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

Phase 1

Conditions: rothelial cancer
MedDRA version: 20.0Level: LLTClassification code 10046714Term: Urothelial carcinoma bladderSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10046723Term: Urothelial carcinoma ureterSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10046728Term: Urothelial carcinoma urethraSystem Organ Class: 100000004864
MedDRA version: 21.1Level: LLTClassification code 10077840Term: Urothelial cancer of renal pelvisSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-001527-39-FR

Lead Sponsor: Seagen Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 150

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 [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, 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 f

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

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

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