Trial of Atezolizumab Plus Chemotherapy After Progression on PD-1 or PD-L1 in Cisplatin-ineligible Patients With Advanced Urothelial Carcinoma
Condition: Urothelial Carcinoma
MeSH terms: Carcinoma; Carcinoma, Transitional Cell
Intervention: Carboplatin; Gemcitabine; Atezolizumab; Docetaxel
Intervention description: Carboplatin AUC 4 IV Day 1 of each 21 day cycle; Gemcitabine 1,000 mg/m2 IV Day 1 and Day 8 of each 21 day cycle; Atezolizumab 1,200 mg IV Day 1 of each 21 day cycle; Docetaxel 75 mg/m2 IV Day 1 of each 21 day Cycle.
Intervention MeSH terms: Carboplatin; Gemcitabine; Docetaxel; Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a single arm phase II study assessing the activity of atezolizumab in combination
      with carboplatin + gemcitabine or docetaxel compared to historical controls of chemotherapy
      only in metastatic or recurrent urothelial carcinoma subjects. Subjects that received a PD 1
      or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated
      with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or
      concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab
      + docetaxel on trial.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information prior to registration. NOTE: HIPAA authorization may be included in the
             informed consent or obtained separately.

          -  Age ≥ 18 years at the time of consent.

          -  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 PS 2,
             creatinine clearance < 60mL/min, CTCAE v4 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.
                  These patients should be treated with atezolizumab + carboplatin + gemcitabine on
                  trial.

               -  Sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen. These
                  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.

          -  REQUIRED archival tumor tissue (prior to treatment with single agent PD-1 or PD-L1
             inhibitor) must be identified prior to registration and obtained during the screening
             period. Confirmation of acquisition should occur prior to C1D1 treatment.
             Unavailability of tissue will render the subject ineligible for study. Biopsy should
             be excisional, incisional or core needle. Fine needle aspiration is insufficient.
             Sample requirement is FFPE block + 1 H&E stained slide or 25 unstained slides + 1 H&E
             stained slide.

          -  Demonstrate adequate organ function as defined in the table below. All screening labs
             to be obtained within 28 days prior to registration.

               -  White blood cell (WBC) ≥ 2 k/mm3

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Platelet >100k

               -  Estimated creatinine clearance ≥ 30 mL/min

               -  Bilirubin 1.5 ≤ (ULN)

               -  Aspartate aminotransferase (AST) ≤ 1.5 × ULN

               -  Alanine aminotransferase (ALT) ≤ 1.5 × ULN

               -  International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial
                  Thromboplastin Time (aPTT) ≤ 2 × ULN (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 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 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.

        Exclusion Criteria:

          -  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).

          -  5. 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, ductal carcinoma in situ treated
             surgically with curative intent, or very low risk or low risk prostate cancer per 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 (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).