| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 | 10046723 |
| E.1.2 | Term | Urothelial carcinoma ureter |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 | 10046728 |
| E.1.2 | Term | Urothelial carcinoma urethra |
| 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 |
- To compare PFS between the experimental arm (enfortumab vedotin + pembrolizumab [Arm A] and the control arm (gemcitabine + cisplatin or carboplatin [Arm B]) by blinded independent central review (BICR)
- To compare overall survival (OS) between the experimental arm (Arm A) and the control arm (Arm B) |
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| E.2.2 | Secondary objectives of the trial |
- To compare ORR between the experimental arm (Arm A) and the control arm (Arm B) by BICR
- To compare time to pain progression (TTPP) from the subject perspective between the experimental arm (Arm A) and the control arm (Arm B)
- To compare average change in pain from the subject perspective between the experimental arm (Arm A) and the control arm (Arm B)
- To evaluate PFS between the experimental arm (Arm A) and the control arm (Arm B) by investigator assessment
- To evaluate ORR between the experimental arm (Arm A) and the control arm (Arm B) by investigator assessment
- To evaluate DOR between the experimental arm (Arm A) and the control arm (Arm B)
- To evaluate DCR between the experimental arm (Arm A) and the control arm (Arm B)
- To evaluate the impact of study treatment on quality of life (QOL), functioning, and symptoms from the subject perspective
- To evaluate the safety profile of each treatment regimen |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible.
2. Subjects must have measurable disease by investigator assessment according to RECIST v1.1.
a. Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy
3. Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted
b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted
4. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgment.
a. Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria:
i. GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] or 24-hour urine)
· Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s
clinical judgment
ii. ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects)
iii. NCI CTCAE Grade ≥2 audiometric hearing loss
iv. NYHA Class III heart failure
5. Subjects must be age 18 years or older.
6. Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed.
7. Subjects must have an ECOG Performance Status score of 0, 1, or 2.
a. Subjects with ECOG performance status of 2 must additionally meet the following criteria:
i. Hemoglobin ≥10 g/dL
ii. GFR ≥50 mL/min
iii. May not have NYHA Class III heart failure
8. Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3 (see protocol)
9. Female subjects of childbearing potential must meet the following conditions:
· Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug.
· Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 1 day prior to administration of the study drug. Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation.
· If heterosexually active must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening, throughout the study period, and for at least 6 months after the final dose of study drug.
· Female subjects must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug.
10. Male subjects who can father children, must meet the following conditions:
· Must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug. Male subjects will be informed about the negative risk to reproductive function and fertility from the study treatment. Prior to treatment male subjects should be advised to seek information on fertility preservation and sperm cryoconservation.
· Must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening and continue throughout study period and for at least 6 months after the final dose of study drug.
· Male subjects with a pregnant or breastfeeding partner(s) must consistently use one of 2 contraception options for preventing secondary exposure to seminal fluid for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final dose of study drug. |
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| E.4 | Principal exclusion criteria |
1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs.
2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor.
3. Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor.
4. Subjects who have received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment.
5. Subjects with uncontrolled diabetes.
6. Subjects with an estimated life expectancy <12 weeks
7. Subjects with ongoing sensory or motor neuropathy Grade 2 or higher.
8. Subjects with active CNS metastases. Subjects 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 subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) subject does not have leptomeningeal disease.
9. Subjects with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to ≤ Grade 1 or returned to baseline.
10. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
11. Subjects who have known active hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] detected) infection, testing for hepatitis B and hepatitis C is required if mandated by country health authority. Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.
13. Subjects with conditions requiring high doses of steroids (>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency.
14. Subjects with a history of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy (eligible exceptions see protocol).
15. Subjects with a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV within 6 months prior to randomization.
16. Subjects who have received radiotherapy within 2 weeks prior to randomization.
17. Subjects who have received major surgery within 4 weeks prior to randomization.
18. Subjects with known severe (≥ Grade 3) hypersensitivity to any excipient contained in the drug formulations of enfortumab vedotin, pembrolizumab, the platinum agent selected by the investigator or gemcitabine.
19. Subjects with active keratitis or corneal ulcerations.
20. History of autoimmune disease that has required systemic treatment in the past 2 years.
a. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
b. Brief (<7 days) use of systemic corticosteroids is allowed when use is considered standard of care.
c. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded.
d. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded.
e. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome will not be excluded.
21. Subjects with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
22. Subjects who have received a prior allogeneic stem cell or solid organ transplant.
23. Subjects who have received a live attenuated vaccine within 30 days prior to randomization.
24. Subjects with active tuberculosis.
25. Subjects with another underlying medical condition that, in the opinion of the investigator, would impair the ability of the subject to receive or tolerate the planned treatment and follow-up; any known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
● PFS per RECIST v1.1 by BICR
● OS |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Response assessments should be performed every 9 weeks (±1-week) timed from the randomization date until 18 months after randomization, then every 12 weeks (±1-week) thereafter.
Survival status will be updated every 12 weeks (±1-week) until death, withdrawal of consent, or study closure, whichever occurs first. |
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| E.5.2 | Secondary end point(s) |
● ORR per RECIST v1.1 by BICR
● TTPP
● Mean change from baseline in worst pain at Week 26
● PFS per RECIST v1.1 by investigator assessment
● ORR per RECIST v1.1 by investigator assessment
● DOR per RECIST v1.1 by BICR
● DOR per RECIST v1.1 by investigator assessment
● DCR per RECIST v1.1 by BICR
● DCR per RECIST v1.1 by investigator assessment
● Mean scores and change from baseline of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30), and EuroQOL 5-dimensions (EQ-5D-5L), visual analogue scale (VAS), and utility scores
● Type, incidence, relatedness, severity and seriousness of AEs
● Type, incidence and severity of laboratory abnormalities
● Treatment discontinuation rate due to AEs |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Response assessments should be performed every 9 weeks (±1-week) timed from the randomization date until 18 months after randomization, then every 12 weeks (±1-week) thereafter. |
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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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 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 | 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 97 |
| 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 |
| China |
| Israel |
| Japan |
| Singapore |
| Thailand |
| United States |
| Switzerland |
| Russian Federation |
| Turkey |
| Ukraine |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
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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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| Subjects will remain on study until death, study closure, or withdrawal of consent, whichever occurs first (survival follow-up every 12 weeks). |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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