An open-label clinical trial evaluating enfortumab vedotin in combination with pembrolizumab with or without chemotherapy, versus chemotherapy alone in previously untreated locally advanced or metastatic urothelial cancer
- Conditions
- rothelial cancerMedDRA version: 20.0Level: LLTClassification code 10046714Term: Urothelial carcinoma bladderSystem Organ Class: 100000004864MedDRA version: 20.0Level: LLTClassification code 10046723Term: Urothelial carcinoma ureterSystem Organ Class: 100000004864MedDRA version: 20.0Level: LLTClassification code 10046728Term: Urothelial carcinoma urethraSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-004542-15-FR
- Lead Sponsor
- Seattle Genetics, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 1095
1. Subjects must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible.
2. Subjects must have measurable disease by investigator assessment according to RECIST v1.1.
a. Subjects 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
3. Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted
b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted
4. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgement.
a. Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria:
i. 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)
· Subjects with a GFR =50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s
clinical judgement
ii. ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects)
iii. NCI CTCAE Grade =2 audiometric hearing loss
iv. NYHA Class III heart failure
5. Subjects must be age 18 years or older or considered an adult by local regulations.
6. 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. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed.
7. Subjects must have an ECOG Performance Status score of 0, 1, or 2.
a. 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
8. Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 5 (see protocol)
9. 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 [ß-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, agree to abstinence (if in line with the usual preferred lifestyle of the subject) or consistently use a condom plus 1 form of highly effective birth control per locally accepted standards 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 peri
1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs.
2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor.
3. Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor.
4. Subjects who have 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.
5. Subjects with uncontrolled diabetes.
6. Subjects with an estimated life expectancy <12 weeks
7. Subjects with ongoing sensory or motor neuropathy Grade 2 or higher.
8. Subjects with active CNS metastases. Subjects with treated CNS metastases are permitted on study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the subject is on a stable dose of =10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) subject does not have leptomeningeal disease.
9. Subjects with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to = Grade 1 or returned to baseline.
10. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
11. Subjects who have a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.
13. Subjects 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. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency.
14. Subjects with a 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 (eligible exceptions see protocol).
15. Subjects with a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV within 6 months prior to randomization.
16. Subjects who have received radiotherapy within 2 weeks prior to randomization.
17. Subjects who have received major surgery (defined as requiring general anesthesia and >24-hour inpatient hospitalization) within 3 weeks prior to randomization.
18. Subjects with known severe (= Grade 3) hypersensitivity to any excipient contained in the drug formulations of enfortumab vedotin, pembrolizumab, the platinum agent selected by the investigator or gemcitabine.
19. Subjects with active keratitis or corneal ulcerations.
20. History of autoimmune disease that has required systemic treatment in the past 2 years.
a. Replacement therapy (e.g.,
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method