Trial to Assess Safety and Efficacy of Lenvatinib (18 mg vs. 14 mg) in Combination With Everolimus in Participants With Renal Cell Carcinoma

Renal Cell Carcinoma Clinical Trial

Official title:

A Randomized, Open-Label (Formerly Double-Blind), Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at Two Different Starting Doses (18 mg vs. 14 mg QD) in Combination With Everolimus (5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03173560
• Other study ID #: E7080-G000-218
• Secondary ID: 2016-002778-11
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 17, 2017
• Est. completion date: March 31, 2024

Study information

• Verified date: August 2023
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Study E7080-G000-218 is a Randomized, open-label (formerly Double-blind), Phase 2 Trial conducted to assess whether a starting dose of lenvatinib 14 milligrams (mg) in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate [ORR] at 24 weeks [ORR24W]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent intolerable Grade 2, or any greater than or equal to (>=) Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 343
• Est. completion date: March 31, 2024
• Est. primary completion date: February 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histological or cytological confirmation of predominant clear cell renal cell carcinoma (RCC) (original tissue diagnosis of RCC is acceptable)
• Documented evidence of advanced RCC
• One prior disease progression episode on or after vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) administered for the treatment of RCC. Prior programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) treatment in addition to 1 prior VEGF-targeted treatment is allowed.
• At least 1 measurable target lesion according to Response Evaluation Criteria in Solid

Tumors (RECIST 1.1) meeting the following criteria:

• Lymph node (LN) lesion that measures at least 1 dimension as >=1.5 centimeter (cm) in the short axis;
• Non-nodal lesion that measures >=1.0 cm in the longest diameter;
• The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion.
• Male or female participants age >=18 years (or any age >=18 years if that age is considered to be an adult per the local jurisdiction) at the time of informed consent
• Karnofsky Performance Status (KPS) of >=70
• Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to (<=) 150/90 millimeters of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1
• Adequate renal function defined as calculated creatinine clearance >=30 milliliters per minute (mL/min) per the Cockcroft and Gault formula
• Adequate bone marrow function defined by:
• Absolute neutrophil count (ANC) >=1500/millimeters cubed (mm^3) (>=1.5*10^9/Liters [L]);
• Platelets >=100,000/mm^3 (>=100*10^9/L);
• Hemoglobin >=9 grams per deciliter (g/dL)
• Adequate blood coagulation function defined by International Normalized Ratio (INR) <=1.5 (except for participants on warfarin therapy where INR must be <=3.0 prior to randomization)
• Adequate liver function defined by:
• Total bilirubin <=1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome;
• Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3* the ULN (in the case of liver metastases <=5* the ULN). Participants with bone metastases with ALP values greater than 3 times can be included.
• Participant must voluntarily agree to provide written informed consent
• Participant must be willing and able to comply with all aspects of the protocol

Exclusion Criteria:

• More than 1 prior VEGF-targeted treatment for advanced RCC
• Participants with Central Nervous System (CNS) metastases are not eligible, unless they have completed local therapy for at least 4 weeks and have discontinued the use of corticosteroids for this indication or are on a tapering regimen of corticosteroids (defined as <=10 mg prednisolone equivalent) before starting treatment in this study. Any signs (example, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.
• Active malignancy (except for RCC or definitively treated basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months
• Any anti-cancer treatment (except for radiation therapy) within 21 days, or any investigational agent within 30 days prior to the first dose of study drug; participants should have recovered from any toxicity related to previous anti-cancer treatment to Common Toxicity Criteria (CTC) grade 0 or 1.
• Prior radiation therapy within 21 days prior to the start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start
• Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity to rapamycins (example, sirolimus, everolimus, temsirolimus) or any of the excipients
• Participants with proteinuria greater than (>) 1+ on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 g/24 hour will be ineligible.
• Fasting total cholesterol ?300 mg/dL (or ?7.75 millimoles [mmol]/L) and/or fasting triglycerides level ?2.5* the ULN. Note: these participants can be included after initiation or adjustment of lipid-lowering medication.
• Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. Note: these participants can be included after initiation or adjustment of glucose-lowering medication.
• Prolongation of QT corrected (QTc) interval to >480 milliseconds (ms)
• Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
• Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib or everolimus
• Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (example, carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
• Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
• Significant cardiovascular impairment within 6 months prior to the first dose of study drug; history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke, or cardiac arrhythmia associated with significant cardiovascular impairment or left ventricular ejection fraction (LVEF) below the institutional normal range as determined by screening multigated acquisition (MUGA) scan or echocardiogram.
• Active infection (any infection requiring systemic treatment)
• Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study
• Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 International Units per Liter [IU/L] or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• Females of childbearing potential who (Note: all females will be considered to be of childbearing potential unless they are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [that is, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before

dosing].):

• do not agree to use a highly effective method of contraception for the entire

study period and for up to 8 weeks after study drug discontinuation, that is:

• total abstinence (if it is their preferred and usual lifestyle)
• an intrauterine device (IUD) or hormone releasing system (IUS)
• a contraceptive implant
• an oral contraceptive (with additional barrier method) (Note: Participants must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study.) OR
• do not have a vasectomized partner with confirmed azoospermia For sites outside of the European Union, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, that is, double barrier methods of contraception, such as condom plus diaphragm or cervical/vault cap with spermicide.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Renal Cell Carcinoma

Intervention

Drug:
• lenvatinib
lenvatinib capsules.
• everolimus
everolimus tablets.

Locations

Country	Name	City	State
Australia	Adelaide Cancer Center	Kurralta Park	South Australia
Australia	Macquarie University	Macquarie Park	New South Wales
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Sunshine Hospital	Saint Albans	Victoria
Australia	Northern Cancer Institute, Saint Leonards	Saint Leonards	New South Wales
Canada	Alberta Health Service - Tom Baker Cancer Centre	Calgary	Alberta
Canada	Juravinski Cancer Centre	Hamilton	Ontario
Canada	British Columbia Cancer Agency	Kelowna	British Columbia
Canada	London Health Sciences Centre	London	Ontario
Canada	Sir Mortimer B Davis Jewish General Hospital	Montreal	Quebec
Canada	Ottawa Hospital Cancer Centre	Ottawa	Ontario
Canada	Sunnybrook Research Institute- University of Toronto	Toronto	Ontario
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Fakultni nemocnice v Motole	Prague
Czechia	Nemocnice Na Bulovce	Prague
Finland	Helsingin Yliopistollinen Keskussairaala	Helsinki
Finland	Tampereen yliopistollinen sairaala	Tampere
Finland	Turun Yliopistollinen Keskussairaala	Turku
Finland	Vaasan Keskussairaala	Vaasa
Greece	Alexandra Hospital	Athens
Greece	Metropolitan hospital	Athens
Greece	University General Hospital of Patras	Patras
Greece	Interbalkan Medical Center of Thessaloniki	Pylaia
Greece	EUROMEDICA General Clinic of Thessaloniki	Thessaloniki
Greece	Papageorgiou General Hospital of Thessaloniki	Thessaloniki
Italy	Presidio Ospedaliero San Donato	Arezzo
Italy	IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia
Italy	AORN A Cardarelli	Napoli
Italy	Azienda Ospedaliera San Camillo Forlanini	Roma
Korea, Republic of	Chonnam National University Hwasun Hospital	Chonam
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggido
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital - Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul Saint Mary's Hospital	Seoul
Netherlands	Hagaziekenhuis	Den Haag
Netherlands	MC Haaglanden	Den Haag
Netherlands	Leids Universitair Medisch Centrum	Leiden
Poland	Szpital Specjalistyczny w Brzozowie	Brzozow
Poland	Copernicus PL Sp. z o.o. Wojewodzkie Centrum Onkologii	Gdansk
Poland	NZOZ Vesalius	Krakow
Poland	SP ZOZ Szpital Uniwersytecki w Krakowie	Krakow
Poland	Centrum Onkologii Ziemi Lubelskiej	Lublin
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Opolskie Centrum Onkologii	Opole
Poland	Mrukmed. Lekarz Beata Madej-Mruk i Partner. Spolka Partnerska	Rzeszow
Poland	MAGODENT Sp. z o.o. Szpital Elblaska	Warszawa
Portugal	Centro Hospitalar E Universitário de Coimbra EPE	Coimbra
Portugal	Champalimaud Cancer Center	Lisboa
Portugal	Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria	Lisbon
Portugal	Centro Hospitalar do Porto - Hospital de Santo António	Porto
Portugal	Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe	Porto
Romania	Medisprof SRL	Cluj-Napoca
Romania	Prof Dr I Chiricuta Institute of Oncology	Cluj-Napoca
Romania	Oncology Center Sfantul Nectarie	Craiova
Romania	Oncocenter Clinical Oncology	Timisoara
Russian Federation	Altay Regional Oncology Center	Barnaul
Russian Federation	Chelyabinsk Regional Clinical Oncology Dispensary	Chelyabinsk
Russian Federation	Central Clinical Hospital With Polyclinic of President Administration of RF	Moscow
Russian Federation	Moscow City Oncology Hospital #62	Moscow
Russian Federation	Moscow Scientific Research Oncology Institute P.A. Herzen	Moscow
Russian Federation	Federal State Institution Medical Radiology Research Center	Obninsk
Russian Federation	Clinical Oncology Dispensary	Omsk
Russian Federation	Regional Clinical Oncology Hospital	Yaroslavl
Spain	Hospital Universitario A Coruna	A Coruna
Spain	Hospital Universitario Germans Trias i Pujol	Badalona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital de la Santa Creu I Sant Pau	Barcelona
Spain	C.H. Regional Reina Sofia	Cordoba
Spain	ICO l'Hospitalet - Hospital Duran i Reynals	Hospitalet de Llobregat
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	Hospital Universitario Son Espases	Palma de Mallorca
Spain	Clinica Universidad Navarra	Pamplona
Spain	Fundacion Instituto Valenciano de Oncologia	Valencia
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Christie Hospital	Manchester
United Kingdom	Mount Vernon Hospital	Northwood
United Kingdom	Singleton Hospital	Swansea
United States	City of Hope National Medical Center	Duarte	California
United States	Texas Oncology PA - US Oncology	Fort Worth	Texas
United States	Optimal Research	Honolulu	Hawaii
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	Baptist Health Medical Group Oncology, LLC - US Oncology	Miami	Florida
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oklahoma Cancer Specialist and Research Institute , LLC	Tulsa	Oklahoma
United States	Innovative Clinical Research Institute, LLC	Whittier	California

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Czechia,  Finland,  Greece,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Romania,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate at Week 24 (ORR24W)	ORR24W was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at the Week 24 (after randomization) time point, during treatment or within 28 days after the last dose date but on or prior to the start of new anticancer therapy based on investigator assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 millimeters (mm). PR: defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response.	At Week 24
Primary	Percentage of Participants With Intolerable Grade 2 or Any Grade >=Grade 3 TEAEs Within 24 Weeks	TEAE was defined as an adverse event (AE) with an onset that had occurred after receiving study drug. A severity grade was defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. As per NCI-CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.	Up to Week 24
Secondary	Progression-free Survival (PFS)	PFS was defined as the time from the date of randomization to the date of the first documentation of PD by investigator assessment or date of death, whichever occurred first according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter (SOD) of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% confidence interval (CI).	From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to date of data cutoff for the primary analysis (up to 29 months)
Secondary	Objective Response Rate (ORR)	ORR was defined as the percentage of participants with a BOR of CR or PR at the at the end of treatment based on investigator assessment according to RECIST v1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR: defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response.	From date of randomization up to first documentation of PD or date of death, whichever occurred first or up to the date of data cut off for the primary analysis (up to 29 months)
Secondary	Number of Participants With TEAEs and Serious TEAEs	TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A serious adverse event (SAE) was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect.	From date of first dose of study drug up to 28 days after last dose of study drug, or date of data cut off for the primary analysis (up to 29 months)
Secondary	Percentage of Participants Who Discontinued Treatment Due to Toxicity	Percentage of participants who discontinued treatment due to toxicity, defined as the percentage of participants who discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to NCI-CTCAE v4.03.	From date of first dose of study drug up to 28 days after last dose of study drug, or date of data cut off for the primary analysis (up to 29 months)
Secondary	Time to Treatment Failure Due to Toxicity	Time to treatment failure due to toxicity was defined as the time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to CTCAE v4.03.	From the date of randomization to the date of discontinuation of study treatment due to TEAEs, or date of data cut off for the primary analysis (up to 29 months)
Secondary	Overall Survival (OS)	OS was defined as the time from the date of randomization until the date of death from any cause. In the absence of confirmation of death, participants will be censored either at the date that the participant was last known to be alive or the date of data cutoff for the primary analysis, whichever comes earlier. Median OS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.	From the date of randomization until the date of death from any cause, or up to date of data cut off for the primary analysis (up to 29 months)
Secondary	Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores	The FKSI-DRS consisted of 9 items that experts and participants had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes.	At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
Secondary	HRQoL Assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 Scores	The EORT QLQ-C30 consisted of 30 questions comprising 9 multiple-item scales and 6 single items. Multiple-item scales of QLQ-C30 consisted of 5 functional scales (physical, role, emotional, cognitive, and social) and 3 symptom scales (fatigue, nausea and vomiting, pain) and a global health status/QOL score. Six single-item scales of QLQ-C30 involved dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties. First 28 questions used a 4-point scale (1 = Not at all to 4 = Very much); and last 2 questions used a 7-point scale (1 = Very poor to 7 = Excellent). Scores for all scales range from 0 to 100. For the overall HRQoL and functioning scales, a higher score was correlated with better HRQoL, whereas a higher score for symptom scales represented worse HRQoL.	At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
Secondary	HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS)	The EQ-5D-3L is a health profile questionnaire assessing quality of life along 5 dimensions. Participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 5-15 with "5" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. The EQ-5D index was calculated by applying preference-based weights (tariffs) to the scores of the five health state dimensions. Index values can range from -1 to 1, with 0 representing a health state equivalent to death and 1 representing perfect health. EQ-5D-3L also included an EQ visual analogue scale (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best).	At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
Secondary	Progression-free Survival After Next Line of Therapy (PFS2)	PFS2, defined as the time from randomization to the date of PD after next line of therapy or death from any cause, whichever occurred first based on investigator assessment according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS2 was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% CI.	From the time of randomization to the date of PD after next line of therapy or death from any cause or the date of data cutoff for the primary analysis, whichever occurs first (up to 29 months)