Advanced/unresectable or metastatic urothelial carcinoma MedDRA version: 20.0 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Have a histologically or cytologically confirmed diagnosis of advanced/unresectable or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra. Both transitional cell and mixed transitional/nontransitional cell histology are allowed, but transitional cell carcinoma must be the predominant histology 2. Have at least 1 measurable target lesion per RECIST 1.1 as assessed by the local site investigator/radiologist, per the following criteria: 1) lymph node lesion measuring =15 mm in the short axis; 2) non-nodal lesion measuring =10 mm in the longest diameter; 3) lesion suitable for repeat measurement with CT/MRI imaging. Lesions in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions 3. Have provided an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated and adequate for PD-L1 evaluation. Formalin-fixed, paraffin-embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. PD-L1 status (CPS =10 or CPS 12 months from completion of the therapy is permitted - Adjuvant platinum-based chemotherapy following radical cystectomy, with recurrence >12 months from completion of the therapy, is permitted 5. Meet criteria for either option a or option b: a. Have a tumor(s) with PD-L1 CPS =10 and be considered ineligible to receive cisplatin-based combination therapy, based on 1 of the following: - ECOG PS 2 within 7 days prior to randomization - CrCl (calculated or measured using the institutional standard) =30 to =60 mL/min - NCI CTCAE Version 4.0 Grade=2 audiometric hearing loss - NCI CTCAE Version 4.0 Grade=2 audiometric hearing loss (25 dB in 2 consecutive frequency ranges) - NCI CTCAE Version 4.0 Grade=2 peripheral neuropathy OR b. In the opinion of the investigator, be considered ineligible to receive any platinum-based chemotherapy (ie, ineligible for cisplatin and carboplatin) based on: - ECOG PS 2 within 7 days prior to randomization and at least 1 of the following: - Documented visceral metastatic disease - CrCl=30 to =60 mL/min - NCI CTCAE Version 4.0 Grade=2 audiometric hearing loss - NCI CTCAE Version 4.0 Grade=2 peripheral neuropathy - Other reason, identified on the case report form, for the participant’s being unable to receive both cisplatin and carboplatin safely. Additional criteria for platinum ineligibility will be considered and allowed on a case-by-case basis, following consultation with the Sponsor 6. Be male or female and=18 years of age and considered an adult per local regulations on the day of signing the informed consent 7. Have ECOG PS 0, 1, or 2 within 7 days prior to randomization and a life expectancy of=3 months 8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of pembrolizumab or lenvatinib/placebo: - Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR - Must agree to use contraception unless confirmed to be azoospermic as detailed below: - Agree to use a
Exclusion criteria
Exclusion criteria: 1. Has disease that is suitable for local therapy administered with curative intent 2. Has tumor with any neuroendocrine or small cell component 3. Has a history of a gastrointestinal condition or procedure (eg, gastric bypass, malabsorption) that, in the opinion of the investigator, may affect oral drug absorption 4. Has had major surgery within 3 weeks prior to the first dose of study intervention 5. Has a pre-existing Grade=3 gastrointestinal or non-gastrointestinal fistula 6. Has radiographic evidence of major blood vessel invasion/infiltration, or has had clinically significant hemoptysis (at least 0.5 teaspoon of bright red blood) or tumor bleeding within 2 weeks prior to the first dose of study intervention 7. Has had significant cardiovascular impairment within 12 months of the first dose of study intervention 8. Has known intolerance or severe hypersensitivity (Grade =3) to pembrolizumab or lenvatinib or any of their excipients 9. Has received lenvatinib as monotherapy or in combination with a PD-1/PD-L1 inhibitor or has previously been enrolled in a clinical study evaluating lenvatinib for bladder cancer, regardless of the treatment received 10. Is a WOCBP who has a positive urine pregnancy test within 24 hours before randomization 11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitor, indoleamine-pyrrole 2,3 dioxygenase (IDO1) inhibitor, or agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), or any other antibody or drug targeting T-cell costimulatory pathways in the adjuvant or advanced/metastatic setting 12. Has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study intervention, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study intervention. Participants must have recovered from all radiation-related toxicities, and must not require corticosteroids 13. Has received a live vaccine within 30 days prior to the first dose of study intervention 14. In the investigator’s judgment, has not recovered from toxicity or other complications from any major surgery prior to starting study intervention 15. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention 16. Has an LVEF below the institutional normal range, as determined by MUGA or ECHO 17. Has history or presence of an abnormal ECG that, in the investigator’s opinion, is clinically meaningful 18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization 19. Has had an active malignancy (except locally advanced or metastatic UC) within the past 36 months 20. Has central nervous system (CNS) metastases, unless the participant has completed local therapy and has discontinued use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs or symptoms of CNS metastases must be stable for at least 4 weeks before starting study intervention 21. Has an active autoimmune disease that has required systemic treatment in the past 2 years. 22. Has a history of (non-infectious) pneumonitis that required systemic
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To compare pembrolizumab (MK-3475) + lenvatinib (MK-7902) to pembrolizumab + placebo with respect to Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) 2. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to Overall Survival (OS) NOTE: As of Amendment 011-03, lenvatinib and matching placebo have been removed from the study. All participants remaining on study will continue on open-label pembrolizumab monotherapy. No further analyses of efficacy endpoints will be performed. Exploratory objectives may not be pursued.;Secondary Objective: 1. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) 2. To evaluate the safety and tolerability of treatment with pembrolizumab + lenvatinib versus pembrolizumab + placebo 3. To evaluate pembrolizumab + lenvatinib and pembrolizumab + placebo with respect to Duration of Response (DOR) per RECIST 1.1 by Blinded Independent Central Review (BICR) 4. To evaluate pembrolizumab + lenvatinib and pembrolizumab + placebo with respect to Disease Control Rate (DCR) per RECIST 1.1 by Blinded Independent Central Review (BICR) 5. To evaluate changes in patient-reported outcomes (PROs) from Baseline and Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29)/Quality of Life (Item 30);Primary end point(s): 1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) 2. Overall Survival (OS);Timepoint(s) of evaluation of this end point: 1. Up to approximately 40 months 2. Up to approximately 40 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) 2. Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) 3. Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) 4. Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score 5. Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score 6. Number of Participants Who Experience an Adverse Event (AE) 7. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE);Timepoint(s) of evaluation of this end point: 1. Up to approximately 40 months 2. Up to approximately 40 months 3. Up to approximately 40 months 4. Up to approximately 40 months 5. Baseline and up to approximately 40 months 6. Up to approximately 40 months 7. Up to approximately 40 months | — |
Countries
Argentina, Australia, Canada, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Taiwan, Turkey, United Kingdom, United States
Outcome results
None listed