A Study of Ixazomib, Given With Dexamethasone in Adults With Multiple Myeloma

Study Overview
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Brief Summary
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The main aim of this study is to learn if ixazomib, given with dexamethasone, stops the cancer from getting worse in people with relapsed or refractory multiple myeloma. It will be compared to another medicine called pomalidomide, given with dexamethasone with people with the same condition. Relapsed means the previous cancer treatment stopped working, over time. Refractory means they did not respond to previous cancer treatment. Another aim is to check for side effects from the study medicines. At the first visit, the study doctor will check who can take part. Participants who can take part will be picked for 1 of 2 treatments by chance. Ixazomib capsules, given with dexamethasone tablets Pomalidomide capsules, given with dexamethasone tablets All participants will take their study medicine on specific days during a 28-day cycle. The 1st dose of study medicines in each 28-day cycle will take place in the clinic, The other doses of the study medicines will be taken at home. This will happen for 6 cycles. After this, all study medicines will be taken at home. After treatment, participants will visit the clinic every 12 weeks for a check-up. If participants cannot attend their clinic for an important reason (for example, due to the COVID-19 pandemic), the clinic will make alternative arrangements using their local procedures.

Detailed Description
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The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have relapsed and/or refractory multiple myeloma (RRMM). This study will compare the efficacy and safety in participants who take ixazomib and dexamethasone to pomalidomide and dexamethasone. It is an open-label, Phase 2 study. The study will enroll approximately 120 participants. Participants will receive: Ixazomib 4 mg + dexamethasone 20 mg (or 10 mg if participant is aged >=75 years) OR Pomalidomide 4 mg + dexamethasone 40 mg (or 20 mg if participant is aged >=75 years) All participants will be asked to take either ixazomib plus dexamethasone (in cases where only 4 mg tablets for dexamethasone are available, the following dexamethasone schedule is recommended for participants aged >=75 years: 12 mg dexamethasone will be given on Days 1, 8, 15, and 22 of every 28-day cycle; and 8 mg dexamethasone will be given on Days 2, 9, 16, and 23 of every 28-day cycle) or pomalidomide 4 mg + dexamethasone 40 mg at recommended doses. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 28 months after the first participant enters the study. Participants will make multiple visits to the clinic, and will be contacted for progression free-survival (PFS) follow-up, in case of study drug discontinuation for up to 4 years from first dose administration. After disease progression, participants will be followed-up for overall survival (OS) every 12 weeks until death or up to 4 years. Alternative methods for administering study procedures/assessments may be considered when it is not possible for the participants to come to the study site due to extenuating circumstances (e.g., due to the COVID-19 pandemic).

Official Title
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A Phase 2, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone and Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Conditions
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Relapsed and/or Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Ixazomib
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a confirmed diagnosis of multiple myeloma (MM) requiring therapy according to International Myeloma Working Group (IMWG) criteria. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Must have had a relapse or progressive disease (PD) after having received 2 or more prior lines of systemic therapy. Note: A line of therapy is defined as 1 or more cycles of a planned treatment program; this may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation (SCT), followed by maintenance is considered 1 line of therapy. Typically each line of therapy is separated by PD. Discussion with the medical monitor may help clarify the number of lines of therapy that a prospective study participant had. Must be refractory to lenalidomide, defined as having received at least 2 consecutive cycles of lenalidomide as a single agent or within a lenalidomide-containing regimen and having had PD during treatment with or within 60 days after the last dose of lenalidomide. The starting dose of lenalidomide should have been 25 mg (or as low as 10 mg in the case of renal function impairment or other safety concern), and the final dose should have been a minimum of 10 mg. Must have received at least 2 consecutive cycles of a bortezomib- or carfilzomib-containing regimen, and either: Achieved at least a partial response (PR) and did not have PD during treatment with or within 60 days after the last dose of bortezomib or carfilzomib, OR Had bortezomib and/or carfilzomib intolerance (defined as discontinuation because of drug-related adverse events [AEs] before completion of the planned treatment course) without PD before the start of the next regimen. Must have measurable disease defined by: Serum M-protein >=1 g/dL (>=10 g/L), OR Urine M-protein >=200 mg/24 hours and must have documented MM isotype by immunofixation (central laboratory). Suitable venous access for the study-required blood sampling, including pharmacokinetic (PK) sampling. Recovered (that is, less than or equal to [<=] Grade 1 nonhematologic toxicity) from the reversible effects of prior anticancer therapy. Must be willing and able to adhere to pomalidomide-related risk mitigation activities if randomized to the pom+dex arm (example, Risk Evaluation and Mitigation Strategies [REMS], pregnancy prevention programs). Exclusion Criteria: Prior allogenic bone marrow transplantation in any prior line of therapy or prior autologous SCT in the last prior line of therapy- unless the autologous SCT was performed a year or more before disease progression. Diagnosed with or treated for another malignancy within 2 years before randomization, or previously diagnosed with another malignancy and have any evidence of residual, persistent, or recurrent disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Diagnosis of smoldering MM, Waldenström's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any cause on clinical examination during the Screening period. Treatment with any investigational products or with chimeric or fully human monoclonal antibodies within 30 days before randomization, systemic anticancer therapy or radiotherapy within 14 days before randomization (Note: spot radiation for areas of pain is permitted), and major surgery within 14 days before randomization. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption or tolerance of study therapy, including difficulty swallowing. Serious infection requiring parenteral antibiotic therapy or any other serious infection within 14 days before randomization. Central nervous system involvement with MM (by clinical symptoms and signs). Ongoing or active systemic infection, known human immunodeficiency virus-ribonucleic acid (RNA) positive, known hepatitis B surface antigen seropositive, or known hepatitis C virus-RNA positive. Systemic treatment with strong cytochrome P-450 3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St. John's wort within 14 days before randomization. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse. History of severe cutaneous reactions, including hypersensitivity reactions such as Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), in the context of treatment with lenalidomide or thalidomide.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pomalidomide 4 mg + Dexamethasone 40 mg<br>Pomalidomide 4 mg, capsules, orally, once daily on Days 1 to 21 of each 28-day cycle, plus dexamethasone 40 mg, (or 20 mg if participant is aged >=75 years), tablets, orally, once daily on Days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or sponsor termination of study up to 2 years. | Drug: Pomalidomide<br>* Pomalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone tablets<br>|
| Experimental: Ixazomib 4 mg + Dexamethasone 20 mg<br>Ixazomib 4 mg as starting dose, capsules, orally, once daily on Days 1, 8, and 15 of each 28-day cycle, with escalation to 5.5 mg at the start of Cycle 2 for participants who tolerated the 4 mg dose in Cycle 1, plus dexamethasone 20 mg (or 10 mg if participant is aged >=75 years), tablets, orally, once daily on Days 1, 2, 8, 9, 15, 16, 22, and 23 of every 28-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or sponsor termination of study up to 2 years. | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;Drug: Dexamethasone<br>* Dexamethasone tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS: Time from randomization to first occurrence of confirmed progressive disease (PD) as assessed by investigator by International Myeloma Working Group(IMWG) response criteria/death from any cause, whichever occurs first. PD requires following: Increase of >=25 % from nadir in: Serum M component (increase must be >=0.5 gram per deciliter [g/dl]); Urine M-component (increase must be >=200 milligram [mg]/24-hour); In participants without measurable serum and urine M-protein levels difference between involved and uninvolved free light chain (FLC) increase of >10 mg/dl; In participants without measurable serum and urine M protein levels and without measurable disease by FLC level: bone marrow plasma cell percentage must be >=10%; Development of new/increase in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia (>11.5mg/dL corrected serum calcium) attributed solely to plasma cell proliferative disease. | From date of randomization until first occurrence of confirmed disease progression or death due to any cause, whichever occurs first (Up to approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death from any cause, up to 3 years are reported. | From date of randomization to death due to any cause (Up to approximately 3 years) | 
| Percentage of Participants With Overall Response | Overall Response Rate (ORR) was defined as the percentage of participants who achieved partial response (PR), very good partial response (VGPR), or complete response (CR) based on laboratory results and IRC assessment using modified IMWG criteria. PR: >=50% reduction of serum M protein + reduction in 24-hour urinary M protein by >=90% or to <200 mg/24-hour; if M protein is not measurable, >=50% decrease in difference between involved and uninvolved FLC levels is required; if not measurable by FLC, >=50% reduction in bone marrow plasma cells, when baseline value >=30% and; if present at baseline, >=50% reduction in size of soft tissue plasmacytomas is required. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein + urine M-protein level <100 mg/24-hour. CR: negative immunofixation on serum + urine; disappearance of soft tissue plasmacytomas; <5 % plasma cells in bone marrow. | From date of randomization until first documentation of CR, VGPR or PR (Up to approximately 3 years) | 
| Duration of Response (DOR) | DOR: Time from first documentation of CR/PR/VGPR to first documentation of PD. Per IMWG criteria, PR:>=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 FLC levels/ >=50% reduction in bone marrow plasma cells, if >=30% at Baseline/ >=50% reduction in size of soft tissue plasmacytomas. VGPR: 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:negative immunofixation on serum + urine+disappearance of soft tissue plasmacytomas+<5% plasma cells in bone marrow. 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. | From date of first documentation of CR, VGPR or PR until first occurrence of confirmed disease progression or death due to any cause, whichever occurs first (Up to approximately 3 years) | 
| Time to Response | Time to response was defined as the time from randomization to the first documentation of PR/VGPR/CR. Per IMWG criteria, PR: >=50% reduction of serum M protein + reduction in 24-hour urinary M protein by >=90% or to <200 mg/24-hour; if M-protein is not measurable, >=50% decrease in difference between involved and uninvolved FLC levels is required; if not measurable by FLC, >=50% reduction in bone marrow plasma cells, when Baseline value >=30% and; if present at Baseline, >=50% reduction in size of soft tissue plasmacytomas is required. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein + urine M-protein level <100 mg/24-hour. CR: negative immunofixation on serum + urine; disappearance of soft tissue plasmacytomas; <5% plasma cells in bone marrow. | From date of randomization until first documentation of CR, VGPR or PR (Up to approximately 3 years) | 
| Time to Progression (TTP) | TTP was defined as the time from the date of randomization to first documentation of PD. Per IMWG criteria, PD required 1 of the following: Increase of >=25% from nadir in: Serum M-component (increase must be >=0.5 g/dl; Urine M-component (increase must be >=200 mg/24-hour); In participants without measurable serum and urine M-protein levels difference between involved and uninvolved FLC levels increase of >10 mg/dl; In participants without measurable serum and urine M protein levels and without measurable disease by FLC level: Bone marrow plasma cell percentage must be >=10%; Development of new or increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (>11.5 mg/dL corrected serum calcium) attributed solely to plasma cell proliferative disease. | From date of randomization until first occurrence of confirmed disease progression or death due to any cause, whichever occurs first (Up to approximately 3 years) | 
| Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 (EORTC QLQ-C30) Physical Domain Score | The 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/quality of life (QOL) scale. The physical domain consisted of 5 items covering participant's daily physical activities on a scale from 1 (not at all) to 4 (very much). Raw scores were linearly transformed to a total score between 0-100, with a high score indicating better physical functioning. | Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days) | 
| HRQOL Based on EORTC QLQ-C30 SubScale Score | The 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 QOL scale. Most of the 30 items had 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Each subscale raw score were linearly transformed to a total score between 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. The Physical domain of the functional subscale is reported in the secondary outcome measure 7. | Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days) | 
| HRQOL Based on EORTC Multiple Myeloma Module 20 (EORTC QLQ-MY20) Score | The EORTC QLQ-MY20 has 20 items across 4 independent subscales, 2 symptoms scales (disease symptoms, side effects of treatment), and 2 functional subscales (body image, future perspective). Scores were averaged and transformed to 0-100 scale. Higher scores for the future perspective scale indicate better perspective of the future, for the body image scale indicate better body image and for the disease symptoms scale indicate higher level of symptomatology. | Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days) | 
| Number of Participants With Responses to HRQOL Based on 5-level Classification System of the EuroQol 5-Dimensional Health Questionnaire (EQ-5D-5L) Score | EQ-5D-5L comprises of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, 5= extremely severe problems. Higher scores indicated greater levels of problems across the five dimensions. | End of Treatment (Up to 28 cycles, each cycle was of 28 days) | 
| HRQOL Based on EuroQol Visual Analogue Scale (EQ VAS) Score | The EQ VAS records the respondent's self-rated health on a 20 centimeter (cm), vertical, visual analogue scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The scores from all dimensions were combined into a single index score that was reported, where higher score was better quality of life. | Baseline and End of Treatment (Up to 28 cycles, each cycle was of 28 days) | 
| Health Care Utilization (HU): Number of Participants With at Least One Medical Encounter | Healthcare resources used during medical encounters included hospitalizations, emergency room stays, or outpatient visits. A hospitalization was defined as at least 1 overnight stay in an Intensive Care Unit and/or non-Intensive Care Unit (acute care unit, palliative care unit, and hospice). | Up to approximately 3 years | 
| HU: Duration of Medical Encounters | Duration of healthcare resources used during medical encounters including hospitalizations, emergency room stays, or outpatient visits was reported in days. A hospitalization was defined as at least 1 overnight stay in an Intensive Care Unit and/or non-Intensive Care Unit (acute care unit, palliative care unit, and hospice). | Up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy