Phase 3 Study of First-line Pembrolizumab With or Without Lenvatinib in Urothelial Carcinoma in Cisplatin-ineligible Participants Whose Tumors Express PD-L1 and Participants Ineligible for Any Platinum-containing Chemotherapy

Phase 1

• Conditions: Advanced/unresectable or metastatic urothelial carcinoma; MedDRA version: 20.0Level: LLTClassification code 10064467Term: Urothelial carcinomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-003752-21-PL
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2019-04-01
• Last Update Posted: 29 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 694

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 <10) must be obtained by the central laboratory during the screening period prior to enrollment
4. Have received no prior systemic chemotherapy for advanced or metastatic UC with the following exceptions:
- Neoadjuvant platinum-based chemotherapy for treatment of muscle-invasive bladder cancer with recurrence >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 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 male condom plus partner use of an additional contraceptive method when having penile-vaginal int

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified