Clinical trial NCT02724020: MLN0128 and MLN0128 + MLN1117 Compared With Everolimus in the Treatment of Adults With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Clear-cell Metastatic Renal Cell Carcinoma
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-03-31
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: From first dose of study drug up to disease progression or death, assessed up to 43 months
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From first dose of study drug through 30 days after the last dose of study drug (approximately up to 31 months)
measure: Overall Survival (OS)
timeFrame: From first dose of study drug through 30 days after the last dose of study drug (up to 51 months)
measure: Time-to-progression (TTP)
timeFrame: From first dose of study drug up to disease progression or death (up to 51 months)
measure: Objective Response Rate (ORR)
timeFrame: From first dose of study drug to disease progression or death (up to 51 months)
measure: Clinical Benefit Rate (CBR)
timeFrame: From first dose of study drug up to disease progression or death (up to 51 months)
measure: CBR With SD Duration of at Least 16 Weeks
timeFrame: Up to Week 16
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Venice
country: United States
facility: Florida Cancer Specialists-Broadway
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Hackensack
country: United States
facility: Hackensack University Medical Center PARTNER
state: New Jersey
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital
state: Ohio
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Weatherford
country: United States
facility: The Center for Cancer and Blood Disorders
state: Texas
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny v Brne
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Prague 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Bordeaux cedex
country: France
facility: Groupe Hospitalier Saint Andre - Hopital Saint Andre
state: Aquitaine
city: Vandoeuvre les Nancy Cedex
country: France
facility: ICL-Alexis Vautrin, Departement dOncologie Medicale
state: Meurthe Et Moselle
city: Paris cedex 13
country: France
facility: Groupe Hospitalier Pitie-Salpetriere
state: Paris
city: Angers Cedex 9
country: France
facility: Institut de Cancerologie de l'Ouest Paul Papin
state: PAYS DE LA Loire
city: Le Mans Cedex 02
country: France
facility: Clinique Victor Hugo - Centre Jean Bernard
state: Sarthe
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G. Pascale
city: Padova
country: Italy
facility: IOV - Istituto Oncologico Veneto IRCCS
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Bielsko-Biala
country: Poland
facility: Beskidzkie Centrum Onkologii im.Jana Pawla II
city: Lodz
country: Poland
facility: Instytut MSF, Ulica Pilota Stanislawa Wigury 19
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Madrid
country: Spain
facility: MD Anderson Cancer Centre
city: Madrid
country: Spain
facility: Hospital Universitario Ramon Y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital (Wonford)
state: Devon
city: Blackburn
country: United Kingdom
facility: Lancashire Teaching Hospitals NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: Barts Hospital
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie
state: Greater Manchester
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
state: South Glamorgan
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: Surrey
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References: