Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase I, Open-label, Multiple-ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C) in Subjects With Metastatic or Locally Advanced Solid Tumors and Expansion to Selected Indications
Brief Summary: This is a Phase 1, open-label, dose-escalation trial of avelumab \[antibody targeting programmed death ligand 1 (anti PD-L1)\] with consecutive parallel group expansion in participants with selected tumor indications. New recruitment is open for all active cohorts.

Active cohorts: Escalation revised dosing regimen cohort.

Closed cohorts: Non-small cell lung cancer (NSCLC, first line), NSCLC (post-platinum), metastatic breast cancer (MBC), colorectal cancer (CRC), urothelial carcinoma (secondary), mesothelioma, gastric/GEJ cancer (first line switch maintenance and second line), and ovarian cancer (secondary and platinum refractory + liposomal doxorubicin), renal cell carcinoma (second line) melanoma and head, neck squamous cell carcinoma (HNSCC), castrate-resistant prostate cancer (CRPC), adrenocortical carcinoma (ACC) urothelial carcinoma (efficacy), gastric/gastroesophageal junction (GEJ) cancer (third line), renal cell carcinoma (RCC, first line) and escalation phase .


Options:
A: Inclusion criteria:

* Histologically- or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra, that is transitional cell or mixed transitional/non-transitional (predominantly transitional) cell type
* Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen (e.g cisplatin, carboplatin) for metastatic or inoperable locally advanced disease; or adjuvant platinum-based therapy following cystectomy for localized muscle-invasive urothelial cancer with recurrence/progression \<=12 months following completion of therapy; or neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer with recurrence \<=12 months following completion of therapy
* No more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer
* Able to provide tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Measureable 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; or are 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 pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
* 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 pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine

Exclusion criteria:

* Urothelial cancer that is suitable for local therapy administered with curative intent
* Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of trial medication
* Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
* Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or 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 of study Day 1 or not recovered from adverse events due to a previously administered agent
* Prior therapy with all choices of active comparator
* Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cancer; or prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer that is Stage T2N0M0 or lower, Gleason score\<= 6, or prostatic-specific antigen (PSA) undetectable
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents
* Active cardiac disease
* Evidence of interstitial lung disease or active non-infectious pneumonitis
* Active infection requiring systemic therapy
* History of severe hypersensitivity reaction to paclitaxel, docetaxel, or to other drugs formulated with polysorbate 80 or polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids
* Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the cytochrome 3A4 (CYP3A4) enzymes
* Pregnant, 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 pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
* Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent, or with an agent directed to another co-inhibitory T-cell receptor
* Human immunodeficiency virus (HIV)
* Active hepatitis B or hepatitis C
* Received a live virus vaccine within 30 days of planned start of trial treatment
B: Inclusion Criteria:

* Evidence of metastatic or surgically unresectable transitional cell carcinoma of the urothelium involving the bladder,urethra,ureter or renal pelvis
* Measurable disease by CT or MRI
* Progression or recurrence after treatment
* i) With at least 1 platinum-containing chemotherapy regimen for metastatic or surgically unresectable locally advanced urothelial cancer, or
* ii) Within 12 months of peri-operative (neo-adjuvant or adjuvant) treatment with a platinum agent in the setting of cystectomy for localized muscle-invasive urothelial cancer
* Subject that have received more than 2 prior lines of chemotherapy must not have liver metastases
* Tumor tissues (archived or new biopsy) must be provided for biomarker analysis
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

Exclusion Criteria:

* Subjects with active cancer that has spread to the central nervous system
* Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured
* Subject with active, known or suspected autoimmune disease
* Subjects with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 day of study drug administration
* Prior treatment with an anti-PD-1,anti-PD-L1,anti-PD-L2,anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, anti-CD137 or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways

Exclusion laboratory criteria:

* Positive test for hepatitis B virus surface antigen (HBV s Ag) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
* Known history of testing positive for human Immunodeficiency virus (HIV) or known acquired Immunodeficiency syndrome (AIDS)

Other protocol-defined inclusion/exclusion criteria apply
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 tumor that is recurrent, metastatic, or persistent:

  * For Cohort A - triple negative breast cancer (estrogen, progesterone, and human epidermal growth factor receptor 2 \[HER2\] negative)
  * For Cohort B - squamous cell carcinoma of the head and neck (including human papilloma virus (HPV)-positive head and neck squamous cell cancer).
  * For Cohort C - urothelial tract cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell or non-transitional cell histology)
  * For Cohort D - adenocarcinoma of the stomach or gastroesophageal junction
  * For Cohort B2 - squamous cell carcinoma of the head and neck (both HPV-positive and -negative head and neck squamous cell cancer)
* Any number of prior treatment regimens
* Measurable disease
* Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1
* Female participants of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment
* Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study treatment

Exclusion Criteria:

* Currently participating in/has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment
* Diagnosis of immunosuppression or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
* Anti-cancer monoclonal antibody treatment within 4 weeks prior to study Day 1 or not recovered from adverse events due to agents administered more than 4 weeks earlier
* Chemotherapy, targeted small molecule therapy or radiation therapy within 2 weeks prior to study Day 1 or not recovered from adverse events 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, or in situ cervical cancer that has undergone potentially curative therapy
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease requiring systemic treatment within the past 3 months or documented history of clinically severe autoimmune disease, or syndrome that requires systemic steroids or immunosuppressive agents
* Evidence of interstitial lung disease
* Active infection requiring systemic therapy
* Known psychiatric or substance abuse disorders
* Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
* Prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-L1, anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
* Known history of human immunodeficiency virus (HIV)
* Known active Hepatitis B or Hepatitis C
* Received live vaccine within 30 days prior to start of study treatment
* Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is Investigational site or Sponsor staff directly involved with this trial, unless prospective Independent Review Board (IRB) approval (by Chair or Designee) is given allowing exception to this criterion for a specific participant

Answer: C