| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced/unresectable or metastatic urothelial carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Urothelial cancer (also known as transition cell carcinoma of the bladder) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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) |
|
| E.2.2 | Secondary objectives of the trial |
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) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (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 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 95 days after the last dose of pembrolizumab or lenvatinib/placebo and refrain from donating sperm during this period:
- 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 intercourse with a WOCBP who is not currently pregnant
9. A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions applies:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective with low user dependency, or be abstinent from heterosexual intercourse as her preferred and usual lifestyle, during the intervention period and for at least 120 days after the last dose of pembrolizumab or lenvatinib/placebo
- A WOCBP must have a negative highly sensitive pregnancy test within 72 hours before the first dose of study intervention
- If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk of including a woman with an early undetected pregnancy
10. The participant (or legally acceptable representative if applicable) provides written informed consent for the study
11. Have adequately controlled BP with or without antihypertensive medications, defined as BP≤140/90 mm Hg at screening and no change in antihypertensive medications within 1 week prior to randomization
12. Have adequate organ function |
|
| E.4 | Principal 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 4 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 72 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 steroids, or current pneumonitis
23. Has an active infection requiring systemic therapy
24. Has a known history of human immunodeficiency virus (HIV) infection
25. Has a known history of or is positive for active hepatitis B or has active hepatitis C
26. Has active tuberculosis
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
28. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
29. Is receiving hemodialysis
30. A participant with urine protein ≥1 g/24 h will be excluded
31. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab and lenvatinib/placebo
32. Has had an allogeneic tissue/solid organ transplan |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR)
2. Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 4 years
2. Up to approximately 4 years |
|
| E.5.2 | 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. Number of Participants Who Experience an Adverse Event (AE)
3. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
4. Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR)
5. Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR)
6. 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
7. 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 4 years
2. Up to approximately 4 years
3. Up to approximately 4 years
4. Up to approximately 4 years
5. Up to approximately 4 years
6. Baseline and up to approximately 4 years
7. Up to approximately 4 years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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