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

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ClinicalTrials.gov Identifier: NCT01335685
Recruitment Status : Completed
First Posted : April 14, 2011
Results First Posted : January 23, 2018
Last Update Posted : January 23, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Study Type: Interventional
Study Design: Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: Multiple Myeloma
Interventions: Drug: Ixazomib
Drug: Melphalan
Drug: Prednisone

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the study at 14 investigative sites in United States Canada, United Kingdom, Spain, and Czech Republic from 27 June 2011 to 29 December 2016.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with a diagnosis of multiple myeloma (previously untreated) were enrolled to receive ixazomib orally at various doses in Phase 1. Only Arm B: Ixazomib 4.0 mg continued in Phase 2.

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

Participant Flow:   Overall Study
    Arm A: Ixazomib 3.0 mg   Arm A: Ixazomib 3.7 mg   Arm B: Ixazomib 3.0 mg   Arm B: Ixazomib 4.0 mg   Arm B: Ixazomib 5.5 mg   Arm C: Ixazomib 3.0 mg   Arm C: Ixazomib 4.0 mg   Arm D: Ixazomib 4.0 mg
STARTED   7   4   3   26   5   6   4   6 
COMPLETED   4   3   1   15   5   1   2   3 
NOT COMPLETED   3   1   2   11   0   5   2   3 
Study Terminated by Sponsor                2                1                1                10                0                4                2                3 
Withdrawal by Subject                1                0                0                1                0                0                0                0 
Reason not Specified                0                0                1                0                0                1                0                0 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety population consisted of participants who received at least 1 dose of any study drug.

Reporting Groups
  Description
Arm A: Ixazomib 3.0 - 3.7 mg Ixazomib 3.0 - 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles).
Arm B: Ixazomib 3.0 - 5.5 mg Ixazomib 3.0 - 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1-4 for in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles).
Arm C: Ixazomib 3.0 - 4.0 mg Ixazomib 3.0 - 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles).
Arm D: Ixazomib 4.0 mg Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles).
Total Total of all reporting groups

Baseline Measures
   Arm A: Ixazomib 3.0 - 3.7 mg   Arm B: Ixazomib 3.0 - 5.5 mg   Arm C: Ixazomib 3.0 - 4.0 mg   Arm D: Ixazomib 4.0 mg   Total 
Overall Participants Analyzed 
[Units: Participants]
 11   34   10   6   61 
Age 
[Units: Years]
Mean (Standard Deviation)
         
Participants Analyzed   11   34   10   6   61 
   74.2  (6.68)   74.3  (4.79)   76.3  (4.27)   73.2  (9.66)   74.5  (5.60) 
Age, Customized 
[Units: Participants]
Count of Participants
         
<75           
Participants Analyzed   11   34   10   6   61 
<75   6   19   2   4   31 
>=75           
Participants Analyzed   11   34   10   6   61 
>=75   5   15   8   2   30 
Sex: Female, Male 
[Units: Participants]
Count of Participants
         
Participants Analyzed   11   34   10   6   61 
Female      3  27.3%      12  35.3%      5  50.0%      3  50.0%      23  37.7% 
Male      8  72.7%      22  64.7%      5  50.0%      3  50.0%      38  62.3% 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
         
Missing           
Participants Analyzed   11   34   10   6   61 
Missing   2   3   0   0   5 
Not Hispanic or Latino           
Participants Analyzed   11   34   10   6   61 
Not Hispanic or Latino   9   31   10   6   56 
Race/Ethnicity, Customized 
[Units: Participants]
Count of Participants
         
Asian           
Participants Analyzed   11   34   10   6   61 
Asian   0   0   1   0   1 
Black or African American           
Participants Analyzed   11   34   10   6   61 
Black or African American   0   1   0   0   1 
White           
Participants Analyzed   11   34   10   6   61 
White   10   32   9   6   57 
Other           
Participants Analyzed   11   34   10   6   61 
Other   1   1   0   0   2 
Region of Enrollment 
[Units: Participants]
Count of Participants
         
Canada           
Participants Analyzed   11   34   10   6   61 
Canada   0   6   2   0   8 
Czech Republic           
Participants Analyzed   11   34   10   6   61 
Czech Republic   6   8   0   1   15 
Spain           
Participants Analyzed   11   34   10   6   61 
Spain   3   15   7   5   30 
United Kingdom           
Participants Analyzed   11   34   10   6   61 
United Kingdom   1   2   1   0   4 
United States           
Participants Analyzed   11   34   10   6   61 
United States   1   3   0   0   4 
Height [1] 
[Units: Cm]
Mean (Standard Deviation)
         
Participants Analyzed   11   33   9   6   59 
   162.24  (7.872)   162.68  (12.087)   164.50  (11.413)   160.50  (16.897)   162.65  (11.615) 
[1] Height data was only available for 11, 33, 9 and 6 participants in the Arms A, B, C and D respectively.
Weight at Baseline 
[Units: Kg]
Mean (Standard Deviation)
         
Participants Analyzed   11   34   10   6   61 
   70.58  (9.389)   73.43  (16.642)   72.77  (20.532)   66.97  (21.404)   72.17  (16.509) 
Body Surface Area at Baseline [1] [2] 
[Units: M^2]
Mean (Standard Deviation)
         
Participants Analyzed   11   33   9   6   59 
   1.782  (0.1426)   1.813  (0.2638)   1.799  (0.3337)   1.718  (0.3650)   1.795  (0.2638) 
[1] Body Surface Area (m^2) = square root [height (cm) x weight (kg) / 3600].
[2] Body Surface Area data was only available for 11, 33, 9 and 6 participants in the Arms A, B, C and D respectively.


  Outcome Measures

1.  Primary:   Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1)   [ Time Frame: Cycle 1, phase 1 (Up to 42 days) ]

2.  Primary:   Very Good Partial Response (VGPR) or Better Response Rate (Phase 2)   [ Time Frame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years) ]

3.  Secondary:   Maximum Inhibition Rate (Emax) (Phase 1)   [ Time Frame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study ]

4.  Secondary:   Time of Occurrence of Emax (TEmax) (Phase 1)   [ Time Frame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study ]

5.  Secondary:   Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)   [ Time Frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D ]

6.  Secondary:   Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)   [ Time Frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D ]

7.  Secondary:   AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)   [ Time Frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D ]

8.  Secondary:   Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1)   [ Time Frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D ]

9.  Secondary:   Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1)   [ Time Frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D ]

10.  Secondary:   Observed Accumulation Ratio for AUCtau (Rac) (Phase 1)   [ Time Frame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D ]

11.  Secondary:   Overall Response Rate (ORR)   [ Time Frame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years) ]

12.  Secondary:   Time to First Response (Phase 2)   [ Time Frame: From the date of enrollment to the date of the first documented response for up to 5.5 years ]

13.  Secondary:   Duration of Response (DOR) (Phase 2)   [ Time Frame: From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years ]

14.  Secondary:   Time to Progression (TTP) (Phase 2)   [ Time Frame: From the date of enrollment to the date of the first documented disease progression for up to 5.5 years ]

15.  Secondary:   Time to Next Therapy (Phase 2)   [ Time Frame: From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years ]

16.  Secondary:   Progression Free Survival (Phase 2)   [ Time Frame: From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years ]

17.  Secondary:   Overall Survival (Phase 2)   [ Time Frame: From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months) ]

18.  Secondary:   Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)   [ Time Frame: From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years ]

19.  Secondary:   Assessments of Quality of Life (Phase 2)   [ Time Frame: Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director
Organization: Takeda
phone: +1-877-825-3327
e-mail: trialdisclosures@takeda.com



Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier: NCT01335685     History of Changes
Other Study ID Numbers: C16006
2010-023772-71 ( EudraCT Number )
First Submitted: April 8, 2011
First Posted: April 14, 2011
Results First Submitted: December 22, 2017
Results First Posted: January 23, 2018
Last Update Posted: January 23, 2018