definite increase in existing bone lesions/soft tissue plasmacytomas size; hypercalcaemia development. High-risk population will include but not be limited to participants carrying mutations including, but not limited to, del17, t(4;14), or t(14;16).
  • Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: First dose of study drug through 30 days after last dose of study drug (Up to 25 months) ]
    ECOG performance status will assess participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hrs), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead.
  • Percentage of Participants with Serious Adverse Events and Adverse Events (AEs) [ Time Frame: First dose of study drug through 30 days after last dose of study drug (Up to 25 months) ]
    A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug.
  • Number of Participants with Any Markedly Abnormal Standard Safety Laboratory Values [ Time Frame: From First dose date of study drug through 30 days after the last dose of study drug (Up to 25 months) ]
    Clinical laboratory evaluations will be performed by a central laboratory. The number of participants with any markedly abnormal standard safety laboratory values collected throughout study.
  • European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ-C30 [ Time Frame: From randomization to second disease progression or death (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ-C30 is completed by the participant. The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1=not at all (best) to 4=very Much (worst) and 2 questions answered on a 7-point scale where 1=very poor (worst) to 7= excellent (best).
  • Correlation between Frailty Status and PFS and OS [ Time Frame: From randomization to every 12 weeks during follow-up after PD on next line therapy (until 60 death events or the FA for OS in global study, whichever occurs later [approximately 88 months]) ]
    Participants frailty status will be assessed on the basis of 4 components: age (<75, 75- 80, and>80 years correspond to frailty scores of 0, 1, and 2, respectively), the charlson comorbidity scoring system without age weighting (scores of ≤ 1 and ≥ 2 correspond to frailty scores of 0 and 1, respectively), the katz index of independence in activities of daily living (scores of >4 and ≤ 4 correspond to frailty scores of 0 and 1, respectively) and lawton instrumental activities of daily living scale (scores of >5 and ≤ 5 correspond to frailty scores of 0 and 1, respectively). The sum of the 4 frailty scores equals the total frailty score. A total frailty score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a total score of 2 or more, to frail. PFS is defined as the time from randomization to the first occurrence of PD as evaluated by an IRC. OS will be measured as the time from the date of randomization to the date of death.
  • Plasma Concentration of Ixazomib [ Time Frame: Cycle 1 Day 1 (1 and 4 hours post dose), Cycle 1 pre-dose on Days 8 and 15; Cycle 2 pre-dose on Days 1 and 8; Cycle 3-10 pre-dose on Day 1; Cycle 5 pre-dose on Day 8 (only for participants who have dose escalated after Cycle 4), each cycle of 28 days ]
  • Time to Resolution of Peripheral Neuropathy (PN) Events [ Time Frame: From First dose date of study drug through 30 days after the last dose of study drug (Up to 25 months) ]
    PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. Time to resolution is defined as the time from the initial onset date (inclusive) to the resolution date for resolved events.
  • Time to Improvement of PN Events [ Time Frame: From First dose date of study drug through 30 days after the last dose of study drug (Up to 25 months) ]
    PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the MedDRA. A PN event is considered to be improved if the event improves from the maximum grade; that is, all the grades recorded after the maximum grade are less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Oral Ixazomib Maintenance Therapy After Initial Therapy in Participants With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation (SCT)
Official Title  ICMJE A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation
Brief Summary

The purpose of this study is to determine the effect of ixazomib maintenance therapy on progression-free survival (PFS) compared with placebo, in participants in China with newly diagnosed multiple myeloma (NDMM) who have had a major response [complete response (CR), very good partial response (VGPR), or partial response (PR)] to initial therapy and who have not undergone stem-cell transplantation (SCT).

This study is a China continuation of the global study C16021 (NCT02312258).

Detailed Description

The drug being tested in this study is called ixazomib. Ixazomib is being tested to slow disease progression and improve overall survival in Chinese participants who have newly diagnosed multiple myeloma (NDMM) who have had a major positive response to initial therapy and have not undergone stem cell transplantation (SCT). This study will look at the effect of ixazomib has on the length of time that participants are free of disease progression and their overall survival.

The study will enroll approximately 105 patients. Participants will be randomly assigned (by chance, like flipping a coin) in 3:2 ratio to one of the two treatment groups—which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

  • Ixazomib 3 mg
  • Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient

All participants will be asked to take one capsule on Days 1, 8, and 15 of every 28-day cycle, for up to 26 cycles or until documented PD or intolerable toxicity, whichever occurs first.

This multi-center trial will be conducted in China. The overall time to participate in this study is until a total of approximately 60 death events have been reported for Chinese participants or FA for OS in the global study (approximately up to 88 months). Participants will make multiple visits to the clinic, and every 4 weeks until the next line of therapy begins for a follow-up assessment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: Ixazomib
    Ixazomib Capsules
  • Drug: Ixazomib Placebo
    Ixazomib placebo-matching capsules
Study Arms  ICMJE
  • Experimental: Ixazomib
    Ixazomib 3 mg, capsules, orally, once on Days 1, 8 and 15 of every 28-day cycle for Cycle 1 through Cycle 4, during which period if the participants have been tolerated, the dose may be escalated to ixazomib 4 mg, capsules, orally, once on Days 1, 8 and 15 of every 28-day cycle for Cycle 5 through Cycle 26. Participants experiencing adverse events (AEs) attributed to study drug during any cycle may continue in the study but may have doses of study drug held or reduced by at least 1 dose level. Reduced doses are: 3 mg, 2.3 mg, 1.5 mg and discontinuation of study drug.
    Intervention: Drug: Ixazomib
  • Placebo Comparator: Placebo
    Ixazomib 3 mg placebo-matching capsules, orally, once on Days 1, 8 and 15 of every 28-day cycle for Cycle 1 through Cycle 4, during which period if the participants have been tolerated , the dose may be escalated to ixazomib 4 mg placebo-matching capsules, orally, once on Days 1, 8 and 15 of every 28-day cycle for Cycle 5 through Cycle 26. Participants experiencing adverse events (AEs) attributed to study drug during any cycle may continue in the study but may have doses of study drug held or reduced by at least 1 dose level. Reduced doses are: 3 mg, 2.3 mg, 1.5 mg and discontinuation of study drug.
    Intervention: Drug: Ixazomib Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 20, 2018)
105
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2026
Estimated Primary Completion Date September 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Adult male or female participants aged 18 years or older with a confirmed diagnosis of symptomatic NDMM according to standard criteria.
  2. Has completed 6 to 12 months (± 2 weeks) of initial therapy, during which the participant was treated to best response, defined as the best response maintained for 2 cycles after the M-protein nadir is reached.
  3. Has documented major response [partial response (PR), very good partial response (VGPR), complete response (CR)] according to the international myeloma working group (IMWG) uniform response criteria, version 2011, after this initial therapy.
  4. Female participants 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 through 90 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence (eg, calendar, ovulation,symptothermal, postovulation methods] and withdrawal are not acceptablemethods of contraception.)

    Male participants, even if surgically sterilized (ie, status postvasectomy), who:

    Agree to practice effective barrier contraception during the entire study Treatment period and through 90 days after the last dose of study drug, or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)

  5. 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 participant at any time without prejudice to future medical care.
  6. Has availability of complete documentation for:

    1. Details of initial disease state, initial therapy, and response
    2. Cytogenetic assessment at diagnosis (cytogenetic assessment performed after diagnosis must be approved by a Millennium project clinician or designee)
    3. ISS staging at diagnosis (requiring beta 2-microglobulin and serum albumin results).
  7. Has eastern cooperative oncology group performance status of 0 to 2.
  8. Suitable venous access for the study-required blood sampling and consent for the specific amounts that will be taken.
  9. Participant is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration.
  10. Participants must meet the following clinical laboratory criteria at study entry:

1. Absolute neutrophil count (ANC) ≥1,000/mm^3 without growth factor support and platelet count ≥ 75,000/mm^3. Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days before randomization.

2. Total bilirubin≤1.5*the upper limit of the normal range (ULN). 3. Alanine aminotransferase and aspartate aminotransferase≤3*ULN. 4. Calculated creatinine clearance≥ 30 mL/min (using the Cockroft-Gault equation.

Exclusion Criteria:

  1. Has multiple myeloma that has relapsed after, or was not responsive to, initial therapy.
  2. Had prior stem-cell transplantation (SCT).
  3. Has radiotherapy within 14 days before randomization.
  4. Had diagnosed or treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy with evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  5. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
  6. Has major surgery within 14 days before randomization.
  7. Has central nervous system involvement.
  8. Infection requiring IV antibiotic therapy or other serious infection within 14 days before randomization.
  9. Has diagnosis of waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
  10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
  11. Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St. John's wort within 14 days before randomization.
  12. Ongoing or active infection, known human immunodeficiency virus positive, active hepatitis B or C infection.
  13. Has comorbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, peripheral neuropathy (PN) that is Grade 1 with pain or Grade 2 or higher of any cause).
  14. Psychiatric illness/social situation that would limit compliance with study requirements.
  15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  16. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or GI procedure that could interfere with the oral absorption or tolerance of treatment.
  17. Treatment with any investigational products within 30 days before randomization.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Takeda Study Registration Call Center +1-877-825-3327 medicalinformation@tpna.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03748953
Other Study ID Numbers  ICMJE C16021CSC
2014-001394-13 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Responsible Party Takeda ( Millennium Pharmaceuticals, Inc. )
Study Sponsor  ICMJE Millennium Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.
PRS Account Takeda
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP