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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. )

Tracking Information
First Submitted Date  ICMJE March 25, 2016
First Posted Date  ICMJE March 31, 2016
Results First Submitted Date  ICMJE February 1, 2021
Results First Posted Date  ICMJE February 21, 2021
Last Update Posted Date February 21, 2021
Actual Study Start Date  ICMJE June 30, 2016
Actual Primary Completion Date February 3, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 1, 2021)
Progression-Free Survival (PFS) [ Time Frame: From first dose of study drug up to disease progression or death (approximately 30 months up to data cut-off) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 30, 2016)
Progression-Free Survival (PFS) [ Time Frame: From first dose of study drug to disease progression or death (approximately 3 years) ]
PFS is defined as the time from the date of randomization to the date of first documentation of Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 or death due to any cause, whichever occurs first. For a participant whose disease has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is Stable Disease (SD) or better. PD is 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 1, 2021)
  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ 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) ]
    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.
  • Overall Survival (OS) [ 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) ]
    Overall survival in months was defined as the time from the date of randomization to the date of death.
  • Time-to-progression (TTP) [ Time Frame: From first dose of study drug up to disease progression or death (approximately 30 months up to data cut-off) ]
    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.
  • Objective Response Rate (ORR) [ Time Frame: From first dose of study drug to disease progression or death (approximately 30 months up to data cut-off) ]
    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.
  • Clinical Benefit Rate (CBR) [ Time Frame: From first dose of study drug up to disease progression or death (approximately 30 months up to data cut-off) ]
    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.
  • CBR With SD Duration of at Least 16 Weeks [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2016)
  • Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug through 30 days after the last dose of study drug (up to 27 months) ]
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
  • Overall Survival (OS) [ Time Frame: From first dose of study drug to death (approximately 3 Years) ]
    Overall survival is defined as the time from the date of randomization to the date of death. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.
  • Time-to-progression (TTP) [ Time Frame: From first dose of study drug until disease progression, or death which occurs first (approximately 3 Years) ]
    Time-to-progression is defined as the time from the date of randomization to the date of first documentation of PD. For a participant whose disease has not progressed, TTP will be censored at the last response assessment that is Stable Disease or better. PD is 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.
  • Objective Response Rate (ORR) [ Time Frame: From first dose of study drug until discontinuation of study drug due to disease progression, unacceptable toxicity, or death which occurs first (approximately 24 months) ]
    ORR is defined as the percentage of participants who achieve a best response of complete response (CR) or partial response (PR) according to RECIST Version 1.1. CR is defined as the disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR is defined as at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the Baseline sum LD.
  • Clinical Benefit Rate (CBR) [ Time Frame: From first dose study drug until discontinuation of study drug due to disease progression, unacceptable toxicity, or death which occurs first (approximately 24 months) ]
    CBR is defined as the percentage of participants who achieve a best response of complete response (CR), partial response (PR) or stable disease (SD) according to RECIST Version 1.1 and will be reported for both CBR with any duration SD and CBR with SD duration of at least 4 months. CR is defined as the disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR is defined as at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the Baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MLN0128 and MLN0128 + MLN1117 Compared With Everolimus in the Treatment of Adults With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Clear-cell Metastatic Renal Cell Carcinoma
Intervention  ICMJE
  • Drug: Everolimus
    Everolimus capsules.
  • Drug: MLN0128
    MLN0128 capsules.
    Other Names:
    • TAK-228
    • INK0128
  • Drug: MLN1117
    MLN1117 capsules.
    Other Names:
    • TAK-117
    • INK1117
Study Arms  ICMJE
  • Active Comparator: Arm A: Single-agent Everolimus 10 mg QD
    Everolimus 10 mg capsules, orally, once daily (QD) 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).
    Intervention: Drug: Everolimus
  • Experimental: Arm B: Single-agent MLN0128 30 mg QW
    MLN0128 30 mg capsules, orally, once weekly (QW) 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).
    Intervention: Drug: MLN0128
  • 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 data cut-off: 6 March 2020).
    Interventions:
    • Drug: MLN0128
    • Drug: MLN1117
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 13, 2018)
96
Original Estimated Enrollment  ICMJE
 (submitted: March 30, 2016)
189
Actual Study Completion Date  ICMJE October 13, 2020
Actual Primary Completion Date February 3, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy,   Canada,   Czechia,   France,   Poland,   Spain,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Hungary,   Russian Federation
 
Administrative Information
NCT Number  ICMJE NCT02724020
Other Study ID Numbers  ICMJE C31005
2015-002133-22 ( EudraCT Number )
U1111-1172-1808 ( Registry Identifier: WHO )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/
Responsible Party Takeda ( Millennium Pharmaceuticals, Inc. )
Study Sponsor  ICMJE Millennium Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Takeda
PRS Account Takeda
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP