Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blinded, Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer: Hoosier Cancer Research Network GU14-182
Brief Summary: This is a multi-institutional, randomized, placebo controlled, double-blinded phase II trial of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer who have achieved at least stable disease on first-line chemotherapy.


Options:
A: Inclusion Criteria

* Considered to be eligible to receive platinum-based chemotherapy, in the investigator's judgment
* Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (\</=) 2
* Histologically documented, locally advanced (T4b, any N; or any T, N2-3) or metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed transitional cell carcinoma \[TCC\] or urothelial cell carcinoma \[UCC\] of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra)
* Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor PD-L1 expression prior to study enrollment; participants who have fewer than 15 unstained slides available at baseline (but no less than \[\<\] 10) may be eligible following discussion with the Medical Monitor
* No prior chemotherapy for inoperable locally advanced or mUC
* For participants who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval more than (\>) 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting
* Prior local intravesical chemotherapy or immunotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment
* Measurable disease, as defined by RECIST v1.1
* Adequate hematologic and end-organ function
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 6 months after the last dose of carboplatin, cisplatin, or gemcitabine or for 5 months after the last dose of atezolizumab
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm

Exclusion Criteria:

* Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
* Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to enrolment
* Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging evaluation during screening and prior radiographic assessments
* Participants with treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: \* Evaluable or measurable disease outside the CNS \* No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm) \* No history of intracranial or spinal cord hemorrhage \* No ongoing requirement for corticosteroid as therapy for CNS disease; anti-convulsants at a stable dose are allowed \* No evidence of significant vasogenic edema \* No stereotactic radiation, whole-brain radiation or neurosurgical resection within 4 weeks prior to Cycle 1, Day 1 \* Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNS-directed therapy and the screening radiographic study \* Screening CNS radiographic study \>/=4 weeks since completion of radiotherapy or surgical resection and \>/=2 weeks since discontinuation of corticosteroids
* Prior treatment with CD137 agonists, anti-CTLA-4, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
* Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[TNF\] agents) within 2 weeks prior to Cycle 1, Day 1 or anticipated requirement for systemic immunosuppressive medications during the study
* Leptomeningeal disease
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
* Uncontrolled tumour-related pain or hypercalcemia
* Significant cardiovascular disease including known left ventricular ejection fraction (LVEF) \<40%
* Severe infections within 4 weeks before randomization or therapeutic oral or IV antibiotics within 2 weeks before randomization
* Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
* Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1
* Life expectancy of \<12 weeks
* Pregnant or lactating, or intending to become pregnant during the study
* Serum albumin \<25 gram per liter (g/L)
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
* History of autoimmune disease
* Participants with prior allogeneic stem cell or solid organ transplantation
* History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
* Positive test for human immunodeficiency virus (HIV)
* Active hepatitis B or hepatitis C
* Active tuberculosis
* Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1
B: Inclusion Criteria:

* Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Age ≥ 18 years at the time of consent.
* ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for protocol therapy.
* Histological or cytological evidence of urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell differentiated) will be permitted provided that the predominant histology is urothelial carcinoma.
* Metastatic and/or unresectable (cT4b) disease
* Must have achieved an objective response (CR/PR) or stable disease (SD) after 4 to 6 cycles of standard first-line platinum-based chemotherapy for mUC (e.g., as per NCCN guidelines). Able to commence study treatment within 2 to 6 weeks of receiving last dose of first-line chemotherapy.
* All subjects must have adequate archival tissue available prior to registration (i.e., at least 20 unstained slides or paraffin block). If acceptable archival tissue is not available, the subject must be willing to consent to providing a core or excisional biopsy for research prior to registration for protocol therapy. If archival tissue is not available and there are no sites amenable to biopsy, enrollment must be discussed with the sponsor-investigator on a case by case basis.
* Female subjects of childbearing potential must have a negative serum pregnancy within three days prior to registration for protocol therapy
* Sexually active, pre-menopausal women of childbearing potential must be willing to use an adequate method of contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> one year.
* Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug.

Exclusion Criteria:

* More than one line of prior chemotherapy for metastatic or locally advanced disease, with the following exception:

  * Prior neoadjuvant/adjuvant chemotherapy will not count as line of therapy if completed greater than 12 months prior to initiation of chemotherapy regimen for metastatic or unresectable disease.
* Current or past participation in a study of an investigational agent or using an investigational device within four weeks of registration for protocol therapy.
* A diagnosis of immunodeficiency or is receiving treatment with systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to registration for protocol therapy.
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two weeks prior to registration for protocol therapy. Note: If the subjects have undergone major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting protocol therapy.
* A known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
* A known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to registration for protocol therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least seven days prior to registration for protocol therapy.
* Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has evidence of active, non-infectious pneumonitis.
* Has a history of interstitial lung disease.
* An active infection requiring systemic therapy.
* A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening period through 120 days after the last dose of protocol therapy.
* Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Examples include nivolumab, MPDL3280, etc.
* A known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* A known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
* Receipt of a live vaccine within 30 days prior to registration for protocol therapy.
* Unresolved toxicity (i.e., \> Grade 1 or above baseline) due to previously administered agents. Exception includes: subjects with ≤ Grade 2 neuropathy are eligible for the study.
C: Inclusion Criteria for dose escalation and expansion phase:

* Signed written informed consent
* Male or female participants aged greater than or equal to 18 years
* Participants must have histologically or cytologically proven metastatic or locally advanced solid tumors, for which no standard therapy exists or standard therapy has failed. Availability of tumor archival material or fresh biopsies is optional for participants in dose escalation
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at trial entry and an estimated life expectancy of at least 3 months
* Disease must be measurable with at least 1 uni-dimensional measurable lesion by RECIST 1.1, except for participants with metastatic castrate-resistant prostate cancer (mCRPC) or metastatic breast cancer (MBC) who may be enrolled with objective evidence of disease without a measureable lesion
* Adequate hematological, hepatic and renal function as defined in the protocol
* Effective contraception for both male and female participants if the risk of conception exists
* Other protocol defined inclusion criteria could apply

Inclusion Criteria for expansion phase:

* Participants must have relapsed, refractory, or progressive disease following last line of treatment (with the exception of the gastric and gastroesophageal junction (GEJ) cancer cohort, which does not require progression). Availability of tumor archival material or fresh biopsies (excluding bone biopsies) is mandatory for eligibility in the expansion cohorts. For participants in the MBC cohort, the biopsy or surgical specimen must have been collected within 90 days prior to the first investigational medicinal product (IMP) administration. Specifically, the following will be required:
* NSCLC post platinum doublet: Histologically or cytologically confirmed stage IIIB or stage IV NSCLC that has progressed after 1 line of platinum-containing doublet chemotherapy. Participants should have received only 1 line of platinum-containing treatment for metastatic disease (i.e., adjuvant treatment with a platinum-containing regimen is not sufficient for eligibility because not received in the context of a metastatic disease). Participants in the NSCLC cohort will only be enrolled in USA
* NSCLC first line: Stage IV (per 7th International Association for the Study of Lung Cancer \[IASLC\] classification) or recurrent NSCLC that is histologically proven. Participants must not have received treatment for their metastatic or recurrent disease. No activating epidermal growth factor receptor (EGFR) mutation nor ALK translocation/re-arrangement
* Gastric and GEJ cancer: Histologically confirmed, unresectable locally advanced or metastatic adenocarcinoma of the gastric and gastro-esophageal junction, treated with first-line chemotherapy combination with or without disease progression. Participants should have received no more than 1 line of treatment for metastatic disease. Participants should not have been treated with trastuzumab (but can be Human Epidermal growth factor Receptor 2 \[HER2\] positive). Participants who received any platinum containing doublet or triplet as a neoadjuvant chemotherapy strategy, but are not ultimately candidates for surgery will also be eligible, as long as they did not have progressive disease after completion of the neoadjuvant chemotherapy. In addition, participants with gastric cancer can enter in the study if their white blood cell (WBC) and lymphocyte count is as defined in the protocol
* MBC: Participants must have histologically confirmed locally advanced or MBC and have tumor that is refractory to or progressive after standard of care therapy. Participants must have received no more than 3 prior lines of cytotoxic therapy for metastatic disease. Participants must have received a taxane and an anthracycline, unless contra-indicated
* Secondary expansion cohorts: Metastatic colorectal cancer (mCRC), Metastatic castrate-resistant prostate cancer (mCRPC), melanoma, ovarian cancer, ACC, mesothelioma, urothelial carcinoma and renal cell carcinoma as defined in the protocol
* Efficacy expansion cohorts: Gastric and GEJ cancer (third line), ovarian cancer (platinum Refractory + liposomal doxorubicin), urothelial carcinoma, and HNSCC as defined in the protocol

