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

NCT ID: NCT02724020

Last Updated: 2021-11-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 96 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2020-10-13

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.

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.

Conditions

Clear-cell Metastatic Renal Cell Carcinoma

Keywords

Drug therapy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: ACTIVE_COMPARATOR

Everolimus

Intervention Type: DRUG

Everolimus capsules.

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).

Group Type: EXPERIMENTAL

MLN0128

Intervention Type: DRUG

MLN0128 capsules.

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).

Group Type: EXPERIMENTAL

MLN0128

Intervention Type: DRUG

MLN0128 capsules.

MLN1117

Intervention Type: DRUG

MLN1117 capsules.

Interventions

Everolimus

Everolimus capsules.

Intervention Type: DRUG

MLN0128

MLN0128 capsules.

Intervention Type: DRUG

MLN1117

MLN1117 capsules.

Intervention Type: DRUG

Other Intervention Names

TAK-228; INK0128; TAK-117; INK1117

Eligibility Criteria

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.

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

10. 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.

11. 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.

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

13. 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.

8. 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).

9. 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.

10. 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.

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

USC Norris Comprehensive Cancer Center

Los Angeles, California, United States

Florida Cancer Specialists-Broadway

Venice, Florida, United States

Florida Cancer Specialists

West Palm Beach, Florida, United States

Hackensack University Medical Center PARTNER

Hackensack, New Jersey, United States

The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital

Columbus, Ohio, United States

Tennessee Oncology

Nashville, Tennessee, United States

The Center for Cancer and Blood Disorders

Weatherford, Texas, United States

CancerCare Manitoba

Winnipeg, Manitoba, Canada

McMaster University

Hamilton, Ontario, Canada

Fakultni nemocnice u sv. Anny v Brne

Brno, , Czechia

Fakultni nemocnice Olomouc

Olomouc, , Czechia

Fakultni nemocnice v Motole

Prague, , Czechia

Groupe Hospitalier Saint Andre - Hopital Saint Andre

Bordeaux, Aquitaine, France

ICL-Alexis Vautrin, Departement dOncologie Medicale

Vandœuvre-lès-Nancy, Meurthe Et Moselle, France

Groupe Hospitalier Pitie-Salpetriere

Paris, Paris, France

Institut de Cancerologie de l'Ouest Paul Papin

Angers, Pays de la Loire Region, France

Clinique Victor Hugo - Centre Jean Bernard

Le Mans, Sarthe, France

Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi

Bologna, , Italy

Istituto Nazionale Tumori Fondazione G. Pascale

Napoli, , Italy

IOV - Istituto Oncologico Veneto IRCCS

Padua, , Italy

Fondazione IRCCS Policlinico San Matteo

Pavia, , Italy

Beskidzkie Centrum Onkologii im.Jana Pawla II

Bielsko-Biala, , Poland

Instytut MSF, Ulica Pilota Stanislawa Wigury 19

Lodz, , Poland

Hospital Duran i Reynals

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Hospital Clinic i Provincial de Barcelona

Barcelona, , Spain

MD Anderson Cancer Centre

Madrid, , Spain

Hospital Universitario Ramon Y Cajal

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Royal Devon and Exeter Hospital (Wonford)

Exeter, Devon, United Kingdom

Lancashire Teaching Hospitals NHS Foundation Trust

Blackburn, England, United Kingdom

Barts Hospital

London, Greater London, United Kingdom

The Christie

Manchester, Greater Manchester, United Kingdom

Velindre Cancer Centre

Cardiff, South Glamorgan, United Kingdom

Royal Surrey County Hospital

Guildford, Surrey, United Kingdom

Countries

Hungary; Russia; United States; Canada; Czechia; France; Italy; Poland; Spain; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-002133-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1172-1808

Identifier Type: REGISTRY

Identifier Source: secondary_id

C31005

Identifier Type: -

Identifier Source: org_study_id