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

Primary Purpose

Multiple Myeloma

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Ixazomib
Melphalan
Prednisone
Sponsored by
Millennium Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Drug Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm A: Ixazomib 3.0 mg

Arm A: Ixazomib 3.7 mg

Arm B: Ixazomib 3.0 mg

Arm B: Ixazomib 4.0 mg

Arm B: Ixazomib 5.5 mg

Arm C: Ixazomib 3.0 mg

Arm C: Ixazomib 4.0 mg

Arm D: Ixazomib 4.0 mg

Arm Description

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]).

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]).

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]).

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]).

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]).

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]).

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]).

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]).

Outcomes

Primary Outcome Measures

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).
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.

Secondary Outcome Measures

Maximum Inhibition Rate (Emax) (Phase 1)
Whole blood 20S proteasome inhibition parameters
Time of Occurrence of Emax (TEmax) (Phase 1)
Whole blood 20S proteasome inhibition parameters
Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)
AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)
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.
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.
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.
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.
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.
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.
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.
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.
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.
Overall Survival (Phase 2)
Overall Survival is the time in months from start of study treatment to date of death due to any cause.
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.
Assessments of Quality of Life (Phase 2)

Full Information

First Posted
April 8, 2011
Last Updated
December 22, 2017
Sponsor
Millennium Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01335685
Brief Title
Study of Oral Ixazomib in Combination With Melphalan and Prednisone in Participants With Newly Diagnosed Multiple Myeloma
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
June 27, 2011 (Actual)
Primary Completion Date
December 29, 2016 (Actual)
Study Completion Date
December 29, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
Drug Therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Enrollment
61 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A: Ixazomib 3.0 mg
Arm Type
Experimental
Arm Description
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]).
Arm Title
Arm A: Ixazomib 3.7 mg
Arm Type
Experimental
Arm Description
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]).
Arm Title
Arm B: Ixazomib 3.0 mg
Arm Type
Experimental
Arm Description
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]).
Arm Title
Arm B: Ixazomib 4.0 mg
Arm Type
Experimental
Arm Description
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]).
Arm Title
Arm B: Ixazomib 5.5 mg
Arm Type
Experimental
Arm Description
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]).
Arm Title
Arm C: Ixazomib 3.0 mg
Arm Type
Experimental
Arm Description
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]).
Arm Title
Arm C: Ixazomib 4.0 mg
Arm Type
Experimental
Arm Description
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]).
Arm Title
Arm D: Ixazomib 4.0 mg
Arm Type
Experimental
Arm Description
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]).
Intervention Type
Drug
Intervention Name(s)
Ixazomib
Intervention Description
Ixazomib capsules
Intervention Type
Drug
Intervention Name(s)
Melphalan
Intervention Description
Melphalan tablets
Intervention Type
Drug
Intervention Name(s)
Prednisone
Intervention Description
Prednisone tablets
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1)
Description
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).
Time Frame
Cycle 1, phase 1 (Up to 42 days)
Title
Very Good Partial Response (VGPR) or Better Response Rate (Phase 2)
Description
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.
Time Frame
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 Measure Information:
Title
Maximum Inhibition Rate (Emax) (Phase 1)
Description
Whole blood 20S proteasome inhibition parameters
Time Frame
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
Title
Time of Occurrence of Emax (TEmax) (Phase 1)
Description
Whole blood 20S proteasome inhibition parameters
Time Frame
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
Title
Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)
Time Frame
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
Title
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)
Time Frame
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
Title
AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)
Time Frame
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
Title
Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1)
Description
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.
Time Frame
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
Title
Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1)
Description
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time Frame
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
Title
Observed Accumulation Ratio for AUCtau (Rac) (Phase 1)
Description
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.
Time Frame
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
Title
Overall Response Rate (ORR)
Description
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.
Time Frame
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)
Title
Time to First Response (Phase 2)
Description
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.
Time Frame
From the date of enrollment to the date of the first documented response for up to 5.5 years
Title
Duration of Response (DOR) (Phase 2)
Description
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.
Time Frame
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
Title
Time to Progression (TTP) (Phase 2)
Description
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.
Time Frame
From the date of enrollment to the date of the first documented disease progression for up to 5.5 years
Title
Time to Next Therapy (Phase 2)
Description
Time to Next Therapy is defined as time from the date of enrollment to the date of subsequent antineoplastic therapy.
Time Frame
From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years
Title
Progression Free Survival (Phase 2)
Description
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.
Time Frame
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
Title
Overall Survival (Phase 2)
Description
Overall Survival is the time in months from start of study treatment to date of death due to any cause.
Time Frame
From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months)
Title
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Description
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.
Time Frame
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
Title
Assessments of Quality of Life (Phase 2)
Time Frame
Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
City
Lebanon
State/Province
New Hampshire
Country
United States
City
Morgantown
State/Province
West Virginia
Country
United States
City
Vancouver
State/Province
British Columbia
Country
Canada
City
Toronto
State/Province
Ontario
Country
Canada
City
Quebec
Country
Canada
City
Brno
Country
Czechia
City
Praha 2
Country
Czechia
City
Badalona
Country
Spain
City
Barcelona
Country
Spain
City
Madrid
Country
Spain
City
Salamanca
Country
Spain
City
San Sebastian
Country
Spain
City
Sevilla
Country
Spain
City
Bournemouth
Country
United Kingdom
City
Brighton
Country
United Kingdom
City
Cambridge
Country
United Kingdom
City
London
Country
United Kingdom
City
Nottingham
Country
United Kingdom
City
Oxford
Country
United Kingdom
City
Uxbridge
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
29954932
Citation
San-Miguel JF, Echeveste Gutierrez MA, Spicka I, Mateos MV, Song K, Craig MD, Blade J, Hajek R, Chen C, Di Bacco A, Estevam J, Gupta N, Byrne C, Lu V, van de Velde H, Lonial S. A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma. Haematologica. 2018 Sep;103(9):1518-1526. doi: 10.3324/haematol.2017.185991. Epub 2018 Jun 28.
Results Reference
derived

Learn more about this trial

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

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