  * Other protocol defined inclusion criteria for expansion phase could apply

Exclusion Criteria for dose escalation and expansion phase:

* Concurrent treatment with a non-permitted drug
* Prior therapy with specific antibody/drug targeting T cell co-regulatory proteins (immune checkpoints)
* Concurrent anticancer treatment, major surgery, or use of any investigational drug within 28 days before the start of trial treatment; or concurrent systemic therapy with immunosuppressive agents, use of hormonal agents within 7 days before the start of trial treatment as defined in the protocol. Note: Participants receiving bisphosphonate or denosumab are eligible provided treatment was initiated at least 14 days before the first dose of avelumab.
* Previous malignant disease other than the target malignancy to be investigated in this trial within the last 5 years with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ
* Rapidly progressive disease (for example, tumor lysis syndrome)
* Active or history of central nervous system metastases
* Receipt of any organ transplantation including allogeneic stem-cell transplantation
* Significant acute or chronic infections as defined in the protocol
* Active or history of any autoimmune disease (Participants with diabetes Type 1, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies
* Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma
* Persisting toxicity related to prior therapy greater than Grade 1 NCI-CTCAE v4.0, however sensory neuropathy less than or equal to Grade 2 is acceptable
* Pregnancy or lactation period
* Known alcohol or drug abuse
* Clinically significant (that is, active) cardiovascular disease
* All other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the investigator, might impair the Participant's tolerance of trial treatment
* Any psychiatric condition that would prohibit the understanding or rendering of informed consent
* Legal incapacity or limited legal capacity
* Non-oncology vaccine therapies for prevention of infection disease (for example, seasonal flu vaccine, human papilloma virus vaccine) within 4 weeks of study drug administration. Vaccination while on study is also prohibited except for administration of the inactivated influenza vaccine
D: Inclusion Criteria:

* Histologically- or cytologically-confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies)
* Ineligible for cisplatin therapy
* No prior systemic chemotherapy for metastatic disease (adjuvant or neoadjuvant platinum-based chemotherapy with recurrence \>12 months since completion of therapy is allowed)
* Available tissue from a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Measurable disease
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
* Adequate organ function
* Female participants of childbearing potential have a negative urine or serum pregnancy test; surgically sterile, or willing to use 2 acceptable methods of birth control, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment
* Male participants must be willing to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study treatment

Exclusion Criteria:

* Disease that is suitable for local therapy administered with curative intent
* Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment
* Prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from AEs due to a previously administered agent
* Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease that has required systemic treatment in past 2 years
* Evidence of interstitial lung disease or active non-infectious pneumonitis
* Active infection requiring systemic therapy
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment
* Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor
* Known human immunodeficiency virus (HIV)
* Known active Hepatitis B or C
* Received a live virus vaccine within 30 days of planned start of study treatment

Answer: B