SGN22E-003 Seattle Genetics

1. Participants 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. Participants must have measurable disease by investigator assessment according to RECIST v1.1 (Appendix J in protocol).

a. 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.

3. Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:

a. Participants that received neoadjuvant chemotherapy with recurrence > 12 months from completion of therapy are permitted.

b. Participants that received adjuvant chemotherapy following cystectomy with recurrence > 12 months from completion of therapy are permitted.

4. Participants must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgement.

a. Participants will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one 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)

• Participants 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. Eastern Cooperative Oncology Group (ECOG) or World Health Organization (WHO) performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects)

iii. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 2 audiometric hearing loss

iv. New York Heart Association (NYHA) Class III heart failure

5. Participants must be age 18 years or older.

6. Archival tumour tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomisation. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed (see Section 7.5 of protocol).

7. Participants must have an ECOG Performance Status score of 0, 1, or 2 (see Appendix B in protocol for conversion of performance status using Karnofsky, if applicable).

a. Participants 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. Participants must have adequate haematologic and organ function as defined by the baseline laboratory values in Table 5 in the protocol.

9. A female participant of childbearing potential is anyone born female who has experienced menarche and who has not undergone surgical sterilisation (e.g., 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 participants 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% (as described in Appendix L of protocol) starting at screening, throughout the study period, and for at least 6 months after the final dose of study drug.

• Female participants 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.

For the remaining inclusion criteria please see protocol pages 40-41. 

1. Participants who have previously received enfortumab vedotin or other Monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).

2. Participants who have received prior treatment with a Programmed death-ligand 1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).

3. Participants who have previously 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).

4. Participants 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 (ongoing hormonal/anti hormonal treatment, e.g., for breast cancer, is allowed, provided that the participant is eligible per exclusion criteria 14).

5. Participants with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥ 8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.

6. Participants with an estimated life expectancy < 12 weeks.

7. Participants with ongoing sensory or motor neuropathy Grade 2 or higher.

8. Participants with active central nervous system (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) participant does not have leptomeningeal disease.

9. Participants 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 randomisation. Routine antimicrobial prophylaxis is permitted.

11. Participants who have known hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid (RNA) [qualitative] detected) infection, testing for hepatitis B and hepatitis C is required if mandated by local country authority.

12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.

13. Participants 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 participants with adrenal insufficiency.

14. Participants 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. Participants with nonmelanoma skin cancer or carcinoma in situ of any type (if complete resection was performed) are allowed.

A history of prostate cancer (T2NXMX or lower with Gleason score ≤ 7) treated with definitive intent (surgically or with radiation therapy) at least 1 year prior to study entry is acceptable, provided that the subject is considered prostate cancer-free and the following criteria are met:

a. Participants who have undergone radical prostatectomy must have undetectable PSA for > 1 year and at screening.

b. Participants who have had radiation must have a Prostate-specific antigen (PSA) doubling time > 1 year (based on at least 3 values determined > 1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (i.e., < 2.0 ng/mL above nadir).

Participants with untreated low-risk prostate cancer (Gleason score ≤ 6) on active surveillance with PSA doubling time > 1 year (based on at least 3 values determined > 1 month apart) are also eligible.

15. Participants with a 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 randomisation (Appendix D in protocol).

16. Participants who have received radiotherapy within 2 weeks prior to randomisation. Participant must have recovered adequately from the toxicity from the intervention prior to starting study treatment.

For the remaining exclusion criteria please see protocol pages 42-43. 

Research Nurse: Amanda Cook (x4656) Amanda.Cook@lthtr.nhs.uk

Administrator: Chris Taylor (x3766)