Clinical trial NCT03416374: 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: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Relapsed and/or Refractory Multiple Myeloma
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2018-01-31
Enrollment: 45
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression-Free Survival (PFS) Rate at 12 Months From the Start of Study Treatment
timeFrame: Up to 12 months
Secondary outcomes:
measure: Overall Survival (OS) From the Start of Study Treatment
timeFrame: Up to 39 months as a maximum
measure: PFS From the Start of Study Treatment
timeFrame: Up to 39 months as a maximum
measure: Percentage of Participants Who Achieved VGPR or Better (CR + VGPR)
timeFrame: Up to 39 months as a maximum
measure: Number of Participants With Minimal Residual Disease (MRD) Positive or Negative in Bone Marrow in Participants Who Achieved CR
timeFrame: Up to 39 months as a maximum
measure: Percentage of Participants Who Achieve or Maintain Any Best Response
timeFrame: Up to 39 months as a maximum
measure: Overall Response Rate (ORR)
timeFrame: Up to 39 months as a maximum
measure: Percentage of Participants Continuing Treatment With Ixazomib at 12 Months From the Start of Study Treatment
timeFrame: 12 months
measure: Duration of Response (DOR)
timeFrame: Up to 39 months as a maximum
measure: Time to Next Treatment (TTNT)
timeFrame: Up to 39 months as a maximum
measure: Duration of Therapy (DOT)
timeFrame: Up to 39 months as a maximum
measure: Patient-Reported Outcome Health-Related Quality of Life (HRQoL) Based on Global Health Status Scale of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
timeFrame: Baseline and End of Treatment (Up to 23 cycles for VRd Group, Up to 32 cycles for KRd and Overall Group, each cycle was of 28 days)
measure: Patient-Reported Outcome HRQoL Based on EORTC Multiple Myeloma Module (EORTC QLQ-MY20) Score
timeFrame: Baseline and End of Treatment (Up to 23 cycles for VRd Group, Up to 32 cycles for KRd and Overall Group, each cycle was of 28 days)
measure: Evaluation of Modified Quality-Adjusted Life-Years (QALYs)
timeFrame: Up to 39 months as a maximum
measure: Healthcare Resource Utilization (HCRU): Number of Events With Hospitalization Per Participants-Month
timeFrame: Up to 39 months as a maximum
measure: Healthcare Resource Utilization (HCRU): Duration of Hospital Stay Per Participants
timeFrame: Up to 39 months as a maximum
measure: Relative Dose Intensity (RDI)
timeFrame: Up to 39 months as a maximum
measure: Percentage of Participants With Bone Lesions (Bone Evaluation)
timeFrame: Up to 39 months as a maximum
measure: Number of Participants Reporting One or More Treatment-Emergent AEs (TEAEs)
timeFrame: Up to 39 months as a maximum
Other outcomes:
Locations:
city: Kamogawa
country: Japan
facility: Kameda Medical Center
state: Chiba
city: Kashiwa
country: Japan
facility: The Jikei University Kashiwa Hospital
state: Chiba
city: Ogaki
country: Japan
facility: Ogaki Municipal Hospital
state: Gifu
city: Maebashi
country: Japan
facility: Gunma University Hospital
state: Gunma
city: Shibukawa
country: Japan
facility: Shibukawa Medical Center
state: Gunma
city: Kobe
country: Japan
facility: Kobe city Medical Center General Hospital
state: Hyogo
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
state: Ishikawa
city: Morioka
country: Japan
facility: Iwate Medical University
state: Iwate
city: Yokohama
country: Japan
facility: Yokohama Municipal Citizen's Hospital
state: Kanagawa
city: Suwa
country: Japan
facility: Suwa Red Cross Hospital
state: Nagano
city: Koshigaya
country: Japan
facility: Dokkyo Medical University
state: Saitama
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Nippon Medical School Hospital
state: Tokyo
city: Itabashi-ku
country: Japan
facility: Nihon University Itabashi Hospital
state: Tokyo
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Tokyo
city: Minato-ku
country: Japan
facility: The Jikei University Hospital
state: Tokyo
city: Mitaka
country: Japan
facility: Kyorin University Hospital
state: Tokyo
city: Shibuya-ku
country: Japan
facility: Japanese Red Cross Medical Center
state: Tokyo
city: Tachikawa
country: Japan
facility: Tokyo Disaster Medical Center
state: Tokyo
city: Hiroshima
country: Japan
facility: Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
city: Kyoto
country: Japan
facility: Kyoto Kuramaguchi Medical Center
city: Niigata
country: Japan
facility: Niigata Cancer Center Hospital
city: Osaka
country: Japan
facility: Osaka Red Cross Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: