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A Study to Evaluate the Efficacy and Safety of Ixazomib in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma Initially Treated With an Injection of Proteasome Inhibitor-Based Therapy

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ClinicalTrials.gov Identifier: NCT03416374
Recruitment Status : Recruiting
First Posted : January 31, 2018
Last Update Posted : March 21, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda

Tracking Information
First Submitted Date  ICMJE January 23, 2018
First Posted Date  ICMJE January 31, 2018
Last Update Posted Date March 21, 2019
Actual Study Start Date  ICMJE March 12, 2018
Estimated Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2018)
Progression-Free Survival (PFS) Rate at 12 Months from the Start of Study Treatment [ Time Frame: Up to 12 months ]
PFS rate is defined as the percentage of participants who are alive and have not had disease progression at 12 months after the date of first dose of treatment in Treatment Period I. PFS will be assessed by International Myeloma Working Group (IMWG) Criteria (2014 version). Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03416374 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2018)
  • Overall Survival (OS) from the Start of Study Treatment [ Time Frame: Up to 39 months as a maximum ]
    OS is defined as the period from the first dose of treatment in Treatment Period I to the time when death (regardless of the cause of death) is confirmed. Patients who are still alive will be censored at the last confirmed date of survival or the date of data cut-off, whichever is earlier.
  • PFS from the Start of Study Treatment [ Time Frame: Up to 39 months as a maximum ]
    PFS is defined as the period from the first dose of treatment in Treatment Period I to the time of confirmed PD or confirmed death (regardless of the cause of death), whichever is earlier. PFS will be assessed by IMWG Criteria.
  • Percentage of Participants who Achieved VGPR or Better (CR + VGPR) [ Time Frame: Up to 39 months as a maximum ]
    VGPR or better (CR + VGPR) will be assessed by IMWG Criteria. Per IMWG criteria, PR (partial response): ≥50% reduction of serum M protein+reduction in 24-hour urinary M protein by ≥90%/ to <200 mg/24-hour or ≥50% decrease in difference between involved and uninvolved free light chain (FLC) levels/ ≥50% reduction in bone marrow plasma cells, if ≥30% at baseline/ ≥50% reduction in size of soft tissue plasmacytomas. VGPR (very good PR): serum+urine M-protein detectable by immunofixation but not on electrophoresis/ ≥90% reduction in serum M-protein+urine M-protein level <100 mg/24-hour. CR (complete response): negative immunofixation on serum+urine+disappearance of soft tissue plasmacytomas+<5% plasma cells in bone marrow.
  • Rate of Minimal Residual Disease (MRD) in Bone Marrow in Participants who Achieved CR [ Time Frame: Up to 39 months as a maximum ]
    MRD is defined as the percentage of participants achieving CR who are MRD-negative. If a participant is MRD-positive at their first evaluation and MRD-negative after re-examination, the participant will be considered to be MRD-negative. CR will be assessed by IMWG Criteria.
  • Percentage of Participants who Achieve or Maintain Any Best Response [ Time Frame: Up to 39 months as a maximum ]
    Best response is defined as the cumulative numbers of participants who achieve each level of best response including PR, VGPR and CR assessed with IMWG Criteria, after each cycle of treatment.
  • Overall Response Rate (ORR) [ Time Frame: Up to 39 months as a maximum ]
    ORR is defined as the percentage of participants who achieve a best response of PR or better including stringent complete response (sCR), VGPR and PR assessed with IMWG Criteria, after the start of the study treatment.
  • Percentage of Participants Continuing Treatment with Ixazomib at 12 Months from the Start of Study Treatment [ Time Frame: 12 months ]
  • Duration of Response (DOR) [ Time Frame: Up to 39 months as a maximum ]
    DOR is defined as the time from the date of first documentation of response ≥PR to the date of first documentation of PD or death due to any cause. PR and PD will be assessed with IMWG Criteria.
  • Patient-Reported Outcome Health-Related Quality of Life (HRQoL) based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [ Time Frame: Up to 39 months as a maximum ]
    EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions (7-point scale where 1=Very poor [worst] to 7= Excellent [best]). Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL.
  • Patient-Reported Outcome HRQoL based on EORTC Multiple Myeloma Module (EORTC QLQ-MY20) Score [ Time Frame: Up to 39 months as a maximum ]
    EORTC QLQ-MY20 has 20 items across 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms, and side effects of treatment). Scores are averaged, and transformed to 0-100 scale. For the future perspective scale, higher score = better perspective of the future. For the body image scale, higher scores = better body image. Higher score for the disease symptoms scale = higher level of symptomatology.
  • Evaluation of modified Quality-Adjusted Life-Years (QALYs) [ Time Frame: Up to 39 months as a maximum ]
    Modified QALYs will be calculated from the score of EORTC QLQ-C30. The health-related quality of life scale score of EORTC QLQ-C30 will be converted into a utility value ranging from 0 to 1, and used to adjust the value of survival years; this value will be assessed as the modified QALY.
  • Healthcare Resource Utilization (HCRU) [ Time Frame: Up to 39 months as a maximum ]
    HCRU will be calculated from Exposure-adjusted rate of hospitalization events (per participants-months) and the duration of hospitalization among participants in Treatment Period I and Treatment Period II.
  • Relative Dose Intensity (RDI) [ Time Frame: Up to 39 months as a maximum ]
    RDI for each study drug is defined as 100*(Total amount of dose taken)/(Total prescribed dose of treated cycles), where total prescribed dose equals [dose prescribed at enrollment* number of prescribed doses per cycle* the number of treated cycles].
  • Percentage of Participants with Bone Lesions (Bone Evaluation) [ Time Frame: Up to 39 months as a maximum ]
  • Number of Participants Reporting One or More Treatment-Emergent AEs (TEAEs) [ Time Frame: Up to 39 months as a maximum ]
    An 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. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
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 to Evaluate the Efficacy and Safety of Ixazomib in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma Initially Treated With an Injection of Proteasome Inhibitor-Based Therapy
Official Title  ICMJE An Open-label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Ixazomib in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma Initially Treated With an Injection of Proteasome Inhibitor-Based Therapy
Brief Summary The purpose of this study is to investigate the efficacy and safety of long-term administration of the oral proteasome inhibitor ixazomib as part of ixazomib in combination with lenalidomide and dexamethasone (IRd) therapy in patients with relapsed and/or refractory multiple myeloma (RRMM) treated initially with an injectable proteasome inhibitor-based therapy.
Detailed Description

The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have RRMM. This study will look at the effectiveness and safety of IRd in participants with RRMM previously receiving an injectable proteasome inhibitor-based therapy. This study consists of two treatment periods, Treatment Period I and Treatment Period II.

The study will enroll 47 patients. All participants will receive following treatment:

- Combination therapy with Bortezomib + Lenalidomide + Dexamethasone (VRd) or combination therapy with Carfilzomib + Lenalidomide + Dexamethasone (KRd), standard recommended dose according to the package insert of each drug, as Treatment Period I, followed by Combination therapy with Ixazomib 4.0 mg + Lenalidomide 25 mg + Dexamethasone 40 mg (IRd) as Treatment Period II

At start of this study, combination therapy of VRd or KRd will be decided by investigator as Treatment Period I after the baseline evaluations. After the start of Treatment Period I, a participant's eligibility for Treatment Period II is then determined 3 cycles. Participants who meet these eligibility criteria II subsequently continue into Treatment Period II and receive IRd.

This multi-center trial will be conducted in Japan. It is anticipated that the treatment phase of this study will last up to 39 months, including 18 months for enrollment. Participants will make multiple visits to the clinic in treatment period, and follow-up period including a follow-up assessment after last dose of study drug.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Relapsed and/or Refractory Multiple Myeloma
Intervention  ICMJE
  • Drug: Ixazomib
    Ixazomib capsules
  • Drug: Bortezomib
    Bortezomib injections
  • Drug: Carfilzomib
    Carfilzomib intravenous infusions
  • Drug: Lenalidomide
    Lenalidomide capsules
  • Drug: Dexamethasone
    Dexamethasone tablets
Study Arms  ICMJE Experimental: Combination Therapy + Ixazomib Therapy
Bortezomib + Lenalidomide + Dexamethasone, or Carfilzomib + Lenalidomide + Dexamethasone, standard recommended dose according to the package insert of each drug (Treatment Period I), followed by Ixazomib (4.0 mg) on Days 1, 8 and 15, plus Lenalidomide (25 mg) on Days 1 to 21, and Dexamethasone (40 mg) on Days 1, 8, 15 and 22, of a 28-day cycle (Treatment Period II)
Interventions:
  • Drug: Ixazomib
  • Drug: Bortezomib
  • Drug: Carfilzomib
  • Drug: Lenalidomide
  • Drug: Dexamethasone
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: January 30, 2018)
47
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 31, 2021
Estimated Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Eligibility for Treatment Period I

  1. Men and women of age 20 years or older at the time of enrollment.
  2. Participants with RRMM.
  3. Participants who are planned to start combination therapy with bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide, and dexamethasone (KRd) as second, third or fourth line of treatment.
  4. Participants with measurable disease defined by one or more of the following three measurements.

    • Serum M-protein: ≥0.5 gram (g)/ deciliter (dL) (≥ 5 g/ liter [L])
    • Urine M-protein: ≥ 200 milligram (mg)/24 hours
    • Serum free light chain assay: involved free light chain concentration ≥ 10 mg/dL (≥ 100 mg/L) provided that the serum free light chain ratio is abnormal
  5. Participants with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2; however, participants with ECOG PS 3 are eligible if they only have symptoms associated with bone lesions.
  6. Participants who are considered by the principal investigator or investigator not to be eligible for transplant; or, if considered eligible for transplant, participants who are planned not to undergo transplant for at least 12 months after the start of the study treatment.
  7. Participants must be registered with, and comply with, the guidelines of the lenalidomide management program.
  8. Participants who, before implementing procedures related to clinical research (excluding standard medical practices), understand that they can withdraw consent at any time without suffering from disadvantages to future treatments, and can provide written informed consent.

    Eligibility for Treatment Period II

  9. Participants must have received an injectable proteasome inhibitor (bortezomib or carfilzomib) in each treatment cycle of Treatment Period I.

Exclusion Criteria:

Eligibility for Treatment Period I

  1. Women who are nursing or pregnant.
  2. Participants with another active malignancy, i.e. synchronous active malignancy or previous malignancy with a disease-free period of less than 5 years, except for participants with carcinoma in situ (intraepithelial carcinoma) or intramucosal carcinoma judged to be cured by topical treatment.
  3. Participants with poorly controlled active thrombosis.
  4. Participants who have participated in a clinical trial of ixazomib or have been treated with ixazomib.
  5. Participants who were refractory to either treatment regimen based on lenalidomide and/or proteasome inhibitor(s).

    Note: Refractory MM is defined as PD on therapy or PD within 60 days after the last dose of a given therapy. Participants who have disease progressed 60 days after the last dose of a given therapy will be considered as relapsed in this study.

  6. Participants with ongoing or active systemic infection, known hepatitis B virus infection, known hepatitis C virus infection, or known positivity to human immunodeficiency virus (HIV).
  7. Participants who underwent major surgery within 14 days prior to enrollment to Treatment Period I. Surgery for bone lesions is not considered as major surgery.
  8. Participants who received radiation therapy within 14 days prior to enrollment to Treatment Period I. If the radiation field is small, 7 days is considered as a sufficient interval between radiation therapy and chemotherapy.
  9. Participants who experience Grade 1 peripheral neuropathy accompanied by pain, or Grade ≥2 peripheral neuropathy.
  10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmia, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months before enrollment to Treatment Period I.
  11. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before enrollment into Treatment Period I.
  12. Participants with central nervous system involvement.
  13. Inability to swallow oral medications, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal conditions that could interfere with the oral absorption or tolerance of treatment.
  14. Psychiatric illness/social situation that would limit compliance with study requirements.
  15. Comorbid systemic illnesses or other severe concurrent disease which, 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.

    Eligibility for Treatment Period II

  16. Participants who do not achieve at least a minimal response (MR) to VRd or KRd in Treatment Period I per the International Myeloma Working Group (IMWG) response criteria, 2014 revision.
  17. Participants who experience Grade 1 peripheral neuropathy accompanied by pain, or Grade ≥2 peripheral neuropathy during Treatment Period I.
  18. Participants with evidence of uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmia, symptomatic congestive heart failure, unstable angina, or myocardial infarction during Treatment Period I.
  19. Participants using potent CYP3A4 inducing agents (rifampicin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or gingko biloba or St. John's wort.
  20. Participants with hypersensitivity to any of the IRd study medications, their analogs, or excipients contained in IRd.
  21. Comorbid systemic illnesses or other severe concurrent disease which, 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 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 Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03416374
Other Study ID Numbers  ICMJE C16043
U1111-1207-0061 ( Other Identifier: WHO )
JapicCTI-183839 ( Registry Identifier: JapicCTI )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com 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
Study Sponsor  ICMJE Takeda
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Takeda
PRS Account Takeda
Verification Date March 2019

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