Study Evaluating the Safety and Tolerability of Weekly Dosing of Oral IXAZOMIB in Adult Patients With Relapsed and Refractory Multiple Myeloma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT00963820
First received: August 20, 2009
Last updated: July 30, 2015
Last verified: July 2015
Results First Received: May 29, 2015  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Multiple Myeloma
Intervention: Drug: Ixazomib citrate

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Sixty (60) participants took part in the study at 6 investigative sites in the United States from 31 October 2009 to database lock on 28 February 2013.

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 (relapsed and/or refractory) were enrolled in the dose escalation phase to determine maximum tolerated dose (MTD). Once the MTD was established, participants were enrolled at the MTD into 1 of the 4 expansion cohorts.

Reporting Groups
  Description
0.24 mg/m^2 Ixazomib citrate, 0.24 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
0.48 mg/m^2 Ixazomib citrate, 0.48 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
0.80 mg/m^2 Ixazomib citrate, 0.80 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
1.20 mg/m^2 Ixazomib citrate, 1.20 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
1.68 mg/m^2 Ixazomib citrate, 1.68 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
2.23 mg/m^2 Ixazomib citrate, 2.23 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
2.97 mg/m^2 Ixazomib citrate, 2.97 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
3.95 mg/m^2 Ixazomib citrate, 3.95 mg/m^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
Relapsed and Refractory (RR) Ixazomib citrate, 2.97 mg/m^2 established Maximum Tolerated Dose (MTD), capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the Relapsed and Refractory (RR) expansion cohort that includes 2 participants from the dose escalation cohort 2.97 mg/m^2. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
VELCADE-relapsed (VR) Ixazomib citrate, 2.97 mg/m^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the VELCADE-relapsed (VR) expansion cohort that includes 1 participant from the dose escalation cohort 2.97 mg/m^2. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
PI naïve Ixazomib citrate, 2.97 mg/m^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in expansion cohort of participants who were proteasome inhibitor-naïve (PI naïve). All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
Carfilzomib Ixazomib citrate, 2.97 mg/m^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the expansion cohort of participants who received their last dose of carfilzomib between 21 and 60 days prior to the first dose of ixazomib citrate. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.

Participant Flow for 2 periods

Period 1:   Dose Escalation Phase
    0.24 mg/m^2     0.48 mg/m^2     0.80 mg/m^2     1.20 mg/m^2     1.68 mg/m^2     2.23 mg/m^2     2.97 mg/m^2     3.95 mg/m^2     Relapsed and Refractory (RR)     VELCADE-relapsed (VR)     PI naïve     Carfilzomib  
STARTED     3     3     3     3     4     3     8     5     0 [1]   0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     3     3     3     3     4     3     8     5     0     0     0     0  
Progressive Disease                 3                 3                 3                 3                 4                 3                 3                 2                 0                 0                 0                 0  
Adverse Event                 0                 0                 0                 0                 0                 0                 3                 1                 0                 0                 0                 0  
Withdrawal by Subject                 0                 0                 0                 0                 0                 0                 1                 2                 0                 0                 0                 0  
Unsatisfactory Therapeutic Response                 0                 0                 0                 0                 0                 0                 1                 0                 0                 0                 0                 0  
[1] Expansion cohorts were not part of Dose Escalation except as noted in comments.

Period 2:   Expansion Phase
    0.24 mg/m^2     0.48 mg/m^2     0.80 mg/m^2     1.20 mg/m^2     1.68 mg/m^2     2.23 mg/m^2     2.97 mg/m^2     3.95 mg/m^2     Relapsed and Refractory (RR)     VELCADE-relapsed (VR)     PI naïve     Carfilzomib  
STARTED     0 [1]   0     0     0     0     0     0     0     11 [2]   10 [3]   6 [4]   4 [5]
COMPLETED     0     0     0     0     0     0     0     0     1 [6]   1 [6]   1 [6]   0  
NOT COMPLETED     0     0     0     0     0     0     0     0     10     9     5     4  
Progressive Disease                 0                 0                 0                 0                 0                 0                 0                 0                 8                 6                 4                 2  
Adverse Event                 0                 0                 0                 0                 0                 0                 0                 0                 1                 3                 0                 0  
Withdrawal by Subject                 0                 0                 0                 0                 0                 0                 0                 0                 1                 0                 1                 1  
Unsatisfactory Therapeutic Response                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 1  
[1] Dose escalation cohorts were not part of the Expansion Phase except as noted in comments.
[2] Includes 2 participants from the dose escalation cohort 2.97 mg/m^2.
[3] Includes 1 participant from the dose escalation cohort 2.97 mg/m^2.
[4] Includes only participants who are proteasome inhibitor (PI)-naïve.
[5] Includes participants with last dose of carfilzomib 21 to 60 days before 1st ixazomib citrate dose.
[6] Participant was ongoing at the time of data cut off for analysis



  Baseline Characteristics
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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.
Safety Population

Reporting Groups
  Description
Overall Study Safety Population

Baseline Measures
    Overall Study  
Number of Participants  
[units: participants]
  60  
Age  
[units: years]
Mean (Standard Deviation)
  63.0  (9.10)  
Gender  
[units: participants]
 
Female     27  
Male     33  
Race/Ethnicity, Customized  
[units: participants]
 
Hispanic or Latino     1  
Not Hispanic or Latino     56  
Missing     3  
Race/Ethnicity, Customized  
[units: participants]
 
White     51  
Black or African American     7  
Other     2  
Region of Enrollment  
[units: participants]
 
United States     60  
Height [1]
[units: cm]
Mean (Standard Deviation)
  168.4  (9.34)  
Weight  
[units: kg]
Mean (Standard Deviation)
  83.26  (18.106)  
Body Surface Area at Baseline [2]
[units: m^2]
Mean (Standard Deviation)
  1.96  (0.247)  
[1] Height data was missing for 1 participant. Mean and standard deviation calculation is based on 59 participants.
[2] Body Surface Area (BSA) was missing for 1 participant. Mean and standard deviation are based on 59 participants.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants Reporting One or More Treatment-Emergent Adverse Events and Serious Adverse Events   [ Time Frame: From the first dose through 30 days after last dose of ixazomib citrate or until the start of subsequent antineoplastic therapy (Up to 354 days) ]

2.  Primary:   Neurotoxicity Grading   [ Time Frame: Cycle 1 Day 1 and End of Study (Up to 354 days) ]

3.  Secondary:   Cmax: Maximum Observed Plasma Concentration for MLN2238   [ Time Frame: Days 1 and 15 of Cycle 1 ]

4.  Secondary:   Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for MLN2238   [ Time Frame: Days 1 and 15 of Cycle 1 ]

5.  Secondary:   AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for MLN2238   [ Time Frame: Days 1 and 15 of Cycle 1 ]

6.  Secondary:   Accumulation Ratio: Day 15 AUC0-168 / Day 1 AUC0-168 for MLN2238   [ Time Frame: Day 15 of Cycle 1 ]

7.  Secondary:   Terminal Elimination Rate Constant (λz) for MLN2238   [ Time Frame: Day 15 of Cycle 1 ]

8.  Secondary:   Terminal Phase Elimination Half-life (T1/2) for MLN2238   [ Time Frame: Day 15 of Cycle 1 ]

9.  Secondary:   Emax: Maximum Inhibition   [ Time Frame: Days 1 and 15 of Cycle 1 ]

10.  Secondary:   TEmax: Time of Occurrence of Emax   [ Time Frame: Days 1 and 15 of Cycle 1 ]

11.  Secondary:   Overall Response to Treatment With Ixazomib Citrate Based on Investigator's Evaluation Over Time   [ Time Frame: Up to 354 days ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
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  More Information
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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


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00963820     History of Changes
Other Study ID Numbers: C16004
U1111-1166-8401 ( Other Identifier: WHO )
Study First Received: August 20, 2009
Results First Received: May 29, 2015
Last Updated: July 30, 2015
Health Authority: United States: Food and Drug Administration