Summary

This phase II trial tests how well enfortumab vedotin (EV) and pembrolizumab works in treating patients with bladder cancer of variant histology (a group of less common types of bladder cancer) that have spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving enfortumab vedotin and pembrolizumab may kill more tumor cells in patients with locally advanced or metastatic bladder cancer of variant histology.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the anti-tumor activity of the combination of enfortumab vedotin (EV) plus pembrolizumab by assessing the overall response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

SECONDARY OBJECTIVES:
I. To evaluate the efficacy of the combination as measured by progression free survival, overall survival, and duration of response.
II. To evaluate the safety as measured by incidence of adverse events assessed up to 2 years.

EXPLORATORY OBJECTIVE:
I. To assess tissue-based assays in archival tissue and correlative changes in peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), blood inflammatory markers and cytokines.

OUTLINE:
Patients receive enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years (up to 35 cycles for pembrolizumab) in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) scan or magnetic resonance imaging (MRI), and collection of blood throughout the trial.

After completion of study treatment, patients are followed up for 28 days and then for up to 2 years.

Eligibility

1. Male or Female
2. Age >= 18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
4. Metastatic disease or unresectable locally advanced disease
5. Histologically documented variant histology (nested, microcytic, micropapillary, lymphoepithelioma-like, plasmacytoid, giant cell, poorly differentiated, lipid-rich, clear cell, sarcomatoid) bladder cancer and non-urothelial bladder cancer of epithelial origin including: squamous cell carcinoma and adenocarcinoma (urachal and non-urachal). Variant histology tumors and non-urothelial tumors of ureter, urethra, urachus, or renal pelvis are included. Patients with mixed cell type are eligible if the predominant histology (over 50%) is variant or non-urothelial. All histological classifications will follow the 2016 World Health Organization (WHO) classifications
6. Untreated or having received any number of lines of prior therapy
7. Tumor tissue samples must be available for submission prior to initiation of study treatment. If not, agree to undergo biopsy
8. Patients must have measurable disease as defined by RECIST criteria 1.1 as at least one lesion that can be accurately measured in at least one dimension (longest diameter of >= 10 mm for non-nodal lesions or short axis of >= 15 mm for nodal lesions) on CT scan, MRI
9. Patients must have adequate organ and marrow function, within 28 days of cycle 1 day 1, at the discretion of the investigator
10. The effects of study drugs on the developing human fetus are unknown. For this reason, female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
11. FCBP and men treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation. Additionally, FCBP and male subjects should use effective contraception for 6 months after the last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Male subjects must not donate sperm and female subjects must not donate ova from screening to 6 months after the last dose
12. A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
13. Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer >= 4 weeks before the start of study therapy
14. Life expectancy > 12 weeks as determined by the Investigator
15. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions
16. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation

Treatment Sites in Georgia