Summary

This phase II trial studies the side effects and best dose of cabozantinib when given together with pembrolizumab and how well it works as first line therapy in treating patients with cisplatin-ineligible urothelial cancer that has spread to nearby tissue or lymph nodes (locally advanced) or has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 cabozantinib and pembrolizumab may work better in treating patients with cisplatin-ineligible metastatic, locally advanced, or unresectable urothelial cancer.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate measurable disease overall response rate (ORR).

SECONDARY OBJECTIVES:
I. To evaluate progression-free survival (PFS) at 6 months (PFS6).
II. To evaluate overall survival (OS).
III. To evaluate toxicities associate with the combination treatment.

EXPLORATORY OBJECTIVES:
I. To evaluate molecular markers for pharmacodynamic pathways associated with response.
II. To evaluate ORR and PFS6 using immune specific disease assessment criteria.

OUTLINE:
Patients receives cabozantinib orally (PO) daily (followed by every other day as needed for tolerability) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Treatment may continue beyond initial radiographic or clinical disease progression as long as the patient is deriving clinical benefit per physician discretion.

After completion of study treatment, patients are followed up to 6 months.

Eligibility

1. PRE-SCREENING ELIGIBILITY: Male or female subject aged >= 18 years
2. PRE-SCREENING ELIGIBILITY: Clinically, subject is a candidate for urothelial diagnostic procedure (fresh soft-tissue biopsy or transurethral resection of bladder tumor [TURBT])
3. PRE-SCREENING ELIGIBILITY: Subject meets general medical criteria for consideration of treatment with immunotherapy using a checkpoint inhibitor
4. Histologically proven transitional cell or urothelial carcinoma
5. Patients with locally advanced or metastatic urothelial carcinoma must meet one of the following: * Patients who are not eligible for cisplatin-containing chemotherapy AND whose tumors express PD-L1 (Combined Positive Score (CPS) >= 10 as determined by an Food and Drug Administration (FDA)-approved test, OR; * Patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status
6. Metastatic (any N+ or M1) or locally advanced, unresectable (T4bN0) disease
7. Measurable disease is required as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
8. Performance status Eastern Cooperative Oncology Group (ECOG) 0 - 2
9. Cisplatin-ineligibility based on >= 1 of the following: * Estimated creatinine clearance between >= 30 and < 60 ml/min (Cockcroft-Gault formula) * ECOG performance status (PS) > 1 * Hearing loss * Baseline neuropathy > grade 1 * Patient refusal
10. Serum albumin >= 2.8 g/dl
11. Alkaline phosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documented bone metastases
12. Negative serum or urine pregnancy test at screening for women of childbearing potential
13. Highly effective contraception for both male and female subjects throughout the study and for at least 120 days after last pembrolizumab treatment administration if the risk of conception exists
14. Must have recovered from adverse effects of any prior surgery, radiotherapy or other antineoplastic therapy to grade =< 2. If not recovered to grade =< 2, these must be deemed to be irreversible adverse events related to prior surgery and /or radiation therapy (such as incontinence or sexual dysfunction) per investigator clinical judgment
15. Recovery to baseline or =< grade 2 Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy. Alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator’s judgment are acceptable.
16. Last dose of any radiation therapy > 2 weeks before first dose of study treatment
17. Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines
18. Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (without granulocyte colony-stimulation factor support within 2 weeks of screening)
19. Platelet count >= 100 x 10^9 /L (without platelet transfusion within 2 weeks of screening)
20. Hemoglobin >= 9 g/dL (may have been transfused)
21. White blood cell count (WBC) >= 2.5 x 10^9/L
22. Total bilirubin level =< 1.5 x the upper limit of normal (ULN) (=< 3 x ULN for subjects with Gilbert’s disease/or unconjugated hyperbilirubenemia)
23. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 2.5 x ULN or AST and ALT levels =< 3 x ULN for subjects with documented metastatic disease. Patient with a history of unconjugated hyperbilirubinemia with otherwise acceptable liver enzyme levels (as per above criteria) may have higher bilirubin levels
24. Urine protein/creatinine ratio (UPCR) =< 2 mg/mg (=< 113.2 mg/mmol)
25. Serum creatinine =< 2.0 x ULN or calculated creatinine clearance >= 30 mL/min (>= 0.5 mL/sec) using the Cockcroft-Gault equation

Treatment Sites in Georgia