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Study of Oral IXAZOMIB in Combination With Lenalidomide and Dexamethasone in Participants With Newly Diagnosed Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT01383928
Recruitment Status : Completed
First Posted : June 28, 2011
Results First Posted : December 18, 2015
Last Update Posted : March 21, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Multiple Myeloma
Interventions Drug: Ixazomib
Drug: Lenalidomide
Drug: Dexamethasone
Enrollment 64
Recruitment Details Participants took part in the study at 15 investigative sites in the United States from 31 October 2011 to 27 November 2017 when the sponsor closed the study.
Pre-assignment Details Participants with newly diagnosed multiple myeloma were enrolled in 1 of the 2 dose escalation treatment arms in Phase 1: ixazomib 3 mg and 3.7 mg induction followed by maintenance. Phase 2 consisted of ixazomib 3 mg during induction followed by maintenance.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg Phase 2: Ixazomib 3 mg
Hide Arm/Group Description Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days). Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days). Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Period Title: Overall Study
Started 7 7 50
Completed [1] 2 0 10
Not Completed 5 7 40
Reason Not Completed
Initiation of ASCT             2             1             18
Adverse Event             1             2             8
Other             1             3             4
Progressive Disease             1             1             5
Withdrawal by Subject             0             0             4
Unsatisfactory Therapeutic Response             0             0             1
[1]
Completed=participants who completed 16 cycles per protocol and entered Maintenance phase.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg Phase 2: Ixazomib 3 mg Total
Hide Arm/Group Description Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days). Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days). Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days). Total of all reporting groups
Overall Number of Baseline Participants 7 7 50 64
Hide Baseline Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants 7 participants 50 participants 64 participants
64.3  (12.04) 61.1  (6.20) 61.5  (10.03) 61.8  (9.82)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
Female
2
  28.6%
3
  42.9%
19
  38.0%
24
  37.5%
Male
5
  71.4%
4
  57.1%
31
  62.0%
40
  62.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
1
   2.0%
1
   1.6%
Not Hispanic or Latino
7
 100.0%
7
 100.0%
48
  96.0%
62
  96.9%
Not Reported
0
   0.0%
0
   0.0%
1
   2.0%
1
   1.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
White
5
  71.4%
7
 100.0%
42
  84.0%
54
  84.4%
Black or African American
1
  14.3%
0
   0.0%
7
  14.0%
8
  12.5%
Other
1
  14.3%
0
   0.0%
0
   0.0%
1
   1.6%
Not Reported
0
   0.0%
0
   0.0%
1
   2.0%
1
   1.6%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 7 participants 7 participants 50 participants 64 participants
7
 100.0%
7
 100.0%
50
 100.0%
64
 100.0%
Height   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 7 participants 6 participants 49 participants 62 participants
171.1  (13.09) 170.9  (7.10) 171.2  (9.30) 171.1  (9.43)
[1]
Measure Analysis Population Description: For this baseline measure, number of participants evaluable were 7, 6 and 49 for each arm, respectively.
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 7 participants 7 participants 50 participants 64 participants
94.29  (17.083) 82.56  (19.295) 81.22  (16.701) 82.80  (17.228)
Body Surface Area (BSA)   [1] 
Mean (Standard Deviation)
Unit of measure:  M^2
Number Analyzed 7 participants 6 participants 49 participants 62 participants
2.109  (0.2192) 1.960  (0.2657) 1.958  (0.2373) 1.975  (0.2390)
[1]
Measure Analysis Population Description: For this baseline measure, number of participants evaluable were 7, 6 and 49 for each arm, respectively.
Type of Myeloma   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
IgG Kappa
2
  28.6%
3
  42.9%
24
  48.0%
29
  45.3%
IgG Lambda
1
  14.3%
1
  14.3%
7
  14.0%
9
  14.1%
IgA Kappa
1
  14.3%
1
  14.3%
10
  20.0%
12
  18.8%
IgA Lambda
1
  14.3%
0
   0.0%
3
   6.0%
4
   6.3%
Biclonal
0
   0.0%
1
  14.3%
1
   2.0%
2
   3.1%
Lambda Free Light Chains
1
  14.3%
0
   0.0%
3
   6.0%
4
   6.3%
Kappa Free Light Chains
1
  14.3%
1
  14.3%
1
   2.0%
3
   4.7%
Unknown
0
   0.0%
0
   0.0%
1
   2.0%
1
   1.6%
[1]
Measure Description: Types of Myeloma was described on the basis of antibodies produced by cancerous plasma cells.
Eastern Cooperative Oncology Group (ECOG) Performance Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
0
3
  42.9%
5
  71.4%
27
  54.0%
35
  54.7%
1
4
  57.1%
1
  14.3%
21
  42.0%
26
  40.6%
2
0
   0.0%
1
  14.3%
2
   4.0%
3
   4.7%
[1]
Measure Description: ECOG performance status is used to assess how the disease affects the daily living abilities of the participant. It ranges on the scale from 0-5 (0= normal activity; 1= symptoms but ambulatory; 2= in bed for less than (<) 50 percent (%) of the time; 3= in bed for greater than (>) 50% of the time; 4= 100% bedridden; 5= dead.
