An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs Chemotherapy in Subjects with Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)

• Register: EUCTR
• Last refreshed on: 16 December 2019
• Main ID: EUCTR2017-003344-21-NL
• Date of registration: 25/05/2018
• Prospective Registration: Yes
• Primary sponsor: Astellas Pharma Global Development, Inc. (APGD)
• Public title: An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs Chemotherapy in Subjects with Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)
• Scientific title: An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs Chemotherapy in Subjects with Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)
• Date of first enrolment: 26/11/2018
• Target sample size: 550
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003344-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Canada, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Portugal, Russian Federation, Spain, Switzerland, Taiwan, United Kingdom, United States

Contacts

• Name: Service Desk - Global Clinical Dev.
• Affiliation: Astellas Pharma Europe B.V.

• Name: Service Desk - Global Clinical Dev.
• Affiliation: Astellas Pharma Europe B.V.

Key inclusion & exclusion criteria

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 t
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 well-maintained/controlled on a stable dose of
hormone replacement therapy (if indicated). Patients with ongoing = Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. 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 i

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Locally advanced or metastatic urothelial cancer
MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Enfortumab Vedotin
Product Code: ASG-22CE
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: ENFORTUMAB VEDOTIN
Current Sponsor code: ASG-22CE
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 1.25-

Trade Name: Paclitaxel Amneal 6 mg/ml
Product Name: Paclitaxel 6 mg/mL
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: PACLITAXEL
CAS Number: 33069-62-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Trade Name: Docetaxel cell pharm 20 mg/ml
Product Name: Docetaxel cell pharm 20 mg/ml
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DOCETAXEL
CAS Number: 114977-28-5
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Trade Name: Javlor 25mg/mL
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: VINFLUNINE
CAS Number: 162652-95-1
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: Docetaxel Amneal Pharma Europe
Product Name: Docetaxel amneal 20mg/ml
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DOCETAXEL
CAS Number: 114977-28-5
Concentration unit: mg/ml milligram(s)/millilitre
Concentrat

Primary Outcome(s)

Main Objective: 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

Timepoint(s) of evaluation of this end point: o Up to 36 months (Primary)
o Up to 24 months (Secondary)

Secondary Objective: 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

Primary end point(s): Overall survival

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Please refer to section E.5.2 and also to the protocol

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)

Secondary ID(s)

2017-003344-21-DE

7465-CL-0301

Source(s) of Monetary Support

Astellas Pharma Global Development, Inc. (APGD)

Ethics review

Status: Approved
Approval date:
Contact: