A Phase II Trial of Pembrolizumab and Ramucirumab in Patients With Progressive Transitional Cell Carcinoma After Treatment With an Immune Checkpoint Inhibitor

• Histologically confirmed transitional cell carcinoma of the urothelium (bladder, urethra, or renal pelvis). Patients with mixed pathology are eligible only if they have predominantly transitional cell tumor based on local pathology review.

• Unresectable, locally advanced or metastatic disease.

• Documented disease progression by RECIST 1.1 criteria to at least one prior line of systemic therapy and no more than three. Prior therapy for advanced disease must include an immune checkpoint inhibitor. Prior therapy in an adjuvant or neoadjuvant setting is not considered as a prior line of systemic chemotherapy, unless patient has rapidly progressed as defined by ≤ 6 months of last dose in this setting. If it is ≤ 6 months, it will be regarded as a prior line of treatment. Prior treatment with intravesicular chemotherapy, bacillus Calmette -Guérin (BCG), or platinum given as a radiation-sensitizing agent will not be considered as a systemic line of treatment.

• A brain scan via CT with contrast or MRI is to be performed to confirm absence of intracranial metastasis.

• The presence of measurable disease based on the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as determined by the site study team. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

• a. Measurable disease must still be present after pretreatment core-needle or excisional biopsy.

• Provided signed informed consent and are amenable to compliance with protocol schedules and testing.

• Provided tissue for biomarker analysis from a newly obtained core or excisional biopsy of a tumor lesion using a non-significant risk procedure prior to enrollment. Repeat samples may be required if adequate tissue is not provided.

• ECOG Performance Status of 0 or 1.

• Age: 18 years of age or older on day of signing consent.

⁃ Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

⁃ The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate \<1000 mg of protein in 24 hours to allow participation in this protocol)

⁃ Adequate organ function, as defined in the table below, with all screening labs performed within 14 days of treatment initiation:

⁃ Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin. If receiving warfarin, the patient must have an INR ≤ 3.0 and no active bleeding (i.e., no bleeding within 14 days prior to first dose of study treatment) or pathological condition present that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices). Patients on anticoagulation therapy with unresected primary tumors or local tumor recurrence following resection are not eligible.

⁃ An anticipated life expectancy of ≥3 months.

⁃ Resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (v 5.0)

⁃ For male patients, are sterile (including vasectomy confirmed by post-vasectomy semen analysis) or agree to use a reliable method of birth control and to not donate sperm during the study and for at least 120 days following the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

⁃ For female patients, are surgically sterile, are postmenopausal, or agree to use a highly effective method of birth control (2 methods preferred) during the study and for 120 days following the last dose of study treatment.

⁃ If female and of childbearing potential, must have a negative serum or urine pregnancy test within 7 days prior to enrollment.

‣ Note: Non-childbearing potential (by other than medical reasons). Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.