Serum Creatinine Category  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
Less than or equal to (<=) 2 mg/dL
7
 100.0%
7
 100.0%
50
 100.0%
64
 100.0%
Greater than (>) 2 mg/dL
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Creatinine Clearance Category  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
30 - 60 mL/min
2
  28.6%
2
  28.6%
8
  16.0%
12
  18.8%
>60 mL/min
5
  71.4%
5
  71.4%
42
  84.0%
52
  81.3%
Corrected Calcium   [1] 
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 7 participants 7 participants 50 participants 64 participants
9.83  (0.275) 9.79  (0.561) 10.01  (0.617) 9.96  (0.583)
[1]
Measure Description: Corrected calcium was calculated using the following formula: serum calcium (mg/dL)+0.98*[4-serum albumin (gram per deciliter [g/dL])]
Hemoglobin  
Mean (Standard Deviation)
Unit of measure:  Gram per liter (g/L)
Number Analyzed 7 participants 7 participants 50 participants 64 participants
103.4  (21.59) 112.0  (16.42) 108.9  (14.36) 108.6  (15.32)
Participants with Lytic Bone Lesions Present  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
Present
5
  71.4%
3
  42.9%
37
  74.0%
45
  70.3%
Not Present
1
  14.3%
2
  28.6%
7
  14.0%
10
  15.6%
Indeterminate
0
   0.0%
0
   0.0%
1
   2.0%
1
   1.6%
Missing
1
  14.3%
2
  28.6%
5
  10.0%
8
  12.5%
Participants with Extramedullary Plasmacytomas   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 50 participants 64 participants
Plasmacytomas Present
1
  14.3%
1
  14.3%
18
  36.0%
20
  31.3%
Plasmacytomas Not Present
2
  28.6%
2
  28.6%
4
   8.0%
8
  12.5%
Not Reported
4
  57.1%
4
  57.1%
28
  56.0%
36
  56.3%
[1]
Measure Analysis Population Description: Participants who performed magnetic resonance imaging (MRI)/computed tomography (CT) scan were eligible for this baseline measure.
1.Primary Outcome
Title Phase 1: Maximum Tolerated Dose (MTD)
Hide Description MTD was highest dose of ixazomib given with combination drugs, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT defined as any of following considered possibly related to therapy: Grade 4 neutropenia (absolute neutrophil count [ANC] <500 cell per cubic millimeter [cells/mm^3]) for >7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for >7 days; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count <10,000/mm^3; Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy; any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia; or <1 week Grade 3 fatigue; delay in initiation of the subsequent therapy cycle by >14 days; <=80% lenalidomide doses administered due to other >=Grade 2 combination study drug-related nonhematologic toxicities requiring therapy discontinuation.
Time Frame Cycle 1 (21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
DLT-evaluable population included all participants who received all Cycle 1 doses of MLN9708 and completed Cycle 1 procedures, or experienced a DLT in Cycle 1 in Phase 1.
Arm/Group Title Phase 1: All Participants
Hide Arm/Group Description:
Ixazomib 3 mg or 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Overall Number of Participants Analyzed 14
Measure Type: Number
Unit of Measure: mg
3.7
2.Primary Outcome
Title Phase 1: Recommended Phase 2 Dose (RP2D)
Hide Description The RP2D of ixazomib was determined after the evaluation of the available data from the phase 1 portion of the trial which included, but was not limited to analyses of efficacy results, toxicity characterization, all grades peripheral neuropathy, and treatment discontinuation. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Time Frame Cycle 1 (21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug.
Arm/Group Title Phase 1: All Participants
Hide Arm/Group Description:
Ixazomib 3 mg or 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Overall Number of Participants Analyzed 14
Measure Type: Number
Unit of Measure: mg
3
3.Primary Outcome
Title Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)
Hide 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. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 7 7
Measure Type: Number
Unit of Measure: percentage of participants
Adverse Event 100 100
Serious Adverse Event 71 29
4.Primary Outcome
Title Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)
Hide Description Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug and reported baseline and at least 1 post-baseline value.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 7 7
Measure Type: Count of Participants
Unit of Measure: Participants
Alanine aminotransferase increased
0
   0.0%
3
  42.9%
Aspartate aminotransferase increased
0
   0.0%
2
  28.6%
Blood creatinine increased
2
  28.6%
0
   0.0%
Shift to the left
0
   0.0%
1
  14.3%
Platelet count decreased
1
  14.3%
0
   0.0%
Blood bicarbonate decreased
1
  14.3%
0
   0.0%
Anaemia
1
  14.3%
0
   0.0%
Neutropenia
1
  14.3%
0
   0.0%
Thrombocytopenia
1
  14.3%
1
  14.3%
Eosinophilia
0
   0.0%
1
  14.3%
Hypokalaemia
1
  14.3%
0
   0.0%
Hyperkalaemia
1
  14.3%
0
   0.0%
Hyperglycaemia
4
  57.1%
0
   0.0%
Hyponatraemia
0
   0.0%
1
  14.3%
Hypomagnesaemia
0
   0.0%
2
  28.6%
Hyperchloraemia
1
  14.3%
0
   0.0%
Iron deficiency anaemia
1
  14.3%
0
   0.0%
5.Primary Outcome
Title Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity
Hide Description TEAE related to neurotoxicity grading based on common terminology criteria for adverse events (CTACE) version 4.03 are reported. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening consequences; urgent intervention indicated; Grade 5= death. Only TEAEs related to neurotoxicity with values are reported.
Time Frame Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug and reported baseline and at least 1 post-baseline value.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 7 7
Measure Type: Count of Participants
Unit of Measure: Participants
Neuropathy Peripheral (Grade 1)
0
   0.0%
1
  14.3%
Neuropathy Peripheral (Grade 2)
2
  28.6%
1
  14.3%
Neuropathy Peripheral (Grade 3)
0
   0.0%
1
  14.3%
Peripheral Sensory Neuropathy (Grade 1)
2
  28.6%
1
  14.3%
Peripheral Sensory Neuropathy (Grade 2)
0
   0.0%
1
  14.3%
Peripheral Sensory Neuropathy (Grade 3)
1
  14.3%
0
   0.0%
Peripheral Motor Neuropathy (Grade 1)
1
  14.3%
0
   0.0%
6.Primary Outcome
Title Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Hide Description Vital signs included body temperature, blood pressure and heart rate.
Time Frame Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 7 7
Measure Type: Count of Participants
Unit of Measure: Participants
Pyrexia
1
  14.3%
3
  42.9%
Bradycardia
1
  14.3%
0
   0.0%
Orthostatic hypotension
0
   0.0%
1
  14.3%
Hypotension
1
  14.3%
1
  14.3%
7.Primary Outcome
Title Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR)
Hide Description CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as 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 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
65
(50.4 to 78.3)
8.Primary Outcome
Title Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events
Hide 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. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. As per Common Terminology Criteria for Adverse Events v4.0 (CTCAE), Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE.
Time Frame Baseline up to 30 days after the last dose of study drug (approximately 1905 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 50
Measure Type: Number
Unit of Measure: percentage of participants
74
9.Primary Outcome
Title Phase 2: Percentage of Participants Experiencing Serious Adverse Events
Hide Description A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
Time Frame Baseline up to 30 days after the last dose of study drug (approximately 1905 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least one dose of any study drug.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 50
Measure Type: Number
Unit of Measure: percentage of participants
46
10.Primary Outcome
Title Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation
Hide 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. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame Baseline up to 30 days after the last dose of study drug (approximately 1905 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least 1 dose of any study drug.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 50
Measure Type: Number
Unit of Measure: percentage of participants
14
11.Secondary Outcome
Title Phase 1: Cmax: Maximum Plasma Concentration for Ixazomib
Hide Description Maximum observed plasma concentration (Cmax) is the peak plasma concentration of ixazomib, obtained directly from the plasma concentration-time curve.
Time Frame Cycle 1, Days 1 and 11
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 7 7
Geometric Mean (Standard Deviation)
Unit of Measure: nanogram per milliliter (ng/mL)
Day 1 Number Analyzed 6 participants 7 participants
33.515  (22.9634) 46.946  (26.6436)
Day 11 Number Analyzed 7 participants 6 participants
58.674  (19.9559) 51.832  (23.5112)
12.Secondary Outcome
Title Phase 1: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib
Hide Description AUC(0-72) is a measure of the area under the plasma concentration time-curve from time zero to 72 hours post-dose for ixazomib.
Time Frame Cycle 1, Days 1 and 11
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 7 7
Geometric Mean (Standard Deviation)
Unit of Measure: hour*nanogram per milliliter (hr*ng/mL)
Day 1 Number Analyzed 5 participants 6 participants
315.450  (75.0886) 284.576  (47.8233)
Day 11 Number Analyzed 7 participants 6 participants
1105.44  (457.5939) 1023.52  (284.3709)
13.Secondary Outcome
Title Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Hide Description Tmax: Time to reach the first maximum plasma concentration (Cmax), equal to time (hours) to Cmax of ixazomib after administration, obtained directly from the plasma concentration-time curve.
Time Frame Cycle 1, Days 1 and 11
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 7 7
Median (Full Range)
Unit of Measure: hours
Day 1 Number Analyzed 6 participants 7 participants
1.035
(0.53 to 1.60)
1.000
(0.50 to 1.47)
Day 11 Number Analyzed 7 participants 6 participants
1.030
(0.50 to 4.00)
0.984
(0.50 to 2.08)
14.Secondary Outcome
Title Phase 1: Rac: Accumulation Ratio of Ixazomib
Hide Description The accumulation ratio (Rac) was estimated as the ratio of AUC (0-72) on Day 11 to the AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time zero to 72 hours post-dose for ixazomib.
Time Frame Cycle 1, Days 1 and 11
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population included all participants, who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 11 assessments were available.
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days).
Overall Number of Participants Analyzed 5 5
Geometric Mean (Standard Deviation)
Unit of Measure: ratio
3.785  (1.4653) 3.967  (0.7546)
15.Secondary Outcome
Title Phase 1: Percentage of Participants With Best Overall Response
Hide Description CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Partial response(PR):>=50% reduction of serum M-protein,urinary M-protein by >=90%/to <200 mg/24 hr reduction.Near CR(nCR):positive immunofixation of serum/urine;soft tissue plasmacytomas disappearance;<=5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as 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 hours. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal.
Time Frame Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment. Results were summarized together for all Phase 1 participants, as per planned analysis.
Arm/Group Title Phase 1: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days).
Overall Number of Participants Analyzed 13
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
92
(64 to 99.8)
16.Secondary Outcome
Title Phase 2: Percentage of Participants With Overall Response (CR+VGPR+PR)
Hide Description Overall response is defined as CR, VGPR or PR based on IMWG Response Criteria for malignant lymphoma. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. VGPR: serum, urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein+urine M-protein level <100 mg/24h. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
94
(83.1 to 98.7)
17.Secondary Outcome
Title Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) After Cycles 4, 8, and 16
Hide Description CR as per IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria is defined as 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 hours. VGPR were applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein; Urine M-protein; Serum FLC assay.
Time Frame Cycles 4, 8, and 16
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least one 1 dose of ixazomib, had measurable disease at baseline, and at least one 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
After 4 cycles
49
(34.1 to 63.9)
After 8 cycles
64
(42.5 to 82.0)
After 16 cycles
92
(61.5 to 99.8)
18.Secondary Outcome
Title Phase 2: Percentage of Participants With Complete Response (CR)
Hide Description CR as per IMWG criteria is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
29
(16.6 to 43.3)
19.Secondary Outcome
Title Phase 2: Percentage of Participants With Stringent Complete Response (sCR)
Hide Description sCR as per IMWG criteria is CR plus normal FLC ratio and absence of clonal cells in bone marrow. CR is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least one 1 dose of ixazomib, had measurable disease at baseline, and at least one 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
22
(11.8 to 36.6)
20.Secondary Outcome
Title Phase 2: Percentage of Participants With Very Good Partial Response (VGPR)
Hide Description VGPR as per IMWG criteria is serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
37
(23.4 to 51.7)
21.Secondary Outcome
Title Phase 2: Percentage of Participants With Near Complete Response (nCR)
Hide Description nCR as per IMWG criteria is positive immunofixation analysis of serum or urine as the only evidence of disease; appearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
10
(3.4 to 22.2)
22.Secondary Outcome
Title Phase 2: Percentage of Participants With Partial Response (PR)
Hide Description PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by 90% or to <200 mg per 24 hours.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
65
(50.4 to 78.3)
23.Secondary Outcome
Title Phase 2: Percentage of Participants With Minimal Response (MR)
Hide Description MR as per IMWG criteria is 25%-49% reduction in serum paraprotein and 50%-89% reduction in urine light chain excretion for 6 weeks.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of ixazomib, had measurable disease at baseline, and at least 1 post-baseline disease assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
6
(1.3 to 16.9)
24.Secondary Outcome
Title Phase 2: Time to Response
Hide Description Time to first response is defined as the time from the date of first dose of study treatment to the date of the first documentation of a confirmed response (PR or better) in a participant who responded + 1 day. PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200 mg per 24 hours.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Response-evaluable population included all participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post-baseline response assessment.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 46
Median (Full Range)
Unit of Measure: months
0.72
(0.7 to 4.5)
25.Secondary Outcome
Title Phase 2: Duration of Response (DOR)
Hide Description DOR was measured as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as >=25% increase from lowest value in: serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; development of new bone lesions or soft tissue plasmacytomas development or increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcaemia development.
Time Frame Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Included a subset of response-evaluable population who achieved response.
Arm/Group Title Phase 2: Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
Overall Number of Participants Analyzed 49
Median (95% Confidence Interval)
Unit of Measure: months
29.0 [1] 
(16.72 to NA)
[1]
Upper limit of 95% confidence interval was not estimable as majority of the participants were censored.
26.Secondary Outcome
Title Time to Disease Progression (TTP)
Hide Description Time to progression was defined as the time from the date of first dose of study treatment to the date of first documentation of PD + 1 day. Participants that did not experience PD will be censored at the last response assessment that is SD or better. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants that received Autologous Stem Cell Transplantation (ASCT) or an alternate cancer therapy were also be censored at the last response assessment that is, SD or better prior to initiation of therapy. Participants without response assessment will be censored at the date of first dose. TTP was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
Time Frame Baseline up to a follow-up of 62.1 months
Hide Outcome Measure Data
Hide Analysis Population Description
modified-intent-to-treat (mITT) population included all participants who received at least one dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.
Arm/Group Title Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Overall Number of Participants Analyzed 57
Median (95% Confidence Interval)
Unit of Measure: months
29.7
(17.41 to 66.0)
27.Secondary Outcome
Title Progression Free Survival (PFS)
Hide Description PFS was defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease or to death due to any cause, whichever occurred first plus 1. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved,uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants who received ASCT or an alternate anticancer therapy were censored at the last response assessment that was SD or better before initiation of therapy. Participants without a response assessment were censored at the date of first dose. PFS was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
Time Frame Baseline up to a follow-up of 62.1 months
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.
Arm/Group Title Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Overall Number of Participants Analyzed 57
Median (95% Confidence Interval)
Unit of Measure: months
29.7
(17.41 to 66.0)
28.Secondary Outcome
Title Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Year 1
Hide Description The Kaplan-Meier estimate reports the percentage of participants surviving at Year 1.
Time Frame 1 year after the first dose of study treatment
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.
Arm/Group Title Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Overall Number of Participants Analyzed 57
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
94
(84 to 98)
29.Secondary Outcome
Title Overall Survival
Hide Description Overall survival was measured as the time from the date of first dose of study treatment to the time of death plus 1 day. For participants who did not die, survival was censored at the date of last contact. Overall Survival was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
Time Frame Baseline up to a follow-up of 62.1 months
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population included all participants who received at least 1 dose of any study drug in Phase 2 or who received at least 1 dose of any study drug and were treated at the phase 2 dose level during Phase 1.
Arm/Group Title Ixazomib 3 mg
Hide Arm/Group Description:
Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 83 cycles (approximately 2037 days).
Overall Number of Participants Analyzed 57
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(60.19 to NA)
[1]
Median and upper limit of 95% confidence interval was not estimable as majority of the participants were censored.
Time Frame From first study drug administration up to 30 days after the last dose (Up to approximately 2067 days)
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg Phase 2: Ixazomib 3.0 mg
Hide Arm/Group Description Ixazomib 3 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received was 83 cycles (approximately up to 2037 days). Ixazomib (MLN9708) 3.7 mg, capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg, capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 25 cycles (approximately 585 days). Ixazomib 3 mg (MLN9708), capsules, orally, twice-weekly on Days 1, 4, 8, and 11, lenalidomide 25 mg capsules, orally, once daily on Days 1-14, dexamethasone 20 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 1-8 and dexamethasone 10 mg, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 in Cycle 9-16 in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy at the dose tolerated at the end of induction until progressive disease or unacceptable toxicity. The maximum number of cycles received in this cohort was 74 cycles (approximately 1875 days).
All-Cause Mortality
Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg Phase 2: Ixazomib 3.0 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/7 (0.00%)   0/7 (0.00%)   1/50 (2.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg Phase 2: Ixazomib 3.0 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/7 (71.43%)   2/7 (28.57%)   23/50 (46.00%) 
Blood and lymphatic system disorders       
Anaemia  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Cardiac disorders       
Atrial fibrillation  1  0/7 (0.00%)  0/7 (0.00%)  2/50 (4.00%) 
Atrial flutter  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Cardiac failure  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Cardio-respiratory arrest  1 [1]  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Gastrointestinal disorders       
Dyspepsia  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Abdominal pain  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Intestinal perforation  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Vomiting  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Impaired gastric emptying  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
General disorders       
Pyrexia  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Non-cardiac chest pain  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Infections and infestations       
Pneumonia  1  1/7 (14.29%)  0/7 (0.00%)  3/50 (6.00%) 
Lung infection  1  0/7 (0.00%)  0/7 (0.00%)  2/50 (4.00%) 
Cellulitis  1  0/7 (0.00%)  0/7 (0.00%)  2/50 (4.00%) 
Skin infection  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Subcutaneous abscess  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Influenza  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Scrotal infection  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Infective myositis  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Sepsis  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Urinary tract infection  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Gastroenteritis viral  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Injury, poisoning and procedural complications       
Femur fracture  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Overdose  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Thoracic vertebral fracture  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Investigations       
Alanine aminotransferase increased  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Transaminases increased  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Metabolism and nutrition disorders       
Hyponatraemia  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Pain in extremity  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Muscular weakness  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Cancer pain  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Nervous system disorders       
Guillain-Barre syndrome  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Syncope  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Headache  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Amnesia  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Cognitive disorder  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Neuropathy peripheral  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Generalised tonic-clonic seizure  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Myelitis transverse  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Renal and urinary disorders       
Tubulointerstitial nephritis  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Renal failure  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Renal tubular necrosis  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Respiratory, thoracic and mediastinal disorders       
Pleuritic pain  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Skin and subcutaneous tissue disorders       
Stevens-Johnson syndrome  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Rash macular  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Vascular disorders       
Deep vein thrombosis  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Thrombophlebitis superficial  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
Hypotension  1  0/7 (0.00%)  0/7 (0.00%)  1/50 (2.00%) 
1
Term from vocabulary, MedDRA 19.0
Indicates events were collected by systematic assessment
[1]
one treatment-emergent death occurred during study and is related to study drug.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1: Ixazomib 3 mg Phase 1: Ixazomib 3.7 mg Phase 2: Ixazomib 3.0 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/7 (100.00%)   7/7 (100.00%)   50/50 (100.00%) 
Blood and lymphatic system disorders       
Neutropenia  1  1/7 (14.29%)  0/7 (0.00%)  4/50 (8.00%) 
Thrombocytopenia  1  1/7 (14.29%)  1/7 (14.29%)  4/50 (8.00%) 
Lymphopenia  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Eosinophilia  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Lymphadenopathy  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Iron deficiency anaemia  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Anaemia  1  1/7 (14.29%)  0/7 (0.00%)  6/50 (12.00%) 
Cardiac disorders       
Palpitations  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Tachycardia  1  0/7 (0.00%)  0/7 (0.00%)  4/50 (8.00%) 
Bradycardia  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Supraventricular extrasystoles  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Ventricular extrasystoles  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Ear and labyrinth disorders       
Tinnitus  1  1/7 (14.29%)  1/7 (14.29%)  4/50 (8.00%) 
Hypoacusis  1  1/7 (14.29%)  0/7 (0.00%)  3/50 (6.00%) 
Endocrine disorders       
Cushingoid  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Eye disorders       
Vision blurred  1  1/7 (14.29%)  1/7 (14.29%)  15/50 (30.00%) 
Cataract  1  0/7 (0.00%)  0/7 (0.00%)  5/50 (10.00%) 
Gastrointestinal disorders       
Diarrhoea  1  4/7 (57.14%)  3/7 (42.86%)  23/50 (46.00%) 
Nausea  1  4/7 (57.14%)  4/7 (57.14%)  20/50 (40.00%) 
Constipation  1  2/7 (28.57%)  3/7 (42.86%)  20/50 (40.00%) 
Dry mouth  1  1/7 (14.29%)  0/7 (0.00%)  8/50 (16.00%) 
Gastrooesophageal reflux disease  1  1/7 (14.29%)  3/7 (42.86%)  3/50 (6.00%) 
Abdominal distension  1  1/7 (14.29%)  1/7 (14.29%)  6/50 (12.00%) 
Abdominal pain upper  1  0/7 (0.00%)  0/7 (0.00%)  5/50 (10.00%) 
Abdominal pain  1  5/7 (71.43%)  0/7 (0.00%)  3/50 (6.00%) 
Stomatitis  1  1/7 (14.29%)  1/7 (14.29%)  2/50 (4.00%) 
Epigastric discomfort  1  1/7 (14.29%)  0/7 (0.00%)  1/50 (2.00%) 
Flatulence  1  1/7 (14.29%)  0/7 (0.00%)  1/50 (2.00%) 
Rectal haemorrhage  1  2/7 (28.57%)  0/7 (0.00%)  1/50 (2.00%) 
Anal fissure  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Gingival pain  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Lip pain  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Oral dysaesthesia  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Palatal oedema  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Tongue erythema  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Vomiting  1  3/7 (42.86%)  0/7 (0.00%)  13/50 (26.00%) 
Dyspepsia  1  0/7 (0.00%)  0/7 (0.00%)  4/50 (8.00%) 
Enlarged uvula  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
General disorders       
Oedema peripheral  1  4/7 (57.14%)  4/7 (57.14%)  22/50 (44.00%) 
Fatigue  1  5/7 (71.43%)  6/7 (85.71%)  24/50 (48.00%) 
Asthenia  1  2/7 (28.57%)  0/7 (0.00%)  9/50 (18.00%) 
Chills  1  1/7 (14.29%)  1/7 (14.29%)  4/50 (8.00%) 
Pain  1  1/7 (14.29%)  0/7 (0.00%)  5/50 (10.00%) 
Gait disturbance  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Localised oedema  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Pyrexia  1  4/7 (57.14%)  0/7 (0.00%)  8/50 (16.00%) 
Peripheral swelling  1  1/7 (14.29%)  0/7 (0.00%)  9/50 (18.00%) 
Non-cardiac chest pain  1  1/7 (14.29%)  0/7 (0.00%)  4/50 (8.00%) 
Infections and infestations       
Upper respiratory tract infection  1  1/7 (14.29%)  2/7 (28.57%)  19/50 (38.00%) 
Sinusitis  1  1/7 (14.29%)  1/7 (14.29%)  8/50 (16.00%) 
Viral upper respiratory tract infection  1  2/7 (28.57%)  0/7 (0.00%)  7/50 (14.00%) 
Oral candidiasis  1  0/7 (0.00%)  0/7 (0.00%)  6/50 (12.00%) 
Oral herpes  1  0/7 (0.00%)  0/7 (0.00%)  4/50 (8.00%) 
Herpes zoster  1  0/7 (0.00%)  1/7 (14.29%)  2/50 (4.00%) 
Folliculitis  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Tinea cruris  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Tooth infection  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Urinary tract infection  1  0/7 (0.00%)  0/7 (0.00%)  4/50 (8.00%) 
Conjunctivitis  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Skin infection  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Injury, poisoning and procedural complications       
Fall  1  1/7 (14.29%)  0/7 (0.00%)  6/50 (12.00%) 
Contusion  1  1/7 (14.29%)  0/7 (0.00%)  4/50 (8.00%) 
Procedural pain  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Spinal compression fracture  1  1/7 (14.29%)  1/7 (14.29%)  0/50 (0.00%) 
Foot fracture  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Investigations       
Blood creatinine increased  1  2/7 (28.57%)  0/7 (0.00%)  5/50 (10.00%) 
Weight decreased  1  1/7 (14.29%)  1/7 (14.29%)  4/50 (8.00%) 
Aspartate aminotransferase increased  1  0/7 (0.00%)  2/7 (28.57%)  3/50 (6.00%) 
Lymphocyte count decreased  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Neutrophil count decreased  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Weight increased  1  0/7 (0.00%)  0/7 (0.00%)  4/50 (8.00%) 
Blood bicarbonate decreased  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Electrocardiogram QT prolonged  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Shift to the left  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Alanine aminotransferase increased  1  2/7 (28.57%)  0/7 (0.00%)  4/50 (8.00%) 
Platelet count decreased  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Metabolism and nutrition disorders       
Hypokalaemia  1  1/7 (14.29%)  0/7 (0.00%)  16/50 (32.00%) 
Hyperglycaemia  1  4/7 (57.14%)  0/7 (0.00%)  6/50 (12.00%) 
Dehydration  1  2/7 (28.57%)  3/7 (42.86%)  5/50 (10.00%) 
Decreased appetite  1  1/7 (14.29%)  0/7 (0.00%)  7/50 (14.00%) 
Hypophosphataemia  1  0/7 (0.00%)  0/7 (0.00%)  9/50 (18.00%) 
Hypocalcaemia  1  0/7 (0.00%)  0/7 (0.00%)  5/50 (10.00%) 
Hypomagnesaemia  1  0/7 (0.00%)  2/7 (28.57%)  4/50 (8.00%) 
Hyperchloraemia  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Increased appetite  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Hyperkalaemia  1  1/7 (14.29%)  0/7 (0.00%)  1/50 (2.00%) 
Hyponatraemia  1  1/7 (14.29%)  0/7 (0.00%)  5/50 (10.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia  1  4/7 (57.14%)  0/7 (0.00%)  15/50 (30.00%) 
Muscle spasms  1  2/7 (28.57%)  2/7 (28.57%)  12/50 (24.00%) 
Musculoskeletal chest pain  1  1/7 (14.29%)  1/7 (14.29%)  5/50 (10.00%) 
Myalgia  1  0/7 (0.00%)  2/7 (28.57%)  6/50 (12.00%) 
Bone pain  1  1/7 (14.29%)  0/7 (0.00%)  5/50 (10.00%) 
Musculoskeletal pain  1  0/7 (0.00%)  0/7 (0.00%)  7/50 (14.00%) 
Joint swelling  1  0/7 (0.00%)  1/7 (14.29%)  4/50 (8.00%) 
Musculoskeletal discomfort  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Osteonecrosis of jaw  1  1/7 (14.29%)  0/7 (0.00%)  1/50 (2.00%) 
Spinal column stenosis  1  1/7 (14.29%)  0/7 (0.00%)  1/50 (2.00%) 
Limb discomfort  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Muscle tightness  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Osteoarthritis  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Back pain  1  5/7 (71.43%)  0/7 (0.00%)  14/50 (28.00%) 
Pain in extremity  1  2/7 (28.57%)  0/7 (0.00%)  17/50 (34.00%) 
Muscular weakness  1  3/7 (42.86%)  0/7 (0.00%)  9/50 (18.00%) 
Flank pain  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Osteopenia  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Nervous system disorders       
Dysgeusia  1  2/7 (28.57%)  2/7 (28.57%)  20/50 (40.00%) 
Dizziness  1  3/7 (42.86%)  1/7 (14.29%)  15/50 (30.00%) 
Tremor  1  5/7 (71.43%)  0/7 (0.00%)  7/50 (14.00%) 
Hypoaesthesia  1  2/7 (28.57%)  2/7 (28.57%)  7/50 (14.00%) 
Paraesthesia  1  1/7 (14.29%)  1/7 (14.29%)  5/50 (10.00%) 
Ageusia  1  1/7 (14.29%)  1/7 (14.29%)  1/50 (2.00%) 
Dysaesthesia  1  0/7 (0.00%)  2/7 (28.57%)  1/50 (2.00%) 
Lethargy  1  1/7 (14.29%)  1/7 (14.29%)  1/50 (2.00%) 
Memory impairment  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Presyncope  1  0/7 (0.00%)  1/7 (14.29%)  1/50 (2.00%) 
Peripheral motor neuropathy  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Sedation  1  1/7 (14.29%)  1/7 (14.29%)  0/50 (0.00%) 
Tension headache  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Neuropathy peripheral  1  5/7 (71.43%)  0/7 (0.00%)  18/50 (36.00%) 
Headache  1  6/7 (85.71%)  0/7 (0.00%)  12/50 (24.00%) 
Peripheral sensory neuropathy  1  3/7 (42.86%)  2/7 (28.57%)  12/50 (24.00%) 
Balance disorder  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Syncope  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Psychiatric disorders       
Insomnia  1  2/7 (28.57%)  6/7 (85.71%)  17/50 (34.00%) 
Anxiety  1  2/7 (28.57%)  1/7 (14.29%)  13/50 (26.00%) 
Depression  1  0/7 (0.00%)  1/7 (14.29%)  4/50 (8.00%) 
Mood altered  1  0/7 (0.00%)  0/7 (0.00%)  4/50 (8.00%) 
Agitation  1  0/7 (0.00%)  2/7 (28.57%)  0/50 (0.00%) 
Mood swings  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Irritability  1  1/7 (14.29%)  0/7 (0.00%)  6/50 (12.00%) 
Renal and urinary disorders       
Pollakiuria  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Renal failure  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Reproductive system and breast disorders       
Breast cyst  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Testicular pain  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea  1  5/7 (71.43%)  1/7 (14.29%)  12/50 (24.00%) 
Cough  1  2/7 (28.57%)  2/7 (28.57%)  10/50 (20.00%) 
Oropharyngeal pain  1  1/7 (14.29%)  2/7 (28.57%)  7/50 (14.00%) 
Nasal congestion  1  3/7 (42.86%)  2/7 (28.57%)  5/50 (10.00%) 
Hiccups  1  0/7 (0.00%)  2/7 (28.57%)  3/50 (6.00%) 
Productive cough  1  0/7 (0.00%)  0/7 (0.00%)  5/50 (10.00%) 
Rhinitis allergic  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Upper-airway cough syndrome  1  1/7 (14.29%)  0/7 (0.00%)  1/50 (2.00%) 
Dysphonia  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Dyspnoea exertional  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Oropharyngeal discomfort  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Skin and subcutaneous tissue disorders       
Rash maculo-papular  1  2/7 (28.57%)  3/7 (42.86%)  16/50 (32.00%) 
Dry skin  1  1/7 (14.29%)  1/7 (14.29%)  5/50 (10.00%) 
Rash  1  0/7 (0.00%)  2/7 (28.57%)  6/50 (12.00%) 
Night sweats  1  1/7 (14.29%)  1/7 (14.29%)  6/50 (12.00%) 
Alopecia  1  0/7 (0.00%)  0/7 (0.00%)  7/50 (14.00%) 
Rash papular  1  0/7 (0.00%)  2/7 (28.57%)  4/50 (8.00%) 
Rash pruritic  1  0/7 (0.00%)  2/7 (28.57%)  4/50 (8.00%) 
Pruritus  1  2/7 (28.57%)  1/7 (14.29%)  3/50 (6.00%) 
Dermatitis acneiform  1  1/7 (14.29%)  1/7 (14.29%)  2/50 (4.00%) 
Hyperhidrosis  1  1/7 (14.29%)  0/7 (0.00%)  4/50 (8.00%) 
Urticaria  1  0/7 (0.00%)  1/7 (14.29%)  3/50 (6.00%) 
Dermatitis exfoliative  1  0/7 (0.00%)  2/7 (28.57%)  0/50 (0.00%) 
Rash erythematous  1  0/7 (0.00%)  1/7 (14.29%)  1/50 (2.00%) 
Acne  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Actinic keratosis  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Dermatitis contact  1  1/7 (14.29%)  0/7 (0.00%)  0/50 (0.00%) 
Pain of skin  1  0/7 (0.00%)  1/7 (14.29%)  0/50 (0.00%) 
Rash macular  1  4/7 (57.14%)  0/7 (0.00%)  4/50 (8.00%) 
Erythema  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Skin exfoliation  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
Vascular disorders       
Flushing  1  2/7 (28.57%)  2/7 (28.57%)  3/50 (6.00%) 
Hot flush  1  1/7 (14.29%)  0/7 (0.00%)  2/50 (4.00%) 
Hypertension  1  0/7 (0.00%)  0/7 (0.00%)  4/50 (8.00%) 
Orthostatic hypotension  1  0/7 (0.00%)  1/7 (14.29%)  2/50 (4.00%) 
Hypotension  1  2/7 (28.57%)  0/7 (0.00%)  2/50 (4.00%) 
Deep vein thrombosis  1  0/7 (0.00%)  0/7 (0.00%)  3/50 (6.00%) 
1
Term from vocabulary, MedDRA 19.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor’s confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
Results Point of Contact
Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier: NCT01383928     History of Changes
Other Study ID Numbers: C16008
U1111-1168-1172 ( Registry Identifier: WHO (UTN) )
First Submitted: June 27, 2011
First Posted: June 28, 2011
Results First Submitted: November 16, 2015
Results First Posted: December 18, 2015
Last Update Posted: March 21, 2019