Atezolizumab and Chemotherapy in Treating Patients with Metastatic or Unresectable and Locally Advanced Urothelial Carcinoma
- Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 28 days prior to registration
- 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 based on consensus definition with any of the following criteria: ECOG performance status (PS) 2, creatinine clearance < 60 mL/min, Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade >= 2 hearing loss, CTCAE v4 grade >= 2 peripheral neuropathy, New York Heart Association (NYHA) class >= 3 heart failure
- Measurable disease according to RECIST 1.1 within 28 days prior to registration
- Must have had progressive metastatic disease after previous treatment with PD-1 or PD-L1 inhibitor (in the adjuvant or metastatic setting). Treatment regimen will be determined based on prior treatment: * PD1 or PDL1 inhibitor with no prior platinum chemotherapy for metastatic disease: patients should be treated with atezolizumab + carboplatin + gemcitabine on trial * Sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen: patients should be treated with atezolizumab + docetaxel on trial
- Most recent therapy does not have to have been a checkpoint inhibitor. Intercurrent treatment is acceptable if subjects meet all other inclusion criteria
- A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for >= 2 weeks, and are asymptomatic
- Previous neoadjuvant or adjuvant chemotherapy that was completed >= 6 months prior to study enrollment is allowed
- White blood cell (WBC) >= 2 k/mm^3 (obtained within 28 days prior to registration)
- Absolute neutrophil count (ANC) >= 1.5 K/mm^3 (obtained within 28 days prior to registration)
- Hemoglobin (Hgb) >= 9 g/dL (obtained within 28 days prior to registration)
- Platelet > 100k (obtained within 28 days prior to registration)
- Estimated creatinine clearance >= 30 mL/min (obtained within 28 days prior to registration) * Cockcroft-Gault formula will be used to calculate creatinine clearance
- Bilirubin 1.5 =< upper limit of normal (ULN) (obtained within 28 days prior to registration) * Except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL
- Aspartate aminotransferase (AST) =< 1.5 x ULN (obtained within 28 days prior to registration)
- Alanine aminotransferase (ALT) =< 1.5 x ULN (obtained within 28 days prior to registration)
- International normalized ratio (INR) or prothrombin time (PT) =< 2 x ULN (obtained within 28 days prior to registration) (Note: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose)
- Activated partial thromboplastin time (aPTT) =< 2 x ULN (obtained within 28 days prior to registration) (Note: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose)
- Females of childbearing potential (FOCBP) must have a negative serum pregnancy test within 28 days prior to registration. These women must also have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of atezolizumab then every 6 weeks thereafter. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is post-menopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
- 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. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method
- Men who are sexually active with FOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving atezolizumab and who are sexually active with women of child-bearing potential (WOCBP) will be instructed to adhere to contraception for a period of 150 days (5 months) after the last dose of investigational product
- As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
- 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)
- Has a known additional malignancy that is progressing or required treatment =< 48 months of study registration. Exceptions: include malignancies with negligible risk of metastasis or death treated with expected curative outcome or undergoing surveillance per investigator's discretion (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 very low risk or low risk prostate cancer per National Comprehensive Cancer Network [NCCN] guidelines)
- 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 (hepatitis C virus [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 or respective chemotherapy regimen (carboplatin + gemcitabine or docetaxel)
I. Evaluate progression-free survival (PFS) among patients to be treated with atezolizumab in combination with carboplatin + gemcitabine or docetaxel, who have cisplatin-ineligible metastatic urothelial carcinoma and who have progressed on prior PD-1 or PD-L1 inhibitor.
I. Assess the safety and tolerability of the combination of atezolizumab plus chemotherapy (carboplatin + gemcitabine or docetaxel).
II. Evaluate objective response rate (ORR) with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related (ir) RECIST.
III. Evaluate clinical benefit rate (CBR) with RECIST 1.1 and irRECIST.
IV. Evaluate PFS with irRECIST.
V. Evaluate overall survival (OS).
VI. Compare PFS compared to historical controls.
VII. Evaluate PFS for atezolizumab + carboplatin and gemcitabine.
VIII. Evaluate PFS for atezolizumab + docetaxel.
I. Compare the efficacy of atezolizumab post disease progression with carboplatin + gemcitabine or docetaxel versus (vs.) treating with carboplatin + gemcitabine alone in a virtual control arm.
II. Assess the PD-L1 status of the tumor at the following time points:
IIa. REQUIRED, if available: Baseline from archival tissue (prior to treatment with PD-1 or PD-L1 inhibitor)
IIb. OPTIONAL (RECOMMENDED): From new biopsy (prior to cycle 1 day 1 [C1D1])
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I: Patients receive carboplatin intravenously (IV) over 30-60 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and atezolizumab IV over 1 hour on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive docetaxel IV over 1 hour and atezolizumab IV over 1 hour on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 100 days, then every 3 months for up to 18 months.
Trial Phase Phase II
Trial Type Treatment
Indiana University / Melvin and Bren Simon Cancer Center
- Primary ID GU17-295
- Secondary IDs NCI-2019-00501
- Clinicaltrials.gov ID NCT03737123