A Phase II Trial of Atezolizumab plus Chemotherapy after Progression on Single Agent PD-1 or PD-L1 Inhibitor in Cisplatin-ineligible Patients with Advanced Urothelial Carcinoma

Inclusion Criteria

Histological or cytological confirmed metastatic or unresectable locally advanced urothelial carcinoma (primary tumor: renal pelvis, ureters, urinary bladder, or urethra

Patients with mixed histologies are eligible

Cisplatin ineligible at the time of diagnosis with metastatic urothelial carcinoma

Demonstrate adequate organ function 

Females of childbearing potential (FOCBP) must have a negative serum pregnancy test within 28 days prior to registration.

Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 150 days (5 months) after treatment discontinuation

Exclusion Criteria

Previous chemotherapy for metastatic disease

Previous autoimmune complication from PD-1 or PD-L1 inhibitor requiring permanent discontinuation of therapy

Previous permanent discontinuation from PD-1 or PD-L1 inhibitor due to an adverse event (patients who had temporary holds or discontinuation of PD-1 or PD-L1 inhibitor and then re-treated are eligible)

Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy

Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)

 Malignancies other than urothelial carcinoma within 5 years prior to study entry with the exception of those with negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (T1/T2a, Gleason score ≤ 3+4, and PSA ≤ 0.5ng/mL undergoing active surveillance and treatment naïve).

Active central nervous system (CNS) metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression within 28 days prior to the first dose of atezolizumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.

Treatment with any investigational drug within 30 days prior to registration

Subjects with an active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids/immunosuppressive medications EXCEPT for syndromes which would not be expected to recur in the absence of an external trigger. (Subjects with vitiligo, autoimmune thyroiditis, or type I diabetes mellitus are permitted to enroll.).

As there is potential for hepatic toxicity with atezolizumab, drugs with a predisposition to hepatoxicity should be used with caution in subjects treated with atezolizumab-containing regimen. 

Subjects should be excluded if they have known history of testing positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Testing is not required

Subjects should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Testing is not required.

History of allergy to atezolizumab, carboplatin, or gemcitabine