Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer

JRCT ID: jRCT2031200284

Registered date:06/01/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Urothelial Cancer
• Date of first enrollment: 11/06/2021
• Target sample size: 990
• Countries of recruitment: United States of America,Japan,Argentina,Japan,Australia,Japan,Belgium,Japan,Canada,Japan,China,Japan,Czech Republic,Japan,Denmark,Japan,France,Japan,Germany,Japan,Hungary,Japan,Israel,Japan,Italy,Japan,South Korea,Japan,Netherlands,Japan,Poland,Japan,Russia,Japan,Singapore,Japan,Spain,Japan,Switzerland,Japan,Taiwan,Japan,Thailand,Japan,Turkey,Japan,United Kingdom,Japan
• Study type: Interventional

Intervention(s)

For global study part, participants will be randomized in a 1:1 manner to one of the study arms.
Participants in Arm A will receive enfortumab vedotin (EV) as IV infusion on Day 1 and 8 of every 3-week cycle and Pembrolizumab as IV infusion on Day 1 of every 3-weel cycle.
Participants in Arm B will receive gemcitabine as IV infusion on Day 1 and 8 of every 3-week cycle. Cisplatin or carboplatin will be administered as IV infusion on Day 1 of every 3-week cycle.
EV may be administered for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs. Pembrolizumab may be administered for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first. Cisplatin or carboplatin plus gemcitabine may be administered for a maximum of 6 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.
Japan-specific Safety run-in will be conducted in accordance with Arm A.
Arm C, combination therapy of EV + pembrolizmab + cisplatin or carboplatin, which was previously conducted abroad will not be conducted in Japan.

Outcome(s)

Primary Outcome

Japan-specific safety run-in
-Type, incidence, relatedness, severity and seriousness of adverse events (AEs) including dose limiting toxicities (DLTs)
-Type, incidence and severity of laboratory abnormalities
-Treatment discontinuation rate due to AEs
For global study:
-Duration of progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR)
-Duration of Overall survival (OS)

Secondary Outcome

For global study:
-PFS per RECIST v1.1 by investigator assessment
-Objective response rate (ORR) per RECIST v1.1 by BICR
-ORR per RECIST v1.1 by investigator assessment
-Duration of response (DOR) per RECIST v1.1 by BICR
-DOR per RECIST v1.1 by investigator assessment
-Disease control rate (DCR) per RECIST v1.1 by BICR
-DCR per RECIST v1.1 by investigator assessment
- Time to pain progression (TTPP)
- Mean change from baseline in worst pain at Week 26
-Mean scores and change from baseline of the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)
-Mean scores and change from baseline of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30)
-Incidence of adverse events (AEs)
-Incidence of laboratory abnormalities
-Treatment discontinuation rate due to AEs

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

- Histologically documented, unresectable locally advanced or metastatic urothelial carcinoma
- Measurable disease by investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
o Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy
- Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
o Participants that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted
o Participants that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted
- Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment
- Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization
- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2
- Adequate hematologic and organ function

Exclude criteria

- Previously received enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADCs)
- Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage urothelial cancer (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor
- Received prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor
- Received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment
- Uncontrolled diabetes
- Estimated life expectancy of less than 12 weeks
- Active central nervous system (CNS) metastases
- Ongoing clinically significant toxicity associated with prior treatment that has not resolved to =< Grade 1 or returned to baseline
- Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
- Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection.
- History of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy
- Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomization
- Receipt of radiotherapy within 2 weeks prior to randomization
- Received major surgery (defined as requiring general anesthesia and >24 hour inpatient hospitalization) within 4 weeks prior to randomization
- Known severe (>= Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin
- Active keratitis or corneal ulcerations
- History of autoimmune disease that has required systemic treatment in the past 2 years
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
- Prior allogeneic stem cell or solid organ transplant
- Received a live attenuated vaccine within 30 days prior to randomization

Related Information

• Primary Sponsor: Gorla Seema
• Secondary Sponsor: Seagen Inc.,Merck Sharp & Dohme Corp.
• Secondary ID(s): NCT04223856