Avelumab in Combination with AXL Inhibitor AVB-S6-500 for the Treatment of Locally Advanced, Unresectable, or Metastatic Urothelial Cancer

Inclusion Criteria

• Age >= 18 years
• Histologically confirmed locally advanced unresectable (T4b or N2/N3 disease) or metastatic urothelial cancer (including renal pelvis, ureters, urinary bladder, urethra)
• Eligible patients must have had either: * Progressed after treatment with at least 1 prior platinum-containing regimen, (e.g., received at least 2 cycles of cisplatin or carboplatin-based regimen) for inoperable locally advanced unresectable or metastatic urothelial carcinoma, OR * Experienced disease progression or recurrence within 12 months of completion of neoadjuvant or adjuvant cisplatin-based chemotherapy, OR * Ineligible for cisplatin-based chemotherapy due to Eastern Co-operative Oncology Group (ECOG) performance status 2, grade >= 2 neuropathy, glomerular filtration rate (GFR) < 60 mL/min, grade >= 2 hearing loss or New York Heart Association class III or worse congestive heart failure * Declined platinum (cisplatin or carboplatin) based chemotherapy after informed discussion with the treating investigator
• Available adequate pretreatment baseline tumor specimen or willingness to undergo biopsy of primary or metastatic lesion if archived specimen is not available * Patients who have inadequate baseline tumor sample even after an attempted biopsy or in whom a biopsy is not feasible or safe, will be able to enroll
• ECOG performance status of =< 2
• At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Patients who are able to understand and sign the informed consent form
• Ability to comply with protocol
• Absolute neutrophil count (ANC) >= 1500/uL (without granulocyte colony-stimulating factor support within 2 weeks prior to the first dose of study treatment)
• Platelet count >= 100,000/uL (without transfusion within 2 weeks prior to the first dose of study treatment)
• Hemoglobin >= 9.0 g/dL; Patients may not be transfused or receive erythropoietic treatment within 7 days prior to the first dose of study treatment, to meet this criterion
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Serum bilirubin =< 1.5 x ULN; Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled
• Institutional normalized ratio (INR) and partial thromboplastin time (aPTT) =< 1.5 x ULN; this applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
• Creatinine clearance >= 30 milliliters per minute (mL/min) (calculated using the Cockcroft-Gault formula)
• For women of childbearing potential: Negative serum or urine pregnancy test at screening
• For both male and female subjects: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of study drug

Exclusion Criteria

• Concurrent systemic treatment with an anticancer treatment or investigational drug within 28 days. Palliative radiation to symptomatic primary tumor or metastases is permitted as long as there are other measurable lesions present outside of the radiation field
• Prior therapy with anti-PD-1 or PD-L1 agents
• Concurrent systemic therapy with corticosteroids (> 10 mg prednisone equivalent) or other immunosuppressive agents within 28 days before starting trial drug. Short-term administration of systemic steroids (less than 7 days), adrenal replacement steroid doses (=< 10 mg daily prednisone equivalent), topical, intranasal and inhaled steroid use is permitted
• Patients with untreated or symptomatic central nervous metastases will be excluded. Patients appropriately treated with either surgery and/or radiation therapy will be eligible to participate in the study 4 weeks after completion of radiation/surgery and if follow up brain imaging after central nervous system (CNS) directed therapy demonstrates stability or improvement in brain metastases
• Active second malignancy or previous history of malignant disease (other than urothelial carcinoma) diagnosed within the last 3 years, with the exclusion of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ and pT2 prostate adenocarcinoma with Gleason score =< 7 (with no dominant pattern 4)
• Prior organ transplantation, including allogenic stem-cell transplantation
• Known history of hepatitis B virus (HBV) infection (including acute and chronic infection) and untreated hepatitis C. Patients with treated hepatitis C virus (HCV) infection will be eligible
• Known hypersensitivity to monoclonal antibody or any biologic drug, history of anaphylaxis, or uncontrolled asthma
• Persisting toxicity related to prior therapy that was > grade 1 according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)4; grade =< 2 sensory neuropathy is allowed
• Pregnant or lactating, or intending to become pregnant during the study * Women who are not postmenopausal (>= 12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative pregnancy test result within 14 days prior to the first dose of study treatment
• Diagnosis of active autoimmune disease requiring systemic immunosuppression. Patients with type 1 diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring systemic immunosuppression are eligible
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation fibrosis in the radiation field (fibrosis) is permitted
• Active infection requiring systemic therapy
• Severe infections within 4 weeks prior to the first dose of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Administration of a live/attenuated vaccine within 4 weeks prior to the first dose of study treatment, within 5 months following the administration of the last dose of study drug, or anticipation that such a live/attenuated vaccine will be required during the study
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study