A study of enfortumab vedotin alone or in combination with other anticancer therapies for the treatment of urothelial cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Seagen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 May 2021 → 20 Feb 2026

Decision date (initial)

2023-09-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Seagen Inc.

External identifiers

EU CT number

2023-503391-24-00

EudraCT number

2018-001527-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Locally Advanced or Metastatic Urothelial Cancer :
● To assess the safety and tolerability of enfortumab vedotin in combination with pembrolizumab and/or chemotherapy.

Randomized Cohort K:
● To assess the antitumor activity of enfortumab vedotin monotherapy or enfortumab vedotin in combination with pembrolizumab as measured by ORR per RECIST Version 1.1 by blinded independent central review (BICR).

Muscle Invasive Bladder Cancer:
● To assess the antitumor activity of neoadjuvant and perioperative enfortumab vedotin monotherapy or neoadjuvant enfortumab vedotin in combination with pembrolizumab as measured by the pathological complete response (pCR) rate, defined as the absence of viable tumor (pT0N0) in examined tissue from radical cystectomy (RC) and pelvic lymph node dissection (PLND) by central pathology review

Secondary objectives 33

1. Locally Advanced or Metastatic Urothelial Cancer: To determine the recommended dose of enfortumab vedotin in combination with pembrolizumab and/or chemotherapy in patients with locally advanced or metastatic urothelial cancer (la/mUC)
2. Locally Advanced or Metastatic Urothelial Cancer: To assess the antitumor activity of enfortumab vedotin in combination with pembrolizumab and/or chemotherapy as measured by overall objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 (for all cohorts) and the modified RECIST 1.1 for immune-based therapeutics (iRECIST) (for cohorts utilizing pembrolizumab)
3. Locally Advanced or Metastatic Urothelial Cancer: To assess the duration of response (DOR) per RECIST Version 1.1 (for all cohorts) and iRECIST (for cohorts utilizing pembrolizumab)
4. Locally Advanced or Metastatic Urothelial Cancer: To assess the disease control rate (DCR) per RECIST Version 1.1 (for all cohorts) and iRECIST (for cohorts utilizing pembrolizumab)
5. Locally Advanced or Metastatic Urothelial Cancer: To assess progression-free survival (PFS) on study therapy per RECIST Version 1.1 (for all cohorts) and iRECIST (for cohorts utilizing pembrolizumab)
6. Locally Advanced or Metastatic Urothelial Cancer: To assess overall survival (OS)
7. Locally Advanced or Metastatic Urothelial Cancer: To assess pharmacokinetics (PK) and the incidence of antitherapeutic antibodies (ATA)
8. Additional: Locally Advanced or Metastatic Urothelial Cancer: To assess Nectin-4 and programmed cell death-ligand 1 (PD-L1) expression levels
9. Additional: Locally Advanced or Metastatic Urothelial Cancer: To assess biomarkers of biological activity and disease resistance, and their potential associations with clinical outcome measures (expansion cohorts only)
10. Randomized Cohort K: To assess the ORR per RECIST Version 1.1 by investigator assessment
11. Randomized Cohort K: To assess the DOR per RECIST Version 1.1 by BICR and investigator assessment
12. Randomized Cohort K: To assess the DCR per RECIST Version 1.1 by BICR and investigator assessment
13. Randomized Cohort K: To assess the PFS on study therapy per RECIST Version 1.1 by BICR and investigator assessment
14. Randomized Cohort K: To assess OS
15. Randomized Cohort K: To assess the safety and tolerability of enfortumab vedotin monotherapy or enfortumab vedotin in combination with pembrolizumab
16. Randomized Cohort K: Additional/Exploratory: To assess PK and the incidence of ATA
17. Randomized Cohort K: Additional/Exploratory: To assess Nectin-4 and PD-L1 expression levels
18. Randomized Cohort K: Additional/Exploratory: To assess biomarkers of biological activity and disease resistance, and their potential associations with clinical outcome measures
19. Randomized Cohort K: Additional/Exploratory: To assess the PFS on subsequent therapy (PFS2) by investigator assessment
20. Randomized Cohort K:Additional/Exploratory: To assess the impact on quality of life (QoL) and symptoms, including pain, from the patient perspective
21. Randomized Cohort K: To assess the ORR, DOR, DCR, and PFS on study therapy per iRECIST for enfortumab vedotin in combination with pembrolizumab (EV+Pembro arm) by investigator assessment
22. Muscle Invasive Bladder Cancer: To assess the event-free survival (EFS) on study therapy by BICR (Cohort L only)
23. Muscle Invasive Bladder Cancer: To assess the EFS on study therapy by investigator
24. Muscle Invasive Bladder Cancer: To assess the pathologic downstaging (pDS) rate, defined as patients with tumors
25. Muscle Invasive Bladder Cancer: To assess the disease free survival (DFS) by BICR (Cohort L only)
26. Muscle Invasive Bladder Cancer: To assess the DFS by investigator
27. Muscle Invasive Bladder Cancer: To assess OS
28. Muscle Invasive Bladder Cancer: To assess the safety and tolerability of enfortumab vedotin monotherapy or enfortumab vedotin in combination with pembrolizumab
29. Muscle Invasive Bladder Cancer: To assess the percentage of planned RC+PLND delayed due to treatment-related adverse events (AEs)
30. Muscle Invasive Bladder Cancer: Additional/Exploratory: To assess Nectin-4 and PD-L1 expression levels
31. Muscle Invasive Bladder Cancer: Additional/Exploratory: To assess biomarkers of biological activity and disease resistance, and their potential associations with clinical outcome measures
32. Muscle Invasive Bladder Cancer: Additional/Exploratory: To assess PK and the incidence of ATA
33. Muscle Invasive Bladder Cancer: Additional/Exploratory: To assess patient-reported experience and patient-reported tolerability of treatment

Conditions and MedDRA coding

Urothelial cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Histologically documented la/mUC, including squamous differentiation or mixed cell types.
2. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2: Participants with ECOG performance status of 2 must meet the following additional criteria: hemoglobin ≥10 g/dL, GFR ≥50 mL/min, may not have NYHA Class III heart failure
3. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K:Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, G and K Combination Arm).
4. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Dose-escalation cohorts: Ineligible for first-line cisplatin-based chemotherapy and no prior treatment for la/mUC, or have disease progression following at least 1 platinum-containing treatment
5. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Cohort A: Ineligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months
6. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Cohort B: Must have disease progression during/following treatment with at least 1 platinum-containing regimen for la/mUC or disease recurrence
7. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Cohort D: Eligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months
8. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Cohort E: Ineligible for cisplatin-based chemotherapy, eligible for carboplatin, and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months
9. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Cohort F: Ineligible for platinum-based chemotherapy, or disease progression during/following at least 1 prior treatment for la/mUC. Eligible for gemcitabine
10. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Cohort G: Eligible for platinum-based chemotherapy (either cisplatin or carboplatin) and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months
11. Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K: Cohort K: Ineligible for cisplatin-based chemotherapy due to at least 1 of the following: Glomerular filtration rate (GFR) <60 mL/min and ≥30 mL/min, ECOG performance status of 2, NCI CTCAE Version 4.03 Grade ≥2 hearing loss, New York Heart Association (NYHA) Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease. No adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
12. Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.: Histologically confirmed MIBC with predominant >50% urothelial histology: Cohorts H and J: Clinical stage cT2-T4aN0M0; Cohort L: Clinical stage cT2-T4aN0M0 or cT1-T4aN1M0: Participants with pT1 disease are eligible only if they have N1 disease on imaging. Mixed cell types are eligible if urothelial cancer is predominant (>50%); Participants with plasmacytoid and/or neuroendocrine tumors are ineligible regardless of component percentage. Urothelial tumors not originating in the bladder (eg, upper tract tumors, urethral tumors) are ineligible.
13. Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.: Must be cisplatin-ineligible
14. Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.: Cohort-specific eligibility: Cohort J, H, and L: No prior systemic treatment, chemoradiation, or radiation therapy for MIBC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-MIBC; Cohort J: Eligible for pembrolizumab.
15. Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.: ECOG performance status of 0, 1, or 2.
16. Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.: Anticipated life expectancy of ≥3 months.
17. Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.: Tumor samples with an associated pathology report from the diagnostic transurethral resection of a bladder tumor done 90 days prior to the first dose of study treatment must be available prior to enrollment and determined to be sufficient for pathology review and biomarker analysis.
18. Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.: Participants must be deemed eligible for RC+PLND.

Exclusion criteria 17

1. la/mUC - Cohorts A, B, D, E, F, G, and K: Received any prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor, except Cohort F.
2. la/mUC - Cohorts A, B, D, E, F, G, and K: Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonists, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (except Cohort F).
3. la/mUC - Cohorts A, B, D, E, F, G, and K: Ongoing sensory or motor neuropathy Grade 2 or higher.
4. la/mUC - Cohorts A, B, D, E, F, G, and K: Active central nervous system (CNS) metastases.
5. la/mUC - Cohorts A, B, D, E, F, G, and K: Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
6. la/mUC - Cohorts A, B, D, E, F, G, and K: Conditions requiring high doses of steroids or other immunosuppressive medications.
7. la/mUC - Cohorts A, B, D, E, F, G, and K: Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
8. la/mUC - Cohorts A, B, D, E, F, G, and K: Uncontrolled diabetes mellitus.
9. MIBC - Cohorts H, J, and L: Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer.
10. MIBC - Cohorts H, J, and L: Received any prior treatment with a CPI
11. MIBC - Cohorts H, J, and L: Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists.
12. MIBC - Cohorts H, J, and L: For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, ≥N2 nodal disease on imaging.
13. MIBC - Cohorts H, J, and L: Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.
14. MIBC - Cohorts H, J, and L: Ongoing sensory or motor neuropathy Grade 2 or higher.
15. MIBC - Cohorts H, J, and L: Conditions requiring high doses of steroids or other immunosuppressive medications.
16. MIBC - Cohorts H, J, and L: Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer
17. MIBC - Cohorts H, J, and L: Participants with a history of another invasive malignancy within 3 years before first dose of study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Locally Advanced or Metastatic Urothelial Cancer ● Type, incidence, severity, seriousness, and relatedness of AEs ● Type, incidence, and severity of laboratory abnormalities
2. Randomized Cohort K ● ORR (confirmed) per RECIST Version 1.1 by BICR
3. Muscle Invasive Bladder Cancer ● pCR rate by central pathology review

Secondary endpoints 26

1. ORR (confirmed) per RECIST Version 1.1 by investigator assessment
2. DOR per RECIST Version 1.1 by BICR
3. DOR per RECIST Version 1.1 by investigator assessment
4. DCR per RECIST Version 1.1 by BICR
5. DCR per RECIST Version 1.1 by investigator assessment
6. PFS per RECIST Version 1.1 by BICR
7. PFS per RECIST Version 1.1 by investigator
8. OS
9. Type, incidence, severity, seriousness, and relatedness of AEs
10. Type, incidence, and severity of laboratory abnormalities
11. Corresponding Additional/Exploratory Endpoints: Selected plasma or serum PK parameters of enfortumab vedotin, MMAE, and TAb
12. Corresponding Additional/Exploratory Endpoints: Incidence of ATA to enfortumab vedotin
13. Corresponding Additional/Exploratory Endpoints: Exploratory biomarkers of clinical activity, including relationship of Nectin-4 expression and PD-L1 expression status to response
14. Corresponding Additional/Exploratory Endpoints: PFS2 by investigator assessment
15. Corresponding Additional/Exploratory Endpoints: Change from baseline in PRO assessments of the EQ-5D-5L, EORTC QLQ-C30, and BPI-SF
16. For the EV+Pembro arm: ORR (confirmed) per iRECIST by investigator assessment
17. For the EV+Pembro arm: DOR per iRECIST by investigator assessment
18. For the EV+Pembro arm: DCR per iRECIST by investigator assessment
19. For the EV+Pembro arm: PFS per iRECIST by investigator assessment
20. ORR (confirmed) per RECIST Version 1.1 by BICR
21. EFS by BICR (Cohort L only)
22. EFS by investigator assessment
23. pDS rate by central pathology review
24. DFS by BICR (Cohort L only)
25. DFS by investigator assessment
26. Percentage of planned RC+PLND delayed due to treatment-related AEs

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Seagen Inc.

Sponsor organisation

Seagen Inc.

Address

21823 30th Drive Southeast

City

Bothell

Postcode

98021-3907

Country

United States

Scientific contact point

Organisation

Seagen Inc.

Contact name

Seagen Clinical Trial Information

Public contact point

Organisation

Seagen Inc.

Contact name

Seagen Clinical Trial Information

Third parties 10

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications