E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced/unresectable or metastatic urothelial carcinoma previously untreated for their advanced disease |
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E.1.1.1 | Medical condition in easily understood language |
Locally advanced or metastatic bladder cancer |
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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 |
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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. Part 1: To evaluate ORR in participants treated with MK-4280A plus EV (Arm A), MK-7684A plus EV (Arm B), and pembrolizumab plus EV (Arm C) per RECIST 1.1 by BICR. 2. Part 1: To evaluate the safety and tolerability in participants treated with MK-4280A plus EV (Arm A), MK-7684A plus EV (Arm B), and pembrolizumab plus EV (Arm C). 3. Part 2: To compare EV plus MK-4280A (Arm A) and/or EV plus MK-7684A (Arm B) to EV plus pembrolizumab (Arm C) with respect to PFS per RECIST 1.1 by BICR. |
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E.2.2 | Secondary objectives of the trial |
1. Part 1: To evaluate PFS in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), & pembrolizumab + EV (Arm C) per RECIST 1.1 by BICR 2. Part 2: To compare EV + MK-4280A (Arm A) and/or EV + MK-7684A (Arm B) versus EV + pembrolizumab (Arm C) with respect to OS 3. Part 2: To evaluate ORR in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), & pembrolizumab + EV (Arm C) per RECIST 1.1 by BICR 4. Part 2: To evaluate safety and tolerability in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), & pembrolizumab + EV (Arm C) 5. Part 1 and Part 2: To evaluate DOR in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B), and pembrolizumab + EV (Arm C) per RECIST 1.1 by BICR 6. Part 1 and Part 2: To evaluate changes in patient-reported outcomes from baseline and TTD using the EORTC QLQ-C30 instrument and EQ-5D-5L in participants treated with MK-4280A + EV (Arm A), MK-7684A + EV (Arm B) & pembrolizumab + EV (Arm C) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The participants must have histologically documented, la/mUC (ie, cancer of the bladder, renal pelvis, ureter, or urethra). Histology will be confirmed locally. • Participants with mixed histology are eligible provided the urothelial component is ≥50% (and <10% plasmacytoid component). • Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally). 2. Participants must have measurable disease by investigator assessment according to RECIST 1.1. • Participants treated with prior radiation therapy must have measurable disease per RECIST 1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy. • Participants who have completed radiotherapy at least 2 weeks prior to randomization may be eligible. Participant must have recovered adequately from the toxicity from the intervention prior to starting study treatment. 3. Participants must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease settings are permitted: • Participants that received neoadjuvant or adjuvant chemotherapy are permitted. • Participants who received anti-PD-1 or PD-L1 therapy for an earlier disease stage with progressive/recurrence >12 months from completion of therapy are permitted. 4. Participants must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable. 5. Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have <Grade 2 neuropathy are eligible. 6. Is male or female, and ≥18 years at the time the participant provides documented informed consent for the study. 7. If male, agrees to the following during the intervention period and for at least 180 days after the last dose of EV: • Refrains from donating sperm PLUS either: • Abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent OR • Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below: - Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. - Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Not a WOCBP OR • A WOCBP and: - Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the intervention period and for at least 120 days (MK-4280A, MK-7684A, or pembrolizumab) or 180 days (EV) after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. - Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. - Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention (for MK-4280A, MK-7684A, or pembrolizumab) or 180 days (EV) days after the last dose of study intervention. - Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy. 9. Provides documented informed consent/assent for the study (either the participant or a legally acceptable representative, if applicable). 10. An ECOG performance status of 0 to 1 assessed within 7 days prior to randomization. 11. Adequate organ function. |
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E.4 | Principal exclusion criteria |
1. Known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy. 2. Participants with treated CNS metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease. 3. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, LAG3, TIGIT, OX-40, CD137). Exception includes participants who received neo-adjuvant or adjuvant anti-PD-1 or PD-L1 therapy for an earlier disease stage (eg, MIUC) with recurrence >12 months from completion of therapy. 4. Received therapy with hematopoietic growth factor such as G-CSF or GM-CSF within 14 days prior to randomization. 5. Received prior systemic anticancer therapy including investigational agents (including EV or other MMAE-based ADCs) within 3 years prior to randomization. Exception includes participants that received neoadjuvant or adjuvant chemotherapy or anti-PD-1/L1 therapy for an earlier disease stage (eg, MIUC). 6. Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. 7. Has received an investigational agent or has used an investigational device within 4 weeks prior to the study intervention administration. 8. Ongoing sensory or motor neuropathy Grade 2 or higher. 9. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency. 10. Severe hypersensitivity (≥Grade 3) to mAb (including pembrolizumab) and/or any of their excipients. 11. Known severe hypersensitivity (≥Grade 3) to any excipient contained in the drug formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20). 12. Active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator. 13. Active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid). 14. A history of uncontrolled diabetes. Uncontrolled diabetes is defined as HbA1c ≥8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. 15. A history of (noninfectious) pneumonitis that required steroids or has current pneumonitis. 16. An active infection (viral, bacterial, or fungal) requiring systemic therapy. Participant may be rescreened after resolution of the infection. 17. A known history of HIV infection. No HIV testing is required unless mandated by local health authority. 18. Hepatitis B (defined as HBsAg reactive) or hepatitis C virus (defined as HCV RNA qualitative is detected) infection. 19. 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. 20. A known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. 21. Had major surgery within 4 weeks prior to first dose of study intervention. 22. Has had an allogenic tissue/solid organ transplant. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Part 1: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by Blinded Independent Central Review (BICR) 2. Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE) 3. Part 1: Percentage of Participants Who Discontinued Study Treatment Due to an AE 4. Part 1: Percentage of Participants Who Experienced at Least One Dose-Limiting Toxicity (DLT) 5. Part 2: Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR |
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E.5.1.1 | 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 21 days 5. Up to approximately 4 years |
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E.5.2 | Secondary end point(s) |
1. Part 1: Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR 2. Part 2: Overall Survival (OS) 3. Part 2: ORR per RECIST 1.1 as assessed by BICR 4. Part 2: Percentage of Participants Who Experienced At Least One AE 5. Part 2: Percentage of Participants Who Discontinued Study Treatment Due to an AE 6. Part 2: Percentage of Participants Who Experienced at Least One DLT 7. Part 1: Duration of Response (DOR) per RECIST 1.1 as assessed by BICR 8. Part 2: DOR per RECIST 1.1 as assessed by BICR 9. Part 1: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score 10. Part 1: Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 11. Part 1: Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) 12. Part 1: Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score 13. Part 1: TTD in the EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 14. Part 1: TTD in the EQ-5D-5L VAS 15. Part 2: Change from Baseline in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score 16. Part 2: Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 17. Part 2: Change from Baseline in EQ-5D-5L VAS 18. Part 2: Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score 19. Part 2: TTD in the EORTC QLQ-C30 Physical Functioning Scale (Items 1-5) Combined Score 20. Part 2: TTD in the EQ-5D-5L VAS |
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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. Up to approximately 21 days 7. Up to approximately 4 years 8. Up to approximately 4 years 9. Baseline and up to approximately 4 years 10. Baseline and up to approximately 4 years 11. Baseline and up to approximately 4 years 12. Up to approximately 4 years 13. Up to approximately 4 years 14. Up to approximately 4 years 15. Baseline and up to approximately 4 years 16. Baseline and up to approximately 4 years 17. Baseline and up to approximately 4 years 18. Up to approximately 4 years 19. Up to approximately 4 years 20. Up to approximately 4 years |
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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 | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First administration of the investigational agents combination in the specified population |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Chile |
Taiwan |
Australia |
Canada |
France |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Spain |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |