Study of Oral Ixazomib in Combination With Melphalan and Prednisone in Participants With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this phase 1/2, open-label study was to evaluate the effect of oral formulation of Ixazomib when added to standard melphalan and prednisone (MP) treatment. Both phases of the study included participants who had newly diagnosed multiple myeloma and were ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years of age) or coexisting conditions and for whom standard MP treatment was indicated.

Detailed Description
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The drug tested in this study was called ixazomib (MLN9708). Ixazomib was tested to treat the people with newly diagnosed multiple myeloma requiring systemic treatment who were not eligible for stem cell transplantation. This study determined the safety, tolerability, efficacy, quality of life (QOL), and pharmacokinetics (PK)/pharmacodynamics (PD) of ixazomib. The study enrolled 61 patients. The study was conducted in 2 parts: 1) phase 1 dose escalation and 2) phase 2 expansion at maximum tolerated dose. Participants were enrolled to receive: Ixazomib 3.0 mg, 3.7 mg, 4.0 mg, or 5.5. mg depending on the treatment assignment This multicenter trial was conducted in the Unites states, Canada, United Kingdom, Spain and Czech Republic. The overall time to participate in this study is 5.5 years. Participants made multiple visits to the clinic and were followed up every 16 weeks after end of treatment until disease progression if stopped treatment before disease progression and then every 16 weeks up to start of next therapy or death whichever occurs first.

Official Title
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An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of Ixazomib (MLN9708), a Next-Generation Proteasome Inhibitor, Administered in Combination With a Standard Care Regimen of Melphalan and Prednisone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Ixazomib
* Drug: Melphalan
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is indicated with standard melphalan prednisone (MP) treatment and is not a candidate for high-dose therapy plus stem cell transplantation (HDT-SCT) for 1 of the following reasons: the participant is 65 years of age or older OR the participant is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT Is diagnosed with symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage according to standard criteria Has measurable disease as specified in study protocol Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Has adequate hematologic, liver, and renal function Exclusion Criteria Has peripheral neuropathy that is greater or equal to Grade 2 Has major surgery or radiotherapy within 14 days before the first dose of study drug Has uncontrolled infection requiring systematic antibiotics Has diarrhea (> Grade 1) Has prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the participantt) Has central nervous system involvement Has cardiac status as described in protocol Has known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of IXAZOMIB - Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome Has Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection Is diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ Has serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Ixazomib 3.0 mg<br>Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|
| Experimental: Arm A: Ixazomib 3.7 mg<br>Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|
| Experimental: Arm B: Ixazomib 3.0 mg<br>Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|
| Experimental: Arm B: Ixazomib 4.0 mg<br>Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|
| Experimental: Arm B: Ixazomib 5.5 mg<br>Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|
| Experimental: Arm C: Ixazomib 3.0 mg<br>Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|
| Experimental: Arm C: Ixazomib 4.0 mg<br>Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|
| Experimental: Arm D: Ixazomib 4.0 mg<br>Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]). | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Melphalan<br>* Melphalan tablets<br>Drug: Prednisone<br>* Prednisone tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1) | The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). | Cycle 1, phase 1 (Up to 42 days) | 
| Very Good Partial Response (VGPR) or Better Response Rate (Phase 2) | VGPR or better response rate is defined as percentage of participants with a complete response (CR) and very good partial response (VGPR). Per International Myeloma Working Group Uniform Response Criteria (IMWG), CR: 1) Negative immunofixation on the serum and urine, 2) Disappearance of any soft tissue plasmacytomas and 3) < 5% plasma cells in bone marrow. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour. | Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Inhibition Rate (Emax) (Phase 1) | Whole blood 20S proteasome inhibition parameters | At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study | 
| Time of Occurrence of Emax (TEmax) (Phase 1) | Whole blood 20S proteasome inhibition parameters | At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study | 
| Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1) |  | Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1) |  | Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D | 
| AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1) |  | Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D | 
| Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1) | Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase. | Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D | 
| Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1) | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. | Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D | 
| Observed Accumulation Ratio for AUCtau (Rac) (Phase 1) | Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1. | Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D | 
| Overall Response Rate (ORR) | ORR is defined as percentage of participants with overall response including CR, VGPR, and partial response (PR). Per IMWG criteria, CR:1)Negative immunofixation on serum and urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. If serum+urine M-protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required. | Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years) | 
| Time to First Response (Phase 2) | Response is defined as CR, VGPR and PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required. | From the date of enrollment to the date of the first documented response for up to 5.5 years | 
| Duration of Response (DOR) (Phase 2) | DOR is defined as time of first documentation of a confirmed PR or better response to first documented PD or start of alternative therapy. DOR was presented for those achieving CR+VGPR+PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required. | From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years | 
| Time to Progression (TTP) (Phase 2) | TTP is defined as time from date of enrollment to date of first documented disease progression (PD). Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder. | From the date of enrollment to the date of the first documented disease progression for up to 5.5 years | 
| Time to Next Therapy (Phase 2) | Time to Next Therapy is defined as time from the date of enrollment to the date of subsequent antineoplastic therapy. | From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years | 
| Progression Free Survival (Phase 2) | Progression Free Survival is defined as time in months from start of study treatment to first documentation of objective tumor progression per investigator assessment or up to death due to any cause, whichever occurs first. Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder. | From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years | 
| Overall Survival (Phase 2) | Overall Survival is the time in months from start of study treatment to date of death due to any cause. | From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | 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. | From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years | 
| Assessments of Quality of Life (Phase 2) |  | Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years | 

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