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. 2023 May 4;2023(5):CD013798. doi: 10.1002/14651858.CD013798.pub2

NCT02811861.

Study characteristics
Methods Study name: CLEAR
Study design: RCT, phase III (three‐arm trial)
Blinding: none, open‐label
Study dates: October 13, 2007 ‐ July 24, 2019 (date of randomisation)
Date of data cut‐off: August 28, 2020 (for final analysis of PFS and interim analysis of OS)
Location: 20 countries (Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Greece, Ireland, Israel, Italy, Japan, Republic of Korea, the Netherlands, Poland, Russian Federation, Spain, Switzerland, UK USA), types of centres: hospitals, university hospitals, medial centres, cancer centres (183 study locations)
Cross‐over study or cross over permitted: not a cross‐over study; not reported whether cross over was permitted at some point (e.g. after progression)
Participants Inclusion criteria:

  • histological or cytological confirmation of renal cell carcinoma (RCC) with a clear‐cell component

  • at least 1 measurable target lesion according to Response Evaluation in Solid Tumors (RECIST) 1.1

  • Karnofsky Performance Status (KPS) of ≥70

  • adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week prior to Cycle 1/Day 1 (C1/D1)

  • adequate organ function per blood work


Exclusion criteria:

  • participants who have received any systemic anticancer therapy for RCC, including anti‐vascular endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer agent

  • participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy (e.g. whole brain radiation therapy (WBRT), surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (e.g. radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study treatment

  • active malignancy (except for RCC, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in‐situ of the cervix or bladder) within the past 24 months. Participants with history of localised and low risk prostate cancer are allowed in the study if they were treated with curative intent and there is no prostate specific antigen (PSA) recurrence within the past 5 years

  • prior radiation therapy within 21 days prior to 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


More exclusion criteria on CT.gov.
Sample size: N = 1069
Age, median (years, range): experimental arm I: 62 (32‐86), experimental arm II: 64 (34‐88), control arm: 61 (29‐82)
Sex (m/f): experimental arm I: 266/91, experimental arm II: 255/100, control arm: 275/82
Prognostic factors:

  • MSKCC prognostic risk group, n(%)

    • Favourable

      • experimental arm I: 98 (27.5), experimental arm II: 96 (27.0) , control arm: 97 (27.2)

    • Intermediate

      • experimental arm I: 227 (63.9), experimental arm II: 227 (63.9), control arm: 228 (63.9)

    • Poor

      • experimental arm I: 42 (11.8), experimental arm II: 33 (9.3), control arm: 37 (10.4)

    • Could not be evaluated

      • experimental arm I: 6 (1.7), experimental arm II: 2 (0.6), control arm: 4 (1.1)

  • IMDC prognostic risk group, n(%)

    • Favourable

      • experimental arm I: 114 (31.9), experimental arm II: 110 (31.0), control arm: 124 (34.7)

    • Intermediate

      • experimental arm I: 195 (54.6), experimental arm II: 210 (59.2) , control arm: 192 (53.8)

    • Poor

      • experimental arm I: 42 (11.8), experimental arm II: 33 (9.3), control arm: 37 (10.4)

    • Could not be evaluated

      • experimental arm I: 6 (1.7), experimental arm II: 2 (0.6), control arm: 4 (1.1)

  • Previous nephrectomy, n(%)

    • Yes

      • experimental arm: 260 (72.8), experimental arm II: 262 (73.8), control arm: 275 (77.0)
Interventions Experimental arm I (n = 355): lenvatinib (18 mg, oral, once/day) + Everolimus (5mg, oral, once/day)
Experimental arm II (n = 352): lenvatinib (20 mg, oral, once/day), Pembrolizumab (200mg, intravenous, every 3 weeks)
Control arm (n=340): Sunitinib (50 mg, oral, once/day) ‐ treatment was 4 weeks on treatment, 2 weeks off treatment (1 cycle = 6 weeks)
Outcomes Primary outcome(s)

  • PFS by independent review (time frame: up to 47 months approximately)


Secondary outcome(s)

  • OS (time frame: up to 67 months approximately)

  • Number of TEAEs and SAEs (time frame: up to 67 months approximately)

  • Number of participants who discontinued treatment due to toxicity (time frame: up to 67 months approximately)

  • Health‐related QoL scores (time frame: up to 47 months)

  • PFS by investigator assessment (time frame: up to 47 months approximately)


Relevant to this review but not reported: TFST
Other outcomes (not relevant to this review): PFS on next‐line therapy, ORR, TTF, AUC, time of clearance
Notes Funding sources: Eisai and Merck Sharp and Dohme
Declaration of Interest: Disclosure forms provided by the authors are available at NEJM.org.
Clinical study report available: no
Study protocol available: yes
Statistical analysis plan available: yes