| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic urothelial cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancerous tumour 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 | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| 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 |
| To compare the overall survival (OS) of subjects with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin (EV) to the OS of subjects treated with chemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
To compare progression-free survival on study therapy (PFS1) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 of subjects treated with EV to subjects treated with chemotherapy
To compare the overall response rate (ORR) per RECIST V1.1 of EV to chemotherapy
To evaluate the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy
To compare the disease control rate (DCR) per RECIST V1.1 of EV to chemotherapy
To assess the safety and tolerability of EV
To assess quality of life (QOL) and Patient Reported Outcomes (PRO) parameters |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Subject is legally an adult according to local regulation at the time of signing informed consent.
3. Subject has histologically or cytologically confirmed urothelial carcinoma. Subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible.
4. Subject must have experienced radiographic progression or relapse during or after a CPI (anti-PD1 or anti-PD-L1) for locally advanced or metastatic disease. Subjects who discontinued CPI treatment due to toxicity are eligible provided that they have evidence of disease progression following discontinuation. The CPI need not be the most recent therapy. Subjects for whom the most recent therapy has been a non-CPI based regimen are eligible if they have progressed/relapsed during or after their most recent therapy.
Locally advanced disease must not be amenable to resection with curative intent per the treating physician.
5. Subject must have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting. If platinum was administered in the adjuvant/neoadjuvant setting subject must have progressed within 12 months of completion.
6. Subject has radiologically documented metastatic or locally advanced disease at baseline.
7. An archival tumor tissue sample should be available for submission to central laboratory prior to study treatment. If an archival tumor tissue sample is not available, a fresh tissue sample should be provided. If a fresh tissue sample cannot be provided due to safety concerns, enrollment into the study must be discussed with the medical monitor.
8. Subject has ECOG PS of 0 or 1
9. The subject has the following baseline laboratory data:
● absolute neutrophil count (ANC) ≥ 1500/mm3
● platelet count ≥ 100 × 10^9/L
● hemoglobin ≥ 9 g/dL
● serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease
● creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection (glomerular filtration rate [GFR] can also be used instead of CrCl)
● alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 3 x ULN for subjects with liver metastases
10. Female subject must either:
● Be of nonchildbearing potential:
● Postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or
● Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy).
● Or, if of childbearing potential:
● Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration,
● And have a negative urine or serum pregnancy test within 7 days prior to Day 1 (Females with false positive results and documented verification of negative pregnancy status are eligible for participation),
● And if heterosexually active, agree to consistently use a condom plus 1 form of highly effective birth control * per locally accepted standards starting at screening and throughout the study period and for at least 6
months after the final study drug administration.
11. Female subject 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 study drug administration.
12. A sexually active male subject with female partner(s) who is of childbearing potential is eligible if:
● Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 6 months after final study drug administration. If the male subject has not had a vasectomy or is not sterile as defined below his female partner(s) is utilizing 1 form of highly effective birth control * per locally accepted standards starting at screening and continue throughout study treatment and for at least 6
months after the male subject receives his final study drug administration.
13. Male subject must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
14. Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6
months after the final study drug administration.
15. Subject agrees not to participate in another interventional study while on treatment in present study.
Waivers to the inclusion criteria will NOT be allowed. |
|
| E.4 | Principal exclusion criteria |
1. Subject has preexisting sensory or motor neuropathy Grade ≥ 2.
2. Subject has active central nervous system (CNS) metastases. Subjects with treated CNS metastases are permitted on study if all the following are true:
● CNS metastases have been clinically stable for at least 6 weeks prior to screening
● If requiring steroid treatment for CNS metastases, the subject is on a stable dose ≤ 20 mg/day of prednisone or equivalent for at least 2 weeks
● Baseline scans show no evidence of new or enlarged brain metastasis
● Subject does not have leptomeningeal disease
3. Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery). Subject with ≤
Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be enrolled when wellmaintained/controlled on a stable dose of hormone replacement therapy (if indicated). Patients with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subject with hypothyroidism or panhypopituitarism related to treatment with PD-1 and PD-L1 inhibitors may be enrolled. Subject on hormone replacement therapy may be enrolled if on a stable dose. Subjects with ongoing immunotherapy related colitis, uveitis, or pneumonitis or subjects with other immunotherapy related AEs requiring high doses of steroids (> 20 mg/day of prednisone or equivalent) are excluded.
4. Subject has prior treatment with EV or other monomethyl auristatin E (MMAE)-based ADCs.
5. Subject has received prior chemotherapy for urothelial cancer with all available study therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy).
Note: after vinflunine cap is reached, subjects who have received both docetaxel and paclitaxel will be excluded.
6. Subject has received more than 1 prior chemotherapy regimen for locally advanced or metastatic urothelial cancer, including chemotherapy for adjuvant or neo-adjuvant disease if recurrence occurred within 12 months of completing therapy. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen.
7. Subject has history of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
8. Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal infection at the time of first dose of EV. Routine antimicrobial prophylaxis is permitted.
9. Subject has known active Hepatitis B (e.g., HBsAg reactive) or active hepatitis C (e.g., HCV RNA [qualitative] is detected).
10. Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2).
11. Subject has documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug.
12. Subject has radiotherapy or major surgery within 4 weeks prior to first dose of study drug.
13. Subject has had chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug.
14. Subject has known hypersensitivity to EV or to any excipient contained in the drug formulation of EV.(including histidine, trehalose dihydrate, and polysorbate 20); OR subject has known hypersensitivity
to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells.
15. Subject has known hypersensitivity to the following: docetaxel, Paclitaxel, vinflunine or to any of the other excipients listed in product label.
16. [Criterion removed].
17. Subject has known active keratitis or corneal ulcerations. Subject with superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
18. Subject has other 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.
19. History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug.
Waivers to the exclusion criteria will NOT be allowed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
o Up to 36 months (Primary)
o Up to 24 months (Secondary) |
|
| E.5.2 | Secondary end point(s) |
● PFS1 by RECIST V1.1
● ORR (CR + PR) by RECIST V1.1
● DCR (CR + PR + SD) by RECIST V1.1
● DOR by RECIST V1.1
● Safety variables (e.g., AEs, laboratory tests, vital sign measurements, 12-lead ECG and ECOG PS)
● QOL and PRO parameters (QLQ-C30 and EQ-5D-5L) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section E.5.2 and also to the protocol |
|
| 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 | Yes |
| 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 | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Brazil |
| Canada |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| Austria |
| France |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Portugal |
| Russian Federation |
| United Kingdom |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | 31 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
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