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MLN0128 and MLN0128 + MLN1117 Compared With Everolimus in the Treatment of Adults With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma

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ClinicalTrials.gov Identifier: NCT02724020
Recruitment Status : Completed
First Posted : March 31, 2016
Results First Posted : February 21, 2021
Last Update Posted : February 21, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Clear-cell Metastatic Renal Cell Carcinoma
Interventions Drug: Everolimus
Drug: MLN0128
Drug: MLN1117
Enrollment 96
Recruitment Details Participants took part in the study at approximately 60-70 investigative sites in North America and Europe from 30 June 2016 up to data cut-off: 6 March 2020.
Pre-assignment Details Participants with a diagnosis of metastatic clear-cell renal cell carcinoma will be randomized at a ratio of 1:1:1 to open label treatment period with single-agent MLN0128 and the combination of MLN0128 and MLN1117 compared with single-agent everolimus.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020). MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020). MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Period Title: Overall Study
Started 32 32 32
Treated (Safety Analysis Set) 32 32 31
Completed 0 0 0
Not Completed 32 32 32
Reason Not Completed
Ongoing at Data Cut-off: 6 Mar 2020             2             0             0
Death             16             18             19
Lost to Follow-up             0             3             0
Site Terminated by Sponsor             13             8             8
Withdrawal by Subject             1             3             5
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD Total
Hide Arm/Group Description Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020). MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020). MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020). Total of all reporting groups
Overall Number of Baseline Participants 32 32 32 96
Hide Baseline Analysis Population Description
Full Analysis Set included all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 32 participants 32 participants 32 participants 96 participants
64.7  (11.41) 61.6  (8.90) 63.3  (9.06) 63.2  (9.83)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants 32 participants 32 participants 96 participants
Female
6
  18.8%
10
  31.3%
7
  21.9%
23
  24.0%
Male
26
  81.3%
22
  68.8%
25
  78.1%
73
  76.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants 32 participants 32 participants 96 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
2
   6.3%
2
   2.1%
Not Hispanic or Latino
28
  87.5%
30
  93.8%
27
  84.4%
85
  88.5%
Unknown or Not Reported
4
  12.5%
2
   6.3%
3
   9.4%
9
   9.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants 32 participants 32 participants 96 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   3.1%
0
   0.0%
0
   0.0%
1
   1.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
1
   3.1%
1
   1.0%
White
27
  84.4%
29
  90.6%
27
  84.4%
83
  86.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
4
  12.5%
3
   9.4%
4
  12.5%
11
  11.5%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Czech Republic Number Analyzed 32 participants 32 participants 32 participants 96 participants
1
   3.1%
1
   3.1%
2
   6.3%
4
   4.2%
France Number Analyzed 32 participants 32 participants 32 participants 96 participants
4
  12.5%
2
   6.3%
2
   6.3%
8
   8.3%
Italy Number Analyzed 32 participants 32 participants 32 participants 96 participants
11
  34.4%
9
  28.1%
4
  12.5%
24
  25.0%
Poland Number Analyzed 32 participants 32 participants 32 participants 96 participants
2
   6.3%
2
   6.3%
1
   3.1%
5
   5.2%
Spain Number Analyzed 32 participants 32 participants 32 participants 96 participants
6
  18.8%
6
  18.8%
7
  21.9%
19
  19.8%
United Kingdom Number Analyzed 32 participants 32 participants 32 participants 96 participants
4
  12.5%
4
  12.5%
9
  28.1%
17
  17.7%
Canada Number Analyzed 32 participants 32 participants 32 participants 96 participants
2
   6.3%
1
   3.1%
2
   6.3%
5
   5.2%
United States Number Analyzed 32 participants 32 participants 32 participants 96 participants
2
   6.3%
7
  21.9%
5
  15.6%
14
  14.6%
Height   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 31 participants 32 participants 31 participants 94 participants
170.23  (8.489) 171.16  (10.626) 172.01  (8.349) 171.13  (9.159)
[1]
Measure Analysis Population Description: Number analyzed is the number of participants with data available for height at Baseline.
Weight   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 31 participants 32 participants 32 participants 95 participants
75.69  (12.449) 78.12  (15.473) 80.40  (17.896) 78.10  (15.419)
[1]
Measure Analysis Population Description: Number analyzed is the number of participants with data available for weight at Baseline.
1.Primary Outcome
Title Progression-Free Survival (PFS)
Hide Description PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time Frame From first dose of study drug up to disease progression or death (approximately 30 months up to data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set included all randomized participants.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description:
Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020).
MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020).
MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Overall Number of Participants Analyzed 32 32 32
Median (95% Confidence Interval)
Unit of Measure: months
3.8
(2.0 to 5.4)
3.6
(1.9 to 5.7)
3.1
(1.9 to 5.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm B: Single-agent MLN0128 30 mg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.388
Comments [Not Specified]
Method Stratified Log-rank Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.33
Confidence Interval (2-Sided) 95%
0.75 to 2.36
Estimation Comments HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category. A hazard ratio < 1 indicated an advantage compared to Everolimus.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.667
Comments [Not Specified]
Method Stratified Log-rank Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.37
Confidence Interval (2-Sided) 95%
0.75 to 2.52
Estimation Comments HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category. A hazard ratio < 1 indicated an advantage compared to Everolimus.
2.Secondary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Hide Description An AE was defined as any untoward medical occurrence in participants administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. TEAE was defined as the event that occur after administration of the first dose of study drug and through 30 days after the last dose of study drug.
Time Frame From first dose of study drug through 30 days after the last dose of study drug (approximately 31 months up to data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set included participants who receive at least 1 dose of study drug.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description:
Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020).
MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020).
MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Overall Number of Participants Analyzed 32 32 31
Measure Type: Count of Participants
Unit of Measure: Participants
32
 100.0%
30
  93.8%
31
 100.0%
3.Secondary Outcome
Title Overall Survival (OS)
Hide Description Overall survival in months was defined as the time from the date of randomization to the date of death.
Time Frame From first dose of study drug through 30 days after the last dose of study drug (approximately 31 months up to data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set included all randomized participants.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description:
Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020).
MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020).
MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Overall Number of Participants Analyzed 32 32 32
Median (95% Confidence Interval)
Unit of Measure: months
22.4 [1] 
(8.2 to NA)
16.2
(9.0 to 19.9)
18.1
(6.2 to 23.4)
[1]
The upper limit of confidence interval (CI) was not estimable due to fewer number of participants with event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm B: Single-agent MLN0128 30 mg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.212
Comments [Not Specified]
Method Stratified Log-rank Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.76
Confidence Interval (2-Sided) 95%
0.89 to 3.49
Estimation Comments HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category. A hazard ratio < 1 indicated an advantage compared to Everolimus.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.546
Comments [Not Specified]
Method Stratified Log-rank Test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.51
Confidence Interval (2-Sided) 95%
0.77 to 2.98
Estimation Comments HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category. A hazard ratio < 1 indicated an advantage compared to Everolimus.
4.Secondary Outcome
Title Time-to-progression (TTP)
Hide Description TTP in months is defined as the time from the date of randomization to the date of first documentation of progression. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time Frame From first dose of study drug up to disease progression or death (approximately 30 months up to data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set included all randomized participants.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description:
Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020).
MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020).
MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Overall Number of Participants Analyzed 32 32 32
Median (95% Confidence Interval)
Unit of Measure: months
3.8
(2.0 to 15.6)
3.5
(1.9 to 7.4)
3.7
(1.9 to 10.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm B: Single-agent MLN0128 30 mg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.156
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.57
Confidence Interval (2-Sided) 95%
0.81 to 3.05
Estimation Comments HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.667
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.42
Confidence Interval (2-Sided) 95%
0.72 to 2.79
Estimation Comments HR obtained by stratified Cox proportion hazard model adjusted for prior lines of therapy and the International Metastatic Renal Cell Carcinoma Database Consortium risk category. A hazard ratio < 1 indicates an advantage compared to Everolimus.
5.Secondary Outcome
Title Objective Response Rate (ORR)
Hide Description ORR was defined as the percentage of participants among response evaluable analysis set who achieve a best overall response of complete response (CR) or partial response (PR) based on investigators assessment of response following RECIST 1.1. CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Time Frame From first dose of study drug to disease progression or death (approximately 30 months up to data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
Response Evaluable Analysis Set included participants who receive at least 1 dose of study drug, have measurable disease at Baseline and have 1 postbaseline disease assessment.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description:
Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020).
MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020).
MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Overall Number of Participants Analyzed 30 26 28
Measure Type: Number
Unit of Measure: percentage of participants
16.7 0 7.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.43
Confidence Interval (2-Sided) 95%
0.08 to 2.29
Estimation Comments Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
6.Secondary Outcome
Title Clinical Benefit Rate (CBR)
Hide Description CBR is defined as the percentage of participants who achieve a best response of CR, PR or stable disease (SD) of any duration. CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame From first dose of study drug up to disease progression or death (approximately 30 months up to data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
Response Evaluable Analysis Set included participants who receive at least 1 dose of study drug, have measurable disease at Baseline and have 1 postbaseline disease assessment.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description:
Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020).
MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020).
MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Overall Number of Participants Analyzed 30 26 28
Measure Type: Number
Unit of Measure: percentage of participants
66.7 61.5 60.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm B: Single-agent MLN0128 30 mg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.28 to 2.52
Estimation Comments Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.29 to 2.50
Estimation Comments Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
7.Secondary Outcome
Title CBR With SD Duration of at Least 16 Weeks
Hide Description CBR with SD duration of at least 4 months (CBR-16) was defined as the percentage of participants who achieve CR or PR of any duration or have SD with duration of at least 16 weeks. CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame Up to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Response Evaluable Analysis Set included participants who receive at least 1 dose of study drug, have measurable disease at Baseline and have 1 postbaseline disease assessment.
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description:
Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020).
MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020).
MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
Overall Number of Participants Analyzed 30 26 28
Measure Type: Number
Unit of Measure: percentage of participants
43.3 30.8 32.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm B: Single-agent MLN0128 30 mg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.17 to 1.63
Estimation Comments Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm A: Single-agent Everolimus 10 mg QD, Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.21 to 1.90
Estimation Comments Odds ratio and 95% CI was obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
Time Frame From first dose of study drug through 30 days after the last dose of study drug (approximately 31 months up to data cut-off)
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. All-cause mortality: Data is reported for Full Analysis Set, defined as all randomized participants. Adverse Events: Data for is reported for Safety Analysis Set, including participants who received at least 1 dose of study drug.
 
Arm/Group Title Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Hide Arm/Group Description Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to data cut-off: 6 March 2020). MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to data cut-off: 6 March 2020). MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to data cut-off: 6 March 2020).
All-Cause Mortality
Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   16/32 (50.00%)   18/32 (56.25%)   19/32 (59.38%) 
Hide Serious Adverse Events
Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   19/32 (59.38%)   13/32 (40.63%)   15/31 (48.39%) 
Blood and lymphatic system disorders       
Anaemia  1  0/32 (0.00%)  0/32 (0.00%)  2/31 (6.45%) 
Cardiac disorders       
Acute myocardial infarction  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Cardiac failure  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Gastrointestinal disorders       
Abdominal pain  1  0/32 (0.00%)  1/32 (3.13%)  1/31 (3.23%) 
Ascites  1  0/32 (0.00%)  0/32 (0.00%)  2/31 (6.45%) 
Diarrhoea  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Stomatitis  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
General disorders       
Asthenia  1  0/32 (0.00%)  2/32 (6.25%)  1/31 (3.23%) 
General physical health deterioration  1  1/32 (3.13%)  0/32 (0.00%)  1/31 (3.23%) 
Pyrexia  1  1/32 (3.13%)  0/32 (0.00%)  1/31 (3.23%) 
Fatigue  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Immune system disorders       
Hypersensitivity  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Infections and infestations       
Pneumonia  1  3/32 (9.38%)  0/32 (0.00%)  0/31 (0.00%) 
Sepsis  1  2/32 (6.25%)  1/32 (3.13%)  0/31 (0.00%) 
Septic shock  1  0/32 (0.00%)  1/32 (3.13%)  1/31 (3.23%) 
Abscess jaw  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Pulmonary sepsis  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Injury, poisoning and procedural complications       
Accidental overdose  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Femur fracture  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Pelvic fracture  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Road traffic accident  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Investigations       
Haemoglobin decreased  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Transaminases increased  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Metabolism and nutrition disorders       
Dehydration  1  1/32 (3.13%)  1/32 (3.13%)  0/31 (0.00%) 
Hypercalcaemia  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Hyperglycaemia  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Musculoskeletal and connective tissue disorders       
Bone pain  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Muscular weakness  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Pathological fracture  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Metastatic renal cell carcinoma  1  0/32 (0.00%)  2/32 (6.25%)  0/31 (0.00%) 
Clear cell renal cell carcinoma  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
T-cell lymphoma  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Nervous system disorders       
Cerebellar haemorrhage  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Psychiatric disorders       
Confusional state  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Renal and urinary disorders       
Acute kidney injury  1  0/32 (0.00%)  2/32 (6.25%)  1/31 (3.23%) 
Chronic kidney disease  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Haematuria  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Renal failure  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Urinary retention  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea  1  1/32 (3.13%)  1/32 (3.13%)  0/31 (0.00%) 
Dyspnoea at rest  1  0/32 (0.00%)  1/32 (3.13%)  0/31 (0.00%) 
Hiccups  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Pleural effusion  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Skin and subcutaneous tissue disorders       
Rash maculo-papular  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
Vascular disorders       
Hypotension  1  0/32 (0.00%)  0/32 (0.00%)  1/31 (3.23%) 
Infarction  1  1/32 (3.13%)  0/32 (0.00%)  0/31 (0.00%) 
1
Term from vocabulary, MedDRA 23.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Arm A: Single-agent Everolimus 10 mg QD Arm B: Single-agent MLN0128 30 mg QW Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   32/32 (100.00%)   29/32 (90.63%)   31/31 (100.00%) 
Blood and lymphatic system disorders       
Anaemia  1  4/32 (12.50%)  6/32 (18.75%)  4/31 (12.90%) 
Leukocytosis  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Gastrointestinal disorders       
Nausea  1  7/32 (21.88%)  22/32 (68.75%)  17/31 (54.84%) 
Vomiting  1  7/32 (21.88%)  14/32 (43.75%)  13/31 (41.94%) 
Diarrhoea  1  13/32 (40.63%)  8/32 (25.00%)  11/31 (35.48%) 
Constipation  1  9/32 (28.13%)  12/32 (37.50%)  5/31 (16.13%) 
Stomatitis  1  12/32 (37.50%)  6/32 (18.75%)  3/31 (9.68%) 
Abdominal pain  1  5/32 (15.63%)  5/32 (15.63%)  6/31 (19.35%) 
Dyspepsia  1  4/32 (12.50%)  4/32 (12.50%)  3/31 (9.68%) 
Dry mouth  1  1/32 (3.13%)  2/32 (6.25%)  5/31 (16.13%) 
Gastrooesophageal reflux disease  1  3/32 (9.38%)  1/32 (3.13%)  3/31 (9.68%) 
Abdominal pain upper  1  2/32 (6.25%)  1/32 (3.13%)  2/31 (6.45%) 
Mouth ulceration  1  3/32 (9.38%)  0/32 (0.00%)  1/31 (3.23%) 
Dysphagia  1  1/32 (3.13%)  2/32 (6.25%)  0/31 (0.00%) 
General disorders       
Asthenia  1  19/32 (59.38%)  12/32 (37.50%)  9/31 (29.03%) 
Fatigue  1  10/32 (31.25%)  6/32 (18.75%)  12/31 (38.71%) 
Pyrexia  1  10/32 (31.25%)  3/32 (9.38%)  5/31 (16.13%) 
Chest pain  1  2/32 (6.25%)  3/32 (9.38%)  1/31 (3.23%) 
Influenza like illness  1  4/32 (12.50%)  1/32 (3.13%)  1/31 (3.23%) 
Chills  1  2/32 (6.25%)  2/32 (6.25%)  1/31 (3.23%) 
Oedema peripheral  1  5/32 (15.63%)  0/32 (0.00%)  0/31 (0.00%) 
Pain  1  1/32 (3.13%)  1/32 (3.13%)  2/31 (6.45%) 
Peripheral swelling  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Infections and infestations       
Urinary tract infection  1  3/32 (9.38%)  2/32 (6.25%)  2/31 (6.45%) 
Influenza  1  2/32 (6.25%)  0/32 (0.00%)  2/31 (6.45%) 
Lower respiratory tract infection  1  0/32 (0.00%)  1/32 (3.13%)  2/31 (6.45%) 
Pneumonia  1  2/32 (6.25%)  1/32 (3.13%)  0/31 (0.00%) 
Upper respiratory tract infection  1  1/32 (3.13%)  2/32 (6.25%)  0/31 (0.00%) 
Nasopharyngitis  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Investigations       
Weight decreased  1  4/32 (12.50%)  9/32 (28.13%)  5/31 (16.13%) 
Blood creatinine increased  1  2/32 (6.25%)  3/32 (9.38%)  2/31 (6.45%) 
Alanine aminotransferase increased  1  0/32 (0.00%)  1/32 (3.13%)  4/31 (12.90%) 
Gamma-glutamyltransferase increased  1  0/32 (0.00%)  1/32 (3.13%)  4/31 (12.90%) 
Blood lactate dehydrogenase increased  1  1/32 (3.13%)  2/32 (6.25%)  0/31 (0.00%) 
Amylase increased  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Aspartate aminotransferase increased  1  0/32 (0.00%)  0/32 (0.00%)  2/31 (6.45%) 
Haemoglobin decreased  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Lipase increased  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite  1  15/32 (46.88%)  10/32 (31.25%)  11/31 (35.48%) 
Hyperglycaemia  1  4/32 (12.50%)  4/32 (12.50%)  8/31 (25.81%) 
Hypertriglyceridaemia  1  5/32 (15.63%)  2/32 (6.25%)  1/31 (3.23%) 
Dehydration  1  1/32 (3.13%)  2/32 (6.25%)  1/31 (3.23%) 
Hypercalcaemia  1  0/32 (0.00%)  2/32 (6.25%)  2/31 (6.45%) 
Hypophosphataemia  1  1/32 (3.13%)  1/32 (3.13%)  2/31 (6.45%) 
Hyperuricaemia  1  0/32 (0.00%)  3/32 (9.38%)  0/31 (0.00%) 
Hypernatraemia  1  0/32 (0.00%)  2/32 (6.25%)  0/31 (0.00%) 
Iron deficiency  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Metabolic acidosis  1  0/32 (0.00%)  2/32 (6.25%)  0/31 (0.00%) 
Hyperkalaemia  1  0/32 (0.00%)  5/32 (15.63%)  2/31 (6.45%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  5/32 (15.63%)  7/32 (21.88%)  2/31 (6.45%) 
Pain in extremity  1  6/32 (18.75%)  2/32 (6.25%)  2/31 (6.45%) 
Arthralgia  1  4/32 (12.50%)  1/32 (3.13%)  3/31 (9.68%) 
Musculoskeletal pain  1  2/32 (6.25%)  2/32 (6.25%)  0/31 (0.00%) 
Bone pain  1  2/32 (6.25%)  1/32 (3.13%)  0/31 (0.00%) 
Groin pain  1  0/32 (0.00%)  2/32 (6.25%)  0/31 (0.00%) 
Nervous system disorders       
Headache  1  6/32 (18.75%)  4/32 (12.50%)  4/31 (12.90%) 
Dizziness  1  3/32 (9.38%)  4/32 (12.50%)  0/31 (0.00%) 
Dysgeusia  1  3/32 (9.38%)  0/32 (0.00%)  3/31 (9.68%) 
Presyncope  1  3/32 (9.38%)  0/32 (0.00%)  0/31 (0.00%) 
Tremor  1  1/32 (3.13%)  0/32 (0.00%)  2/31 (6.45%) 
Memory impairment  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Somnolence  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Psychiatric disorders       
Anxiety  1  3/32 (9.38%)  2/32 (6.25%)  2/31 (6.45%) 
Insomnia  1  3/32 (9.38%)  2/32 (6.25%)  2/31 (6.45%) 
Renal and urinary disorders       
Haematuria  1  2/32 (6.25%)  1/32 (3.13%)  1/31 (3.23%) 
Dysuria  1  2/32 (6.25%)  1/32 (3.13%)  0/31 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea  1  10/32 (31.25%)  10/32 (31.25%)  5/31 (16.13%) 
Cough  1  11/32 (34.38%)  10/32 (31.25%)  3/31 (9.68%) 
Dyspnoea exertional  1  2/32 (6.25%)  2/32 (6.25%)  0/31 (0.00%) 
Epistaxis  1  4/32 (12.50%)  0/32 (0.00%)  0/31 (0.00%) 
Nasal dryness  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Skin and subcutaneous tissue disorders       
Pruritus  1  3/32 (9.38%)  12/32 (37.50%)  6/31 (19.35%) 
Rash  1  3/32 (9.38%)  3/32 (9.38%)  5/31 (16.13%) 
Dermatitis acneiform  1  6/32 (18.75%)  2/32 (6.25%)  0/31 (0.00%) 
Dry skin  1  4/32 (12.50%)  0/32 (0.00%)  3/31 (9.68%) 
Rash maculo-papular  1  1/32 (3.13%)  1/32 (3.13%)  3/31 (9.68%) 
Erythema  1  2/32 (6.25%)  0/32 (0.00%)  0/31 (0.00%) 
Vascular disorders       
Hypertension  1  6/32 (18.75%)  3/32 (9.38%)  4/31 (12.90%) 
Hypotension  1  4/32 (12.50%)  1/32 (3.13%)  1/31 (3.23%) 
1
Term from vocabulary, MedDRA 23.0
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
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier: NCT02724020    
Other Study ID Numbers: C31005
2015-002133-22 ( EudraCT Number )
U1111-1172-1808 ( Registry Identifier: WHO )
First Submitted: March 25, 2016
First Posted: March 31, 2016
Results First Submitted: February 1, 2021
Results First Posted: February 21, 2021
Last Update Posted: February 21, 2021