Clinical Trials Register

Summary
EudraCT Number:	2018-001527-39
Sponsor's Protocol Code Number:	SGN22E-002
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-02-04
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2018-001527-39

A.3

Full title of the trial

A study of enfortumab vedotin (ASG-22CE) as monotherapy or in combination with other anticancer therapies for the treatment of urothelial cancer

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

SGN22E-002

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Seagen Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Seagen Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Seagen Inc.
B.5.2	Functional name of contact point	Seagen Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	21823 30th Drive SE
B.5.3.2	Town/ city	Bothell
B.5.3.3	Post code	WA 98021
B.5.3.4	Country	United States
B.5.4	Telephone number	+1866 333 7436
B.5.6	E-mail	EU-Regulatory@seagen.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	PADCEV
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Enfortumab vedotin
D.3.2	Product code	ASG-22CE
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ENFORTUMAB VEDOTIN
D.3.9.2	Current sponsor code	ASG-22CE
D.3.9.4	EV Substance Code	SUB185524
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	KEYTRUDA
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Pembrolizumab
D.3.2	Product code	MK-3475
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	SUB167136
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Urothelial cancer

E.1.1.1

Medical condition in easily understood language

Urothelial cancer

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.1.2 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

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

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10077840
E.1.2	Term	Urothelial cancer of renal pelvis
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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)

E.2.2

Secondary objectives of the trial

-To assess the ORR per RECIST Version 1.1 by investigator assessment
-To assess the DOR per RECIST Version 1.1 by BICR and investigator assessment
-To assess the DCR per RECIST Version 1.1 by BICR and investigator assessment
-To assess the PFS on study therapy per RECIST Version 1.1 by BICR and investigator assessment
-To assess OS
-To assess the safety and tolerability of EV monotherapy or enfortumab vedotin in combination with pembrolizumab
Additional/Exploratory:
-To assess:
-PK and the incidence of ATA
- Nectin-4 and PD-L1 expression levels
- biomarkers of biological activity and disease resistance, and their potential associations with clinical outcome measures
- the PFS on subsequent therapy (PFS2) by investigator assessment
- the impact on quality of life (QoL) and symptoms, including pain, from the patient perspective
- the ORR, DOR, DCR, and PFS on study therapy per iRECIST for EV in combination with pembrolizumab (EV+Pembro arm) by investigator assessment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients must have histologically documented locally advanced or metastatic urothelial (previously known as transitional cell) cancer (ie, cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous differentiation or mixed cell types are eligible. Patients with locally advanced disease that is resectable with curative intent are ineligible.
2.Patients in Cohort K must be eligible for CPI therapy.
3. Cohort-specific eligibility:
Randomized Cohort K (EV Mono arm and EV+Pembro arm): Patients must be ineligible for cisplatin-based chemotherapy at the time of enrollment due to at least 1 of the following criteria:
i. Glomerular filtration rate (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)
ii. ECOG performance status of <= 2 (refer to inclusion criterion #6 for additional criteria for subjects with ECOG 2)
iii. NCI CTCAE Version 4.03 Grade ≥2 hearing loss
iv. NYHA Class III heart failure
Patients must not have received prior systemic treatment for locally advanced or metastatic disease. Patients may not have previously received adjuvant/neoadjuvant
platinum-based therapy within 12 months prior to randomization.
4. Minimum age of 18 years
5. Patients must have measurable disease according to RECIST Version 1.1 (Eisenhauer 2009). Lesions in a prior irradiated field must have progressed to be considered measurable.
6. An ECOG performance status of 0, 1, or 2 .
• 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
7. Anticipated life expectancy of ≥3 months as assessed by the investigator.
8. Have adequate organ function as defined in the following table. Specimens must be collected within 7 days prior to the start of study treatment.
9. A female subject of childbearing potential is anyone born female who has experienced menarche and who has not undergone surgical sterilization (eg, hysterectomy, bilateral
salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person over age 45 in the absence of other biological, physiological, or pharmacological causes. 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 3 days prior to Day 1. 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. A male subject who can father children is anyone born male who has testes and who has not undergone surgical sterilization (eg, vasectomy followed by a clinical test proving
that the procedure was effective). 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 (as
described in Appendix M) 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.
11. The patient must provide written informed consent.

E.4

Principal exclusion criteria

1. Received any prior treatment with a CPI. A CPI is defined as a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab,
pembrolizumab, nivolumab, durvalumab, or avelumab). Patients in Expansion Cohort F may have previously received treatment with a CPI.
2. Received any prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists).
3. Ongoing sensory or motor neuropathy Grade 2 or higher.
4. Active central nervous system [CNS] metastases. Patients with treated CNS metastases are permitted on study if all the following are true:
a. CNS metastases have been clinically stable for at least 6 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis.
b. If requiring steroid treatment for CNS metastases, the patient is on a stable dose <10 mg/day of prednisone or equivalent for at least 2 weeks.
c. Patient does not have leptomeningeal disease.
5. Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
6. Patients 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.
7. Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
8. 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. Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ (eg, breast carcinoma, cervical cancer) who have undergone potentially curative therapy are not excluded. Patients with low-risk prostate cancer (T1-T2a, Gleason score ≤6, and prostate specific antigen [PSA] <10 ng/mL) either treated with definite intent any time prior to screening or untreated in active surveillance are not excluded.
9. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial
prophylaxis is permitted.
10. Patients with a positive hepatitis B surface antigen and/or antihepatitis B core antibody; patients with a negative polymerase chain reaction (PCR) assay are permitted with either
universal prophylaxis or the use of a pre-emptive approach. The approach will be selected in accordance with regional or national guidelines for patients who receive anticancer therapies.
11. Active hepatitis C infection or known human immunodeficiency virus (HIV) infection. Patients who have been curatively treated for hepatitis C infection are permitted if they
have documented sustained virologic response of 12 weeks. No HIV testing is required unless mandated by local health authority.
12. Patients with active tuberculosis.
13. 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 NYHA Class III–IV (see Appendix E) within 6 months prior to the first dose of enfortumab vedotin. Patients with NYHA Class III are permitted in Cohort K.
14. Radiotherapy or major surgery within 2 weeks prior to first dose of study drug. Patient must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
15. Treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion No. 2 that is not completed 4 weeks prior to first dose of
study drug.
16. Known severe (≥ Grade 3) hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose
dihydrate, and polysorbate 20). Known severe (≥ Grade 3) hypersensitivity to pembrolizumab or to any excipient contained in the drug formulations of pembrolizumab.
17. Patients with active keratitis or corneal ulcerations. Patients with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator.
19. History of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
20. Prior allogeneic stem cell or solid organ transplant.

Please refer to protocol to see complete exclusion criteria

E.5 End points

E.5.1

Primary end point(s)

ORR (confirmed) per RECIST Version 1.1 by BICR

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 9 weeks starting from Cycle 1 Day 1 through EOT and for up to one year, then every 12 weeks.

E.5.2

Secondary end point(s)

• ORR (confirmed) per RECIST Version 1.1 by investigator assessment
• DOR per RECIST Version 1.1 by BICR
• DOR per RECIST Version 1.1 by investigator assessment
• DCR per RECIST Version 1.1 by BICR
• DCR per RECIST Version 1.1 by investigator assessment
• PFS per RECIST Version 1.1 by BICR
• PFS per RECIST Version 1.1 by investigator
• OS
• Type, incidence, severity, seriousness, and relatedness of AEs
• Type, incidence, and severity of laboratory abnormalities
Corresponding Additional/Exploratory Endpoints
• Selected plasma or serum PK parameters of enfortumab vedotin, MMAE, and TAb
• Incidence of ATA to enfortumab vedotin
• Exploratory biomarkers of clinical activity, including relationship of Nectin-4 expression and PD-L1 expression status to response
• PFS2 by investigator assessment
• Change from baseline in PRO assessments of the EQ-5D-5L, EORTC QLQ-C30, and BPI-SF
For the EV+Pembro arm:
• ORR (confirmed) per iRECIST by investigator assessment
• DOR per iRECIST by investigator assessment
• DCR per iRECIST by investigator assessment
• PFS per iRECIST by investigator assessment

E.5.2.1

Timepoint(s) of evaluation of this end point

Following documentation of PFS2, patients will enter the survival follow-up period and be followed every 12 weeks for survival status until death, study closure, or withdrawal of consent, whichever occurs first.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarker

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Canada

United States

France

Italy

Spain

E.8.7

Trial has a data monitoring committee

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

The study will be closed 5 years after enrollment of the last patient, or when no patients remain in long-term follow-up, whichever occurs first.

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

150

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard of care

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-16

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
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