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

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02724020
• Collaborator: (none)
• Enrollment: 96
• Locations: 36
• Arms: 3
• Actual Duration (Months): 51.4
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of single-agent MLN0128 and the combination of MLN0128 + MLN1117 compared with everolimus in the treatment of participants with metastatic clear-cell renal cell carcinoma (mccRCC) that have progressed on vascular endothelial growth factor (VEGF)-targeted therapy.

Condition or Disease	Intervention/Treatment	Phase
Clear-cell Metastatic Renal Cell Carcinoma	Drug: Everolimus; Drug: MLN0128; Drug: MLN1117	Phase 2

Detailed Description

The drugs being tested in this study are called MLN0128 and MLN1117. MLN0128 and MLN1117 are being tested to treat people who have mccRCC. This study will assess the efficacy and safety of MLN0128 and MLN1117 as well as how it is processed by the body in participants with advanced or mccRCC.

The study will enroll approximately 96 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups:

• Everolimus 10 mg once daily

• MLN0128 30 mg once weekly

• MLN0128 4 mg once daily for 3 days per week + MLN1117 200 mg once daily for 3 days per week

All participants will be asked to take the study drug at the same time on each scheduled day.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 2 years after last participant is randomized, or when the last participant discontinues study treatment (approximately 3 years). Participants will make multiple visits to the clinic including a follow-up visit 30 to 40 days after receiving their last dose of study drug or prior to start of subsequent anticancer therapy for safety assessment. Participants will then be followed for Progression Free and Overall Survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Single-Agent MLN0128 and the Combination of MLN0128+MLN1117 Compared With Everolimus in the Treatment of Adult Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma That Has Progressed on Vascular Endothelial Growth Factor-Targeted Therapy
• Actual Study Start Date: Jun 30, 2016
• Actual Primary Completion Date: Feb 3, 2020
• Actual Study Completion Date: Oct 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A: Single-agent Everolimus 10 mg QD 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 end of study).	Drug: Everolimus; Everolimus capsules.
Experimental: Arm B: Single-agent MLN0128 30 mg QW 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 end of study).	Drug: MLN0128; MLN0128 capsules.; Other Names: TAK-228 INK0128
Experimental: Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD 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 end of study).	Drug: MLN0128; MLN0128 capsules.; Other Names: TAK-228 INK0128 ; Drug: MLN1117; MLN1117 capsules.; Other Names: TAK-117 INK1117

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [From first dose of study drug up to disease progression or death, assessed up to 43 months]

   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.

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From first dose of study drug through 30 days after the last dose of study drug (approximately up to 31 months)]

   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.

2. Overall Survival (OS) [From first dose of study drug through 30 days after the last dose of study drug (up to 51 months)]

   Overall survival in months was defined as the time from the date of randomization to the date of death.

3. Time-to-progression (TTP) [From first dose of study drug up to disease progression or death (up to 51 months)]

   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.

4. Objective Response Rate (ORR) [From first dose of study drug to disease progression or death (up to 51 months)]

   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.

5. Clinical Benefit Rate (CBR) [From first dose of study drug up to disease progression or death (up to 51 months)]

   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.

6. CBR With SD Duration of at Least 16 Weeks [Up to Week 16]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female participants aged 18 years or older.

2. Histologically confirmed renal cell carcinoma (RCC) with a clear-cell component.

3. Evidence that the RCC is advanced or metastatic.

4. Radiologic evidence of PD (according to RECIST Version 1.1) either during or within 6 months after stopping their most recent systemic therapy for RCC before enrollment into this study.

5. At least 1, prior line of VEGF-targeted therapy, but not more than 4 total prior lines of systemic therapy. Exposure to more than 1 line of VEGF-targeted therapy is acceptable. Participants may also have received prior therapies with interferon, interleukin 2 (IL-2), anti-PD1 antibodies, cabozantinib or other experimental agents, but not prior therapy with any agent that targets phosphoinositide 3-kinase (PI3K), serine/ threonine-specific protein kinase (AKT), or mechanistic (or mammalian) target of rapamycin (mTOR).

6. Karnofsky Performance Status (KPS) greater than or equal to (>=) 70%.

7. Life expectancy of >=3 months.

8. Female participants who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 1 highly effective method of contraception, and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labelling [example, United States Prescribing Information (USPI), Summary of Product Characteristics (SmPC), etc;]) after the last dose of study drug, OR

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.).

Male participants, even if surgically sterilized (that is, status postvasectomy), who:

• Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug (or longer, as mandated by local labelling [example, USPI, SmPC, etc]), OR

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.).

• Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug.

1. Suitable venous access for the study-required blood sampling.

2. Screening clinical laboratory values:

• Absolute neutrophil count >=2000 per microliter (/mcL) and platelet count

=100,000/mcL;

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to (<=) 2.5*the upper limit of normal (ULN);

• Total bilirubin <=1.5*ULN;

• Estimated creatinine clearance by Cockcroft-Gault >=40 milliliter per minute (mL/min) / 1.73 square meter (m^2);

• Glycosylated hemoglobin (HbA1c) less than (<) 7.0%, fasting serum glucose <=130 milligram per deciliter (mg/dL), and fasting triglycerides <=300 mg/dL.

1. At least 14 days since the end of prior systemic VEGF-targeted treatment (that is, sunitinib, pazopanib, axitinib, or sorafenib), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity (except alopecia and hypothyroidism) either to Grade 0 or 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.03) or to baseline.

2. At least 21 days since the last dose of bevacizumab, other antibody, or interferon.

3. Voluntary written consent given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion Criteria:

1. Central nervous system (CNS) metastasis.

2. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection, or any other condition that might compromise the participant's participation in the study.

3. Known human immunodeficiency virus infection.

4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.

5. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of everolimus, MLN0128, or MLN1117. In addition, participants with enteric stomata are excluded.

6. Women who are either breast feeding or pregnant.

7. History of any of the following within the last 6 months before administration of the first dose of study drug

• Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures;

• Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures;

• Requirement for inotropic support (excluding digoxin), or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia);

• Placement of a pacemaker for control of rhythm;

• New York Heart Association Class III or IV heart failure;

• Pulmonary embolism.

1. Significant active cardiovascular or pulmonary disease including:

• Uncontrolled hypertension (that is, either systolic blood pressure greater than [>] 160 millimeter of mercury [mm Hg]; diastolic blood pressure >95 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle 1 Day 1 is allowed;

• Pulmonary hypertension.

• Uncontrolled asthma or oxygen saturation <90% by arterial blood gas analysis or pulse oximetry on room air.

• Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement.

• Medically significant (symptomatic) bradycardia.

• History of arrhythmia requiring an implantable cardiac defibrillator.

• Baseline prolongation of the rate-corrected QT interval (QTc; example, repeated demonstration of QTc interval >480 millisecond [ms], or history of congenital, long-QT syndrome, or torsades de pointes).

1. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer, superficial bladder cancer, very low risk prostate on observation, or carcinoma in situ of any type are not excluded if they have undergone complete resection.

2. Prior therapy with agents that target Phosphatidylinositide 3-kinases (PI3K), Protein kinase B (AKT), or mechanistic target of rapamycin (mTOR). Participants with known hypersensitivity to everolimus or rapamycin derivatives are also excluded.

3. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

4. Participants who have taken a proton pump inhibitor (PPI) within 3 days before receiving the first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
2	Florida Cancer Specialists-Broadway	Venice	Florida	United States	33916
3	Florida Cancer Specialists	West Palm Beach	Florida	United States	33401
4	Hackensack University Medical Center PARTNER	Hackensack	New Jersey	United States	07601
5	The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital	Columbus	Ohio	United States	43210
6	Tennessee Oncology	Nashville	Tennessee	United States	37203
7	The Center for Cancer and Blood Disorders	Weatherford	Texas	United States	76086
8	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
9	McMaster University	Hamilton	Ontario	Canada	L8N 4A6
10	Fakultni nemocnice u sv. Anny v Brne	Brno		Czechia	656 91
11	Fakultni nemocnice Olomouc	Olomouc		Czechia	775 20
12	Fakultni nemocnice v Motole	Prague 5		Czechia	150 06
13	Groupe Hospitalier Saint Andre - Hopital Saint Andre	Bordeaux cedex	Aquitaine	France	33075
14	ICL-Alexis Vautrin, Departement dOncologie Medicale	Vandoeuvre les Nancy Cedex	Meurthe Et Moselle	France	54511
15	Groupe Hospitalier Pitie-Salpetriere	Paris cedex 13	Paris	France	75651
16	Institut de Cancerologie de l'Ouest Paul Papin	Angers Cedex 9	PAYS DE LA Loire	France	49933
17	Clinique Victor Hugo - Centre Jean Bernard	Le Mans Cedex 02	Sarthe	France	72015
18	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi	Bologna		Italy	40138
19	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli		Italy	80131
20	IOV - Istituto Oncologico Veneto IRCCS	Padova		Italy	35128
21	Fondazione IRCCS Policlinico San Matteo	Pavia		Italy	27100
22	Beskidzkie Centrum Onkologii im.Jana Pawla II	Bielsko-Biala		Poland	43-300
23	Instytut MSF, Ulica Pilota Stanislawa Wigury 19	Lodz		Poland	90-302
24	Hospital Duran i Reynals	L'Hospitalet de Llobregat	Barcelona	Spain	08023
25	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
26	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain	08036
27	MD Anderson Cancer Centre	Madrid		Spain	28033
28	Hospital Universitario Ramon Y Cajal	Madrid		Spain	28034
29	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
30	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
31	Royal Devon and Exeter Hospital (Wonford)	Exeter	Devon	United Kingdom	EX2 5DW
32	Lancashire Teaching Hospitals NHS Foundation Trust	Blackburn	England	United Kingdom	BB2 3HH
33	Barts Hospital	London	Greater London	United Kingdom	EC1M 6BQ
34	The Christie	Manchester	Greater Manchester	United Kingdom	M20 4BX
35	Velindre Cancer Centre	Cardiff	South Glamorgan	United Kingdom	CF14 2TL
36	Royal Surrey County Hospital	Guildford	Surrey	United Kingdom	GU2 7XX

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Dec 3, 2018
• Statistical Analysis Plan - Dec 3, 2018

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02724020
• Other Study ID Numbers: C31005; 2015-002133-22; U1111-1172-1808
• First Posted: Mar 31, 2016
• Last Update Posted: Nov 19, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug therapy
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Everolimus; Serabelisib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at approximately 60-70 investigative sites in Czech Republic, France, Italy, Poland, Spain, United Kingdom, Canada and United States from 30 June 2016 to 13 October 2020.
Pre-assignment Detail	Participants with a diagnosis of metastatic clear-cell renal cell carcinoma were 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
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 end of study).	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 end of study).	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 end of study).
Period Title: Overall Study
STARTED	32	32	32
Treated (Safety Analysis Set)	32	32	31
COMPLETED	0	0	0
NOT COMPLETED	32	32	32

Baseline Characteristics

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
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 end of study).	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 end of study).	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 (Median duration of treatment was 9.43 weeks up to end of study).	Total of all reporting groups
Overall Participants	32	32	32	96
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.7 (11.41)	61.6 (8.90)	63.3 (9.06)	63.2 (9.83)
Sex: Female, Male (Count of Participants)
Female	6 18.8%	10 31.3%	7 21.9%	23 24%
Male	26 81.3%	22 68.8%	25 78.1%	73 76%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	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) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 3.1%	0 0%	0 0%	1 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 3.1%	1 1%
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%
Unknown or Not Reported	4 12.5%	3 9.4%	4 12.5%	11 11.5%
Region of Enrollment (Count of Participants)
Czech Republic	1 3.1%	1 3.1%	2 6.3%	4 4.2%
France	4 12.5%	2 6.3%	2 6.3%	8 8.3%
Italy	11 34.4%	9 28.1%	4 12.5%	24 25%
Poland	2 6.3%	2 6.3%	1 3.1%	5 5.2%
Spain	6 18.8%	6 18.8%	7 21.9%	19 19.8%
United Kingdom	4 12.5%	4 12.5%	9 28.1%	17 17.7%
Canada	2 6.3%	1 3.1%	2 6.3%	5 5.2%
United States	2 6.3%	7 21.9%	5 15.6%	14 14.6%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	170.23 (8.489)	171.16 (10.626)	172.01 (8.349)	171.13 (9.159)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	75.69 (12.449)	78.12 (15.473)	80.40 (17.896)	78.10 (15.419)

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
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, assessed up to 43 months

Outcome Measure Data

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
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 end of study).	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 end of study).	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 end of study).
Measure Participants	32	32	32
Median (95% Confidence Interval) [months]	3.8	3.6	3.1

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.388
	Comments
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 0.75 to 2.36
	Parameter Dispersion	Type: Value:
	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.

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.667
	Comments
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.75 to 2.52
	Parameter Dispersion	Type: Value:
	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)
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 up to 31 months)

Outcome Measure Data

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
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 end of study).	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 end of study).	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 end of study).
Measure Participants	32	32	31
Count of Participants [Participants]	32 100%	30 93.8%	31 96.9%

3. Secondary Outcome

Title	Overall Survival (OS)
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 (up to 51 months)

Outcome Measure Data

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
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 end of study).	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 end of study).	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 end of study).
Measure Participants	32	32	32
Median (95% Confidence Interval) [months]	22.4	16.2	18.1

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.76
	Confidence Interval	(2-Sided) 95%; 0.89 to 3.49
	Parameter Dispersion	Type: Value:
	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.

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.546
	Comments
	Method	Stratified Log-rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 0.77 to 2.98
	Parameter Dispersion	Type: Value:
	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)
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 (up to 51 months)

Outcome Measure Data

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
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 end of study).	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 end of study).	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 end of study).
Measure Participants	32	32	32
Median (95% Confidence Interval) [months]	3.8	3.5	3.7

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.156
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 95%; 0.81 to 3.05
	Parameter Dispersion	Type: Value:
	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.

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.667
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; 0.72 to 2.79
	Parameter Dispersion	Type: Value:
	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)
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 (up to 51 months)

Outcome Measure Data

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
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 end of study).	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 end of study).	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 end of study).
Measure Participants	32	32	31
Number [percentage of participants]	15.6 48.8%	0 0%	6.5 20.3%

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	As prespecified in the protocol, the statistical analysis was performed between arms - Arm A: Single-agent Everolimus 10 mg QD and Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.08 to 2.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio and 95% CI were obtained using a stratified CMH model with prior lines of therapy and the international metastatic renal cell carcinoma database consortium risk category.
Other Statistical Analysis		As prespecified in protocol, the statistical analysis was performed between arms - Arm A: Single-agent Everolimus 10 mg QD and Arm C: Combination of MLN0128 4 mg QD + MLN1117 200 mg QD only for this outcome measure.

6. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
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 (up to 51 months)

Outcome Measure Data

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
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 end of study).	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 end of study).	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 end of study).
Measure Participants	32	32	31
Number [percentage of participants]	62.5 195.3%	50.0 156.3%	54.8 171.3%

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.24 to 1.69
	Parameter Dispersion	Type: Value:
	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.

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.28 to 2.21
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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 end of study).	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 end of study).	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 end of study).
Measure Participants	32	32	31
Number [percentage of participants]	40.6 126.9%	25.0 78.1%	29.0 90.6%

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.16 to 1.38
	Parameter Dispersion	Type: Value:
	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.

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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.20 to 1.80
	Parameter Dispersion	Type: Value:
	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.

Adverse Events

Time Frame	All-cause mortality: From first dose of study drug through end of the study (up to 51 months); Serious and other (non-serious) AEs: From first dose of study drug through 30 days after the last dose of study drug (up to 31 months)
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 (N= 32, 32, 32). Adverse Events: Data for is reported for Safety Analysis Set, including participants who received >=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
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 end of study).		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 end of study).		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 end of study).
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/32 (50%)		18/32 (56.3%)		19/32 (59.4%)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/32 (59.4%)		13/32 (40.6%)		15/31 (48.4%)
Blood and lymphatic system disorders
Anaemia	0/32 (0%)		0/32 (0%)		2/31 (6.5%)
Cardiac disorders
Acute myocardial infarction	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Cardiac failure	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Gastrointestinal disorders
Abdominal pain	0/32 (0%)		1/32 (3.1%)		1/31 (3.2%)
Ascites	0/32 (0%)		0/32 (0%)		2/31 (6.5%)
Diarrhoea	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Stomatitis	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
General disorders
Asthenia	0/32 (0%)		2/32 (6.3%)		1/31 (3.2%)
General physical health deterioration	1/32 (3.1%)		0/32 (0%)		1/31 (3.2%)
Pyrexia	1/32 (3.1%)		0/32 (0%)		1/31 (3.2%)
Fatigue	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Immune system disorders
Hypersensitivity	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Infections and infestations
Pneumonia	3/32 (9.4%)		0/32 (0%)		0/31 (0%)
Sepsis	2/32 (6.3%)		1/32 (3.1%)		0/31 (0%)
Septic shock	0/32 (0%)		1/32 (3.1%)		1/31 (3.2%)
Abscess jaw	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Pulmonary sepsis	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Injury, poisoning and procedural complications
Accidental overdose	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Femur fracture	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Pelvic fracture	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Road traffic accident	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Investigations
Haemoglobin decreased	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Transaminases increased	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Metabolism and nutrition disorders
Dehydration	1/32 (3.1%)		1/32 (3.1%)		0/31 (0%)
Hypercalcaemia	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Hyperglycaemia	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Musculoskeletal and connective tissue disorders
Bone pain	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Muscular weakness	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Pathological fracture	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic renal cell carcinoma	0/32 (0%)		2/32 (6.3%)		0/31 (0%)
Clear cell renal cell carcinoma	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
T-cell lymphoma	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Nervous system disorders
Cerebellar haemorrhage	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Psychiatric disorders
Confusional state	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Renal and urinary disorders
Acute kidney injury	0/32 (0%)		2/32 (6.3%)		1/31 (3.2%)
Chronic kidney disease	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Haematuria	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Renal failure	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Urinary retention	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/32 (3.1%)		1/32 (3.1%)		0/31 (0%)
Dyspnoea at rest	0/32 (0%)		1/32 (3.1%)		0/31 (0%)
Hiccups	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Pleural effusion	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Vascular disorders
Hypotension	0/32 (0%)		0/32 (0%)		1/31 (3.2%)
Infarction	1/32 (3.1%)		0/32 (0%)		0/31 (0%)
Other (Not Including 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/32 (100%)		29/32 (90.6%)		31/31 (100%)
Blood and lymphatic system disorders
Anaemia	4/32 (12.5%)		6/32 (18.8%)		4/31 (12.9%)
Leukocytosis	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Gastrointestinal disorders
Nausea	7/32 (21.9%)		22/32 (68.8%)		17/31 (54.8%)
Vomiting	7/32 (21.9%)		14/32 (43.8%)		13/31 (41.9%)
Diarrhoea	13/32 (40.6%)		8/32 (25%)		11/31 (35.5%)
Constipation	9/32 (28.1%)		12/32 (37.5%)		5/31 (16.1%)
Stomatitis	12/32 (37.5%)		6/32 (18.8%)		3/31 (9.7%)
Abdominal pain	5/32 (15.6%)		5/32 (15.6%)		6/31 (19.4%)
Dyspepsia	4/32 (12.5%)		4/32 (12.5%)		3/31 (9.7%)
Dry mouth	1/32 (3.1%)		2/32 (6.3%)		5/31 (16.1%)
Gastrooesophageal reflux disease	3/32 (9.4%)		1/32 (3.1%)		3/31 (9.7%)
Abdominal pain upper	2/32 (6.3%)		1/32 (3.1%)		2/31 (6.5%)
Mouth ulceration	3/32 (9.4%)		0/32 (0%)		1/31 (3.2%)
Dysphagia	1/32 (3.1%)		2/32 (6.3%)		0/31 (0%)
General disorders
Asthenia	19/32 (59.4%)		12/32 (37.5%)		9/31 (29%)
Fatigue	10/32 (31.3%)		6/32 (18.8%)		12/31 (38.7%)
Pyrexia	10/32 (31.3%)		3/32 (9.4%)		5/31 (16.1%)
Chest pain	2/32 (6.3%)		3/32 (9.4%)		1/31 (3.2%)
Influenza like illness	4/32 (12.5%)		1/32 (3.1%)		1/31 (3.2%)
Chills	2/32 (6.3%)		2/32 (6.3%)		1/31 (3.2%)
Oedema peripheral	4/32 (12.5%)		0/32 (0%)		0/31 (0%)
Pain	1/32 (3.1%)		1/32 (3.1%)		2/31 (6.5%)
Peripheral swelling	3/32 (9.4%)		0/32 (0%)		0/31 (0%)
Infections and infestations
Urinary tract infection	2/32 (6.3%)		2/32 (6.3%)		2/31 (6.5%)
Influenza	2/32 (6.3%)		0/32 (0%)		2/31 (6.5%)
Lower respiratory tract infection	0/32 (0%)		1/32 (3.1%)		2/31 (6.5%)
Pneumonia	2/32 (6.3%)		1/32 (3.1%)		0/31 (0%)
Upper respiratory tract infection	1/32 (3.1%)		2/32 (6.3%)		0/31 (0%)
Nasopharyngitis	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Investigations
Weight decreased	4/32 (12.5%)		9/32 (28.1%)		5/31 (16.1%)
Blood creatinine increased	2/32 (6.3%)		3/32 (9.4%)		2/31 (6.5%)
Alanine aminotransferase increased	0/32 (0%)		1/32 (3.1%)		4/31 (12.9%)
Gamma-glutamyltransferase increased	0/32 (0%)		1/32 (3.1%)		4/31 (12.9%)
Blood lactate dehydrogenase increased	1/32 (3.1%)		2/32 (6.3%)		0/31 (0%)
Amylase increased	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Aspartate aminotransferase increased	0/32 (0%)		0/32 (0%)		2/31 (6.5%)
Haemoglobin decreased	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Lipase increased	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Metabolism and nutrition disorders
Decreased appetite	15/32 (46.9%)		10/32 (31.3%)		11/31 (35.5%)
Hyperglycaemia	4/32 (12.5%)		4/32 (12.5%)		8/31 (25.8%)
Hypertriglyceridaemia	5/32 (15.6%)		2/32 (6.3%)		1/31 (3.2%)
Dehydration	1/32 (3.1%)		2/32 (6.3%)		1/31 (3.2%)
Hypercalcaemia	0/32 (0%)		2/32 (6.3%)		2/31 (6.5%)
Hypophosphataemia	1/32 (3.1%)		1/32 (3.1%)		2/31 (6.5%)
Hyperuricaemia	0/32 (0%)		3/32 (9.4%)		0/31 (0%)
Hypernatraemia	0/32 (0%)		2/32 (6.3%)		0/31 (0%)
Iron deficiency	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Metabolic acidosis	0/32 (0%)		2/32 (6.3%)		0/31 (0%)
Hyperkalaemia	0/32 (0%)		5/32 (15.6%)		2/31 (6.5%)
Musculoskeletal and connective tissue disorders
Back pain	5/32 (15.6%)		7/32 (21.9%)		2/31 (6.5%)
Pain in extremity	6/32 (18.8%)		2/32 (6.3%)		2/31 (6.5%)
Arthralgia	4/32 (12.5%)		1/32 (3.1%)		3/31 (9.7%)
Musculoskeletal pain	2/32 (6.3%)		2/32 (6.3%)		0/31 (0%)
Bone pain	2/32 (6.3%)		1/32 (3.1%)		0/31 (0%)
Groin pain	0/32 (0%)		2/32 (6.3%)		0/31 (0%)
Nervous system disorders
Headache	6/32 (18.8%)		4/32 (12.5%)		4/31 (12.9%)
Dizziness	3/32 (9.4%)		4/32 (12.5%)		0/31 (0%)
Dysgeusia	3/32 (9.4%)		0/32 (0%)		3/31 (9.7%)
Presyncope	3/32 (9.4%)		0/32 (0%)		0/31 (0%)
Tremor	1/32 (3.1%)		0/32 (0%)		2/31 (6.5%)
Memory impairment	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Somnolence	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Psychiatric disorders
Anxiety	3/32 (9.4%)		2/32 (6.3%)		2/31 (6.5%)
Insomnia	3/32 (9.4%)		2/32 (6.3%)		2/31 (6.5%)
Renal and urinary disorders
Haematuria	2/32 (6.3%)		1/32 (3.1%)		1/31 (3.2%)
Dysuria	2/32 (6.3%)		1/32 (3.1%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	10/32 (31.3%)		10/32 (31.3%)		5/31 (16.1%)
Cough	11/32 (34.4%)		10/32 (31.3%)		3/31 (9.7%)
Dyspnoea exertional	2/32 (6.3%)		2/32 (6.3%)		0/31 (0%)
Epistaxis	4/32 (12.5%)		0/32 (0%)		0/31 (0%)
Nasal dryness	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Skin and subcutaneous tissue disorders
Pruritus	3/32 (9.4%)		12/32 (37.5%)		6/31 (19.4%)
Rash	3/32 (9.4%)		3/32 (9.4%)		5/31 (16.1%)
Dermatitis acneiform	6/32 (18.8%)		2/32 (6.3%)		0/31 (0%)
Dry skin	4/32 (12.5%)		0/32 (0%)		3/31 (9.7%)
Rash maculo-papular	1/32 (3.1%)		1/32 (3.1%)		3/31 (9.7%)
Erythema	2/32 (6.3%)		0/32 (0%)		0/31 (0%)
Vascular disorders
Hypertension	6/32 (18.8%)		3/32 (9.4%)		4/31 (12.9%)
Hypotension	4/32 (12.5%)		1/32 (3.1%)		1/31 (3.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.