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The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

Clinical Trial Details

Geo Regions

Category

Genitourinary Cancer

Enfortumab vedotin

A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer

Phase 1 /2

NCT03288545

Active Not-enrolling

Globe

Locations

United States, Canada, France, Italy, Puerto Rico, Spain

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Study design
Participant Group/Arm

EXPERIMENTAL: EV + Pembrolizumab in cisplatin-ineligible 1L and in 2L

Dose Escalation: Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: pembrolizumab

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Cohort A: EV + Pembrolizumab in cisplatin-ineligible 1L

Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: pembrolizumab

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Optional Cohort B: Enfortumab Vedotin + Pembrolizumab in 2L

Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: pembrolizumab

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Cohort D: Enfortumab Vedotin + Cisplatin in 1L

Enfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: cisplatin

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Cohort E: Enfortumab Vedotin + Carboplatin in 1L

Enfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: carboplatin

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Optional Cohort F: Enfortumab Vedotin+Gemcitabine in 1L and 2L

Enfortumab vedotin and gemcitabine on days 1 and 8 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: gemcitabine

IV infusion on days 1 and 8 every 21 days

Participant Group/Arm

EXPERIMENTAL: Cohort G: Enfortumab Vedotin + Platinum + Pembrolizumab in 1L

Enfortumab vedotin on days 1 and 8 plus cisplatin or carboplatin on day 1 plus pembrolizumab on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: pembrolizumab

IV infusion on day 1 every 21 days

DRUG: cisplatin

IV infusion on day 1 every 21 days

DRUG: carboplatin

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Cohort H: Enfortumab vedotin in MIBC neoadjuvant setting

Enfortumab vedotin on days 1 and 8 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

Participant Group/Arm

EXPERIMENTAL: Optional Cohort J:EV+Pembrolizumab in MIBC neoadjuvant setting

Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: pembrolizumab

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Randomized Cohort K: Enfortumab Vedotin Monotherapy

Enfortumab vedotin on days 1 and 8 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

Participant Group/Arm

EXPERIMENTAL: Randomized Cohort K: Enfortumab Vedotin + Pembrolizumab

Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

DRUG: pembrolizumab

IV infusion on day 1 every 21 days

Participant Group/Arm

EXPERIMENTAL: Cohort L: Enfortumab vedotin in MIBC in perioperative setting

Enfortumab vedotin on days 1 and 8 and every 21 days

Intervention/Treatment

DRUG: enfortumab vedotin (EV)

Intravenous (IV) infusion on days 1 and 8 every 21 days

Study design table for Clinical Trial
Key eligibility criteria
Inclusion criteria
  • 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.
    • 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.
    • Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, G and K Combination Arm).
    • 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.
    • 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.
    • Cohort B: Must have disease progression during/following treatment with at least 1 platinum-containing regimen for la/mUC or disease recurrence.
    • 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.
    • 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.
    • Cohort F: Ineligible for platinum-based chemotherapy, or disease progression during/following at least 1 prior treatment for la/mUC. Eligible for gemcitabine.
    • 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.
    • 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 randomizatio
  • 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.
    • Must be cisplatin-ineligible.
    • 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.
    • ECOG performance status of 0, 1, or 2.
    • Anticipated life expectancy of ≥3 months.
    • 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.
    • Participants must be deemed eligible for RC+PLND.
  • 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.
    • 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).
    • Ongoing sensory or motor neuropathy Grade 2 or higher.
    • Active central nervous system (CNS) metastases.
    • Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
    • Conditions requiring high doses of steroids or other immunosuppressive medications.
    • Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
    • Uncontrolled diabetes mellitu
  • MIBC - Cohorts H, J, and L
    • Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer.
    • Received any prior treatment with a CPI.
    • Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists.
    • For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, ≥N2 nodal disease on imaging.
    • Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.
    • Ongoing sensory or motor neuropathy Grade 2 or higher.
    • Conditions requiring high doses of steroids or other immunosuppressive medications.
    • Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
    • Participants with a history of another invasive malignancy within 3 years before first dose of study dru
Exclusion criteria
  • 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.
    • 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).
    • Ongoing sensory or motor neuropathy Grade 2 or higher.
    • Active central nervous system (CNS) metastases.
    • Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
    • Conditions requiring high doses of steroids or other immunosuppressive medications.
    • Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
    • Uncontrolled diabetes mellitus
  • MIBC - Cohorts H, J, and L
    • Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer.
    • Received any prior treatment with a CPI.
    • Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists.
    • For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, ≥N2 nodal disease on imaging.
    • Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.
    • Ongoing sensory or motor neuropathy Grade 2 or higher.
    • Conditions requiring high doses of steroids or other immunosuppressive medications.
    • Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
    • Participants with a history of another invasive malignancy within 3 years before first dose of study drug
Key dates
Study start date
  • October 2017
Estimated Study Completion Date
  • December 2026
Key endpoints
Primary Outcome Measures
Outcome Measure

Type, incidence, severity, seriousness, and relatedness of adverse events (Dose escalation and Expansion Parts 1 to 3 cohorts only)

Measure Description

Descriptive statistics will be used to summarize results.

Time Frame

Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.

Outcome Measure

Type, incidence, and severity of laboratory abnormalities (Dose escalation and Expansion Parts 1 to 3 cohorts only)

Measure Description

Descriptive statistics will be used to summarize results.

Time Frame

Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.

Outcome Measure

Confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR) (Cohort K only)

Measure Description

The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1

Time Frame

Up to 3 years

Outcome Measure

Pathological complete response (pCR) rate per central pathology review (MIBC cohorts only)

Measure Description

The proportion of patients with absence of viable tumor tissue at the time of radical cystectomy.

Time Frame

Up to approximately 5 months

Primary Outcome Measures table for Clinical Trial
Secondary Outcome Measures:
Outcome Measure

Incidence of dose-limiting toxicity (DLT)

Measure Description

Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).

Time Frame

21 days

Outcome Measure

Confirmed ORR by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

Measure Description

The proportion of patients with confirmed CR or PR according to RECIST 1.1.

Time Frame

Up to 3 years

Outcome Measure

Confirmed ORR by BICR according to RECIST 1.1 (Dose escalation and Cohort A only)

Measure Description

The proportion of patients with confirmed CR or PR according to RECIST 1.1

Time Frame

Up to 3 years

Outcome Measure

Confirmed ORR by investigator assessment per the modified RECIST 1.1 for immune-based therapeutics (iRECIST) (Dose escalation and Part 1-3 cohorts with pembrolizumab only)

Measure Description

The proportion of patients with confirmed CR or PR according to iRECIST.

Time Frame

Up to 3 years

Outcome Measure

Disease control rate (DCR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

Measure Description

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.

Time Frame

Up to 5 years

Outcome Measure

DCR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)

Measure Description

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1

Time Frame

Up to 3 years

Outcome Measure

DCR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts using pembrolizumab only)

Measure Description

Proportion of patients with CR, PR, or SD according to iRECIST.

Time Frame

Up to 3 years

Outcome Measure

Duration of response (DOR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

Measure Description

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per RECIST 1.1) or to death due to any cause, whichever comes first.

Time Frame

Up to 5 years

Outcome Measure

DOR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)

Measure Description

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per RECIST 1.1 or to death due to any cause, whichever comes first

Time Frame

Up to 5 years

Outcome Measure

DOR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)

Measure Description

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per iRECIST or to death due to any cause, whichever comes first.

Time Frame

Up to 5 years

Outcome Measure

Progression free survival on study therapy (PFS) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

Measure Description

The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first.

Time Frame

Up to 5 years

Outcome Measure

PFS by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)

Measure Description

The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first

Time Frame

Up to 5 years

Outcome Measure

PFS by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)

Measure Description

The time from start of study treatment to first documentation of objective tumor progression (PD per iRECIST) on or following study therapy, or to death due to any cause, whichever comes first.

Time Frame

Up to 5 years

Outcome Measure

Event-free (EFS) on study therapy by BICR (Cohort L only)

Measure Description

The time from the start of study treatment to the first occurrence of any of the following events: (1) Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC+PLND. (2) Failure to undergo RC+PLND for participants with residual muscle-invasive disease and/or any radiographic disease present. (3) Gross residual disease left behind at time of RC+PLND. (4) Local or distant recurrence post-RC as assessed by CT or MRI and/or biopsy. (5) Death from any cause.

Time Frame

Up to 3 years

Outcome Measure

Event-free (EFS) on study therapy by investigator assessment (MIBC cohorts only)

Measure Description

The time from the start of study treatment to the first occurrence of any of the following events: (1) Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC+PLND. (2) Failure to undergo RC+PLND for participants with residual muscle-invasive disease and/or any radiographic disease present. (3) Gross residual disease left behind at time of RC+PLND. (4) Local or distant recurrence post-RC as assessed by CT or MRI and/or biopsy. (5) Death from any cause.

Time Frame

Up to 3 years

Outcome Measure

Overall survival (OS) (all cohorts)

Measure Description

The time from start of study treatment to date of death due to any cause.

Time Frame

Up to 5 years

Outcome Measure

Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

Cmax will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

PK parameter for monomethyl auristatin E (MMAE): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

Cmax will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

PK parameter for total antibody (Tab): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

Cmax will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

Blood samples for ATA analysis will be collected.

Time Frame

Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.

Outcome Measure

PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

Tmax will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

PK parameter for MMAE: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

Tmax will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

PK parameter for Tab: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

Tmax will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

PK parameter for enfortumab vedotin: Area under the concentration-time curve (AUC) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

AUC will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

PK parameter for MMAE: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

AUC will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

PK parameter for Tab: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Measure Description

AUC will be derived from the PK blood samples collected.

Time Frame

Through 2 cycles of treatment, up to 42 days

Outcome Measure

Pathologic downstaging (pDS) rate by central pathology review (MIBC cohorts only)

Measure Description

The pDS rate is defined as patients with tumors \

Time Frame

Up to approximately 5 months

Outcome Measure

Disease-free survival (DFS) by investigator assessment (MIBC cohorts only)

Measure Description

DFS is defined as the time from RC to the time of first occurrence of a DFS event, including local recurrence of urothelial cancer (UC), urinary tract recurrence of UC, distant metastasis of UC, or death from any cause.

Time Frame

Up to approximately 5 years

Outcome Measure

DFS by BICR (Cohort L only)

Measure Description

DFS is defined as the time from RC to the time of first occurrence of a DFS event

Time Frame

Up to 3 years

Outcome Measure

Type, incidence, severity, seriousness, and relatedness of AEs (Randomized Cohort K and MIBC cohorts only)

Measure Description

Descriptive statistics will be used to summarize results.

Time Frame

Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years

Outcome Measure

Type, incidence, and severity of laboratory abnormalities (Randomized Cohort K and MIBC cohorts only)

Measure Description

Descriptive statistics will be used to summarize results.

Time Frame

Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years

Outcome Measure

Percentage of planned radical cystectomy and pelvic lymph node dissections (RC+PLND) delayed due to treatment-related AEs (MIBC cohorts only)

Measure Description

Delayed is defined as greater than 12 weeks after the last dose of treatment.

Time Frame

Up to approximately 5 months

Secondary Outcome Measures table for Clinical Trial
Number of participants

348

Collaborators and investigators

Sponsor: Astellas Pharma Global Development, Inc.

Collaborator: Merck Sharp & Dohme LLC, Seagen Inc.

This information is current as of October 18th 2023.

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More Information Close NCT# stands for National Clinical Trial number. This is a unique identification code given to each clinical trial registered on ClinicalTrials.gov. The format is "NCT" followed by an 8-digit number (for example, NCT00000419). Also called the ClinicalTrials.gov identifier. NCT03